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UWE Bristol Sepsis in the Intensive Care

UWE Bristol Sepsis in the Intensive Care. Name Diane Standring Title Senior lecturer critical care. Learning outcomes. To revise the pathophysiology of sepsis To consider key elements of the sepsis bundle To relate elements to pathophysiology To Consider evidence behind recommendations.

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UWE Bristol Sepsis in the Intensive Care

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  1. UWE BristolSepsis in the Intensive Care Name Diane Standring Title Senior lecturer critical care

  2. Learning outcomes • To revise the pathophysiology of sepsis • To consider key elements of the sepsis bundle • To relate elements to pathophysiology • To Consider evidence behind recommendations

  3. Definitions • Sepsis : defined as infection plus systemic manifestations of infection • Severe sepsis: sepsis plus sepsis induced organ dysfunction or hypoperfusion Schulman (2003) describes the phenomenon as the “unifier of critical care”

  4. Incidence • Associated with a mortality of 82% (Cuneen & Cartwright 2004). • Incidence is increasing and likely to continue (Dellinger et al 2008) • 27% of patients admitted UK ITU (n92) met severe sepsis criteria within 24 hours of admission and accounted for 40% of the ITU budget (Bray 2006). • Risk of sepsis increases with age (Desbiens 2006) & pre-existing co-morbidity

  5. The disease continuum Severesepsis Sepsis Death SIRS Infection A non-specific clinical response including >2 of the following: As well as infection, SIRS can also be caused by trauma, burns, pancreatitis and other insults • Temperature >38oC or <36oC • Heart rate >90 beats/min • Respiratory rate >20/min • White blood cell count >12,000/mm3or <4,000/mm3 or >10% immature neutrophils

  6. The disease continuum Severesepsis SIRS Death Sepsis Infection SIRS with a presumed or confirmed infectious process

  7. The disease continuum Severesepsis SIRS Sepsis Death Infection Sepsis with signs of at least one acute organ dysfunction • Renal • Respiratory • Hepatic • Haematological • Central nervous system • Unexplained metabolic acidosis • Cardiovascular Septic shockSevere sepsis with hypotension refractory to adequate volume resuscitation

  8. Pathogens involved in sepsisAn overview Gram negative Only 60% of severe sepsis/septic shock cases are associated with confirmed infection WHY ? Gram positive Fungal infection 20% Mixed bacterial 45% 19% Other mixed 10% 3% 3% Unconfirmed

  9. Bacterial pathogens in sepsisA final common pathway? Gram-negative Gram-positive e.g. Neisseria meningitidis Escherichia coli e.g. Staphylococcus aureus Streptococcus pneumoniae Enterococcus faecalis Endotoxin and other toxins Cell wall components Extracellular products Host immune response Host immune response INFLAMMATION SEPSIS

  10. Host response Pathogen Infection Endothelial dysfunction Inflammation Other factors Coagulation/fibrinolysis Loss of homeostasis Organ dysfunction Death Host response to infection

  11. Homeostasis Homeostasis Inflammation Coagulation Fibrinolysis

  12. Anti-inflammatory mediators e.g. IL-10, IL-1ra receptor antagonists Host responses Pathogen Infection Pro-inflammatory mediators e.g. Tumour necrosis factor, IL-1, IL-6, IL-8, nitric oxide Leucocyte activation Mitochondrial dysfunction Inflammation Microvascular flow redistribution Endothelial dysfunction Tissue factor expression Organ dysfunction Tissue injury Inhibition of fibrinolysis Activation of coagulation Microvascular coagulation/thrombosis Death Pathogenesis of sepsis

  13. In sepsis Fibrinolysis Endothelial dysfunction Inflammation Coagulation Loss of homeostasis

  14. Pathogen Infection Anti-inflammatory mediators IL-4, IL-10, IL-11, IL-13, IL-1r Monocyte/macrophage Pro-inflammatory cytokines Tumour necrosis factor, IL-1, IL-6, IL-8 Neutrophil activation, aggregation, degranulation; release of oxygen free radicals and proteases Platelet activation – aggregation T-cell IL-2, Interferon-, GM-CSF Endothelial damage Inflammatory response to microbial toxins GM-CSF: granulocyte macrophage colony-stimulating factor

  15. Tumour necrosis factor (TNF) Cytokines: IL-6, IL-8, IL-10 Oxygen free radicals Platelet activating factor Proteases Prostaglandins Leukotrienes Bradykinin Inflammation Coagulation Suppressed fibrinolysis Monocyte TNF IL-1 Microvascular thrombosis Neutrophil Tissue factor Adhesion IL-6, IL-8 Endothelial damage Endothelium Macrophages Site of inflammationChemotactic mediators (e.g. selectins) attract leucocytes to site of inflammation white blood cell adhesion to endothelium IL: interleukin

  16. White blood cell adhesion Rolling TNF, IL-1 Receptors Activation of integrins Selectins Direct signalling ICAM-1 Chemokines ICAM: intercellular adhesion molecule, TNF: tumour necrosis factor, IL: interleukin

  17. Loss of inflammatory control in sepsis INFLAMMATORY RESPONSE Anti-inflammatory/pro-inflammatory mediators and cytokines • Hyper-responsive • Sepsis, severe sepsis and MODS • Hypo-responsive • Overwhelming sepsis • Excess compensation/CARS • Immunosuppression • Increased susceptibility to secondary infection Balanced response Death Death Resolution

  18. Host response Pathogen Infection Endothelial dysfunction Inflammation Other factors Coagulation/fibrinolysis Loss of homeostasis Organ dysfunction Death Endothelial dysfunction in sepsis

  19. The role of the endothelium • Interaction with leucocytes • Release of cytokines and inflammatory mediators • Release of mediators of vasodilatation and vasoconstriction • Functional effects on the coagulation system Formation of fibrin clot Tissue injury

  20. Host response Pathogen Infection Endothelial dysfunction Inflammation Other factors Coagulation/fibrinolysis Loss of homeostasis Organ dysfunction Death coagulation and fibrinolysis

  21. Endothelial dysfunction Tissue factor Common coagulation pathway Thrombin generation InflammationLeucocyte aggregation/adhesion Fibrin clot formation and platelet activation Reduced fibrinolysis Microvascular thrombosis Procoagulant state Thrombin

  22. Reduced fibrinolysis in sepsis Thrombin Pro-coagulant mechanism TAFI Reduced fibrinolysis PAI-1 Microthrombi remain TNF-, IL-1 Endothelial dysfunction TAFI: tissue activatable fibrinolysis inhibitor, PAI-1: plasminogen activation inhibitor-1,

  23. Coagulation pathways 3.12 Extrinsic pathway Intrinsic pathway XIIa Kallikrein HMW kininogen IX VII Tissue factor VIIa + + XIa XI + IXa VIII Common pathway + + X Xa V Ca2+ + Prothrombin Thrombin + Fibrinogen Fibrin XIIIa Fibrinopeptides A+B Cross-linked fibrin CLOT FORMATION HMW kininogen: high molecular weight kininogen

  24. Host response Pathogen Infection Endothelial dysfunction Inflammation Other factors Coagulation/fibrinolysis Loss of homeostasis Organ dysfunction Death Other factors involved in the host

  25. Glucose ? Glycolysis Electron-transport chain krebs cycle ? ? ? e- Lactate Pyruvate ? ? ADP ATP Bioenergetic failure Cell shutdown Cell death (apoptosis and necrosis) ? Potential point of disruption Energy disruption in sepsis: mitochondrial dysfunction TCA: tricarboxylic acid, ADP: adenosine diphosphate, ATP: adenosine triphosphate

  26. Mitochondrial dysfunction in sepsis • Organs may sometimes fail despite adequate perfusion with oxygenated blood • Oxygen utilization at a cellular level may be impaired in sepsis – ‘dysoxia’ • Mitochondrial inhibition is likely to have a role in organ dysfunction • Levels of pro-inflammatory cytokines, nitric oxide and other reactive species can inhibit mitochondrial function

  27. Protein C • Endogenous protein C is a vitamin K-dependent protein produced in the liver. • The activation of endogenous protein C takes place on the endothelium; endogenous protein C is cleaved in the presence of calcium ions to form endogenous activated protein C. • In sepsis, damage to vascular endothelium diminishes the body’s ability to convert endogenous protein C to endogenous activated protein C.

  28. Take a deep breath !

  29. protein C in sepsis (??) Infection Pro-inflammatory mediators Leucocyte activation Activated inflammation Endothelial injury Tissue factor expression Increased PAI-1 Activated coagulation Thrombin generation Endogenous protein C TAFIactivated Inactivation Activated protein C Coagulopathy Suppressed fibrinolysis Microvascular endothelial dysfunction Tissue injury Organ failure/shock Death PAI-1: plasminogen activation inhibitor 1 TAFI: tissue activatable fibrinolysis inhibitor

  30. Surviving sepsis campaign 2001,2003,2006,2007(Dellinger et al 2008) • 11 international critical care organisations • Multidisciplinary • Systematic review of literature • 25% reduction in sepsis mortality by 2007 (!) • Sepsis resuscitation bundle • Sepsis Management bundle

  31. Improving outcomes • Early aggressive fluid management • Early start antibiotics • Early ethical decision making • Early use of central line • Early use of central blood gas analysis (lactate) • Early involvement of ITU

  32. Sepsis resuscitation bundle • Measure serum lactate • Blood cultures prior to Antibiotic Tx • Administer broad spectrum antibiotics within 3 hours of ED admission or 1 hour of non ED admission • If hypotensive or lactate >4.0mmol/L • Give 20ml/kg crystalloid • Vasopressors to maintain MAP .65mmHg • Persistant hypotension and lactate > 4.0mmol/l • CVP >8 mmHg • Sv02 .65%

  33. Sepsis management bundle • Antibiotic therapy • Source identification and control • Fluid therapy • Vasopressors • Inotropic therapy • Steroids • Activated protein C • Blood products

  34. Sepsis management bundle cont. • Mechanical Ventilation • Sedation analgesia and neuromuscular blockade • Glucose control • Renal replacement • Bicarbonate therapy • DVT prophylaxis • Stress ulcer prophylaxis • Consider limitation of support

  35. Group work • In groups of 7 (X 6 groups) • Consider the aspect of the sepsis bundle you have been given. • Explore the research / evidence base • Contribute from your own experience ? Use of guideline, protocol ? theory practice gap Prepare to feedback to whole group

  36. Things to consider • How does this management issue relate to pathophysiology of sepsis • Is the research conclusive or conflicting • What is the evidence base used by the surviving sepsis campain 30 minutes

  37. Topics • Fluid therapy and blood products • Vasopressors and inotropes • Steroids • Activated protein C • Mechanical ventilation • Glucose control

  38. Sepsis management bundle Antibiotic therapy • Board spectum within 1 hour • Do not wait for culture results

  39. Sepsis management bundle Source identification and control • Early surgical intervention except pancreatic necrosis • Consider re citing invasive lines

  40. Sepsis management bundle (a) Fluid therapy • Crystalloid Vs Collid • CVP > 8 in self ventilating patients > 12 in vented • 300-500 ml challenges over 30 mins • Beware cardiac filling pressures increasing without concurrent rise in BP

  41. Sepsis management bundle (a) Vasopressors • MAP >65mmHg • Noradrenaline or dopamine • Adrenaline if poor response • No renal dopamine !

  42. Sepsis management bundle (a) Inotropic therapy • Dobutamine for myocardial dysfunction • Do not drive cardiac index to supranormal

  43. Sepsis management bundle (a) Steroids • Consider hydrocortisone when hypotension poorly responsive to fluid challenges • ACTH testing not recomended • Steroids maybe weaned once vasopressors off • Do not use in the absence of shock

  44. Sepsis management bundle (a) Activated protein C • Consider if sepsis induced organ dysfunction and high risk of death (APACHE > 25) • Do not use with single organ failure or APACHE <20

  45. Sepsis management bundle (a) Blood products • RBC if haemoglobin below 7.0 • Do not use FFP to treat clotting results unless active bleeding • Administer platelets if • Very low • Low with some bleeding risk • Normal but require surgery

  46. Sepsis management bundle Mechanical Ventilation • 6ml/kg tidal volume with ALI/ARDS • Limit plateau pressure to 30cmH20 • Allow PaC02 to rise if necessary • Consider prone positioning • Elevate 30-40 degrees semi recumbent • Consider NIV where appropriate • Use a weaning protocol and SBT

  47. Sepsis management bundle Sedation analgesia and neuromuscular blockade • Use protocols and goals • Use sedation scoring and daily sedation hold • Avoid neuromuscular block

  48. Sepsis management bundle • Glucose control • Sliding scale insulin to control hypoglycemia • Aim 8.3 mmol/L • Provide a glucose calorie source

  49. Sepsis management bundle Renal replacement • As approriate Bicarbonate therapy • Do not use for haemodynamic purposes

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