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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;101:1644-55. Opal SM, Thijs L, Cavaillon JM, et al. Relationships between coagulation and inflammatory processes. Crit Care Med . 2000;28:S81-2.
The definitions for SIRS and sepsis can also be used to describe a disease continuum with respect to the severity of the illness.
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.
Society of Critical Care Medicine (SCCM), European Society of Intensive Care Medicine (ESICM), The American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS)
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.
Various innate factors are now known to have independent effects on the risk for sepsis and the outcome.
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.
cell adhesion molecules
SIRS, MODS, Sepsis
To know definitions of SIRS, sepsis, septic shock, MODS To learn basic pathophysiologyBut first, a real case:
86/ Malay/ Lady U/L HPT and IHD Presented to Hospital Tampin A&E on 29/4/2012 C/O: › Poor oral intake x 2/52 › Lethargy x 2/7 › Minimal URTI sx › Previously ADL independent
Laboratory: › FBC: WCC 15.48 ( N 45, L 49) / Hb 14.4 / Plt 161 › RP: Urea 19.4 / Creat 131 / Na 147 / K 4.6 › UFEME: Leu 3+ / Nitrate neg /Blood moderate / Ketone small CXR: Hyperinflated lungs ECG: T inversion leads II, III, avF, v5, v6
Diagnosis: › Sepsis 2’ UTI with dehydration 2’ poor oral intake Admitted to Ward 2 › Fluid therapy 3 pints over 24H › Vital signs monitoring › CBD › Strict IO monitoring › Blood c&s, Urine c&s › IV Zinacef 750mg stat and TDS › Nasal prong 3L/min
Day 2: AM rounds: Condition same Tolerating minimal fluid Urine output >30ml/H Spiking temperature PM rounds: Patient appears weak. c/o chestpain started at 8pm BP 96/63 P 130 ECG Sinus tachycardia. ST depression II, III, avF, v4-v6
Treated as ACS Started on: › S/L GTN 0.5mg stat, and PRN › S/c clexane 60mg stat and OD › T isordil 10mg BD › T aspirin 300mg stat, 100mg OD › KIV inotrope
VBG: uncompensated metabolic acidosis RP: Urea 20/ Creat 120/ Na 154 / K 4.3 IVD changed to HSD5 DIL issued to family members
Explained to family members regarding patient’s ill condition: › Sepsis › Kidney injury › ACS In the event of cardiac arrest, family not keen for active resuscitation DNR issued
Day 3: › Fever settled › Vital signs stable without inotrope › Hydration improves, good urine output › Seen by dietician and started on RT feeding 200cc/3hourly › IVD 2 pints HS and 1 pint D5 over 24H
Day 4 - Day 7: › General condition improving › Vital signs stable › Hydration status normal, good urine output › Completed IV Zinacef › Completed S/c Clexane › L hand thrombophlebitis › On IV Ciprofloxacin 400mg BD › Off IVD › Cont RT feeding
Day 8: › Temp 38.7 › BP 136/74 › P 92 › RR 28 – 32 › Sp02 97 under RA › L hand thrombophlebitis › Chest: bibasal crepitations › CXR: pneumonic changes L LZ › Cont IV Ciprofloxacin 400mg BD
Day 10: › GCS E3V4M5 › Spiking temp 38 › Tolerating RT feeding › BP 136/74. P 86. RR 28. Sp02 95-96 under RA › Chest bibasal crepts › Noted L LL swelling – upto calf and knee. Tender calf. Feeble DPA and PTA ? L LL DVT
Discussed with family members the need for transfer to HTJS for US doppler Family members refused Consented for S/C Clexane DIL reinformed
Day 11: › General condition ill, gasping › BP lowish 90/60 › P 113 › RR 28 › Sp02 95% under NP 3L/min › Fluid resuscitation
Day 12: (11/5/2012) › Patient succumbed to her illness › Unresponsive, P not palpable, BP unrecordable at 4.10pm › No activity on cardiac monitor >15 minutes › Pupils fixed dilated
DNR as requested by family members Informed family members Time of death: 4.25pm Cause of death: Sepsis 2’ UTI complicated with: › Acute kidney injury › Acute coronary syndrome › Nosocomial infection
• Infection: A microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms.• Bacteremia: The presence of viable bacteria in the blood.
• Systemic Inflamatory Response Syndrome (SIRS): The systemic inflammatory response to a variety of severe clinical insults (For example, infection).• Sepsis: The systemic inflammatory response to infection.
• Temperature >38 degrees Celsius or <36 degrees Celsius.• Heart rate>90 beats per minute.• Respiratory rate>20 breaths per minute or PaCO2<32mmHg.• White blood cell count > 12,000/cu mm, <4,000/ cu mm, or >10% band forms.
• Sepsis: • Known or suspected infection, plus • >2 SIRS Criteria.• Severe Sepsis: • Sepsis plus >1 organ dysfunction. • MODS. • Septic Shock.
• 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.
• Multiple Organ Dysfunction Syndrome (MODS): The presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention.
Adapted from: Bone RC et al. Chest. 1992;101:1644-55.Opal SM et al. Crit Care Med. 2000;28:S81-2.
Infection/ Trauma SIRS Sepsis Severe SepsisA clinical response arising SIRS with a presumed or from a nonspecific insult, confirmed infectious including ≥2 of the process 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 = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644.
Infection/ Trauma SIRS Sepsis Severe Sepsis • Sepsis with ≥1 sign of organ failure – Cardiovascular (refractory hypotension) – Renal – Respiratory Shock – Hepatic – Hematologic – CNS – Unexplained metabolic acidosisBone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207.
Infection PhysiologicInflammation Biochemical Severe Sepsis Specific Organ Severity
Pre-existing disease › Cardiac, Pulmonary, Renal › HIV Age (extremes of age) Gender (males) Genetics › TNF polymorphisms (TNF promoter high secretor genotype)
• Hemodynamic Alterations • Hyperdynamic State (“Warm Shock”) • Tachycardia. • Elevated or normal cardiac output. • Decreased systemic vascular resistance. • Hypodynamic State (“Cold Shock”) • Low cardiac output.
• Myocardial Depression.• Altered Vasculature.• Altered Organ Perfusion.• Imbalance of O2 delivery and Consumption.• Metabolic (Lactic) Acidosis.
• Stage 1. In response to injury / infection, the local environment produces cytokines.• Stage 2. Small amounts of cytokines are released into the circulation: • Recruitment of inflammatory cells.
• Stage 3. Failure to control inflammatory cascade: • Loss of capillary integrity. • Stimulation of Nitric Oxide Production. • Maldistribution of microvascular blood flow. • Organ injury and dysfunction.
•Knaus, et al. (1986): •Direct correlation between number of organ systems failed and mortality. •Mortality Data:#OF D1 D2 D3 D4 D5 D6 D71 22% 31% 34% 35% 40% 42% 41%2 52% 67% 66% 62% 56% 64% 68%3 80% 95% 93% 96% 100 100 100 % % %
• Multiple Organ Dysfunction (MODS) and Multiple Organ Failure (MOF) result from diffuse cell injury / death resulting in compromised organ function.• Mechanisms of cell injury / death: • Cellular Necrosis (ischemic injury). • Apoptosis. • Leukocyte-mediated tissue injury. • Cytopathic Hypoxia
• Cytokine production leads to massive production of endogenous vasodilators.• Structural changes in the endothelium result in extravasation of intravascular fluid into interstitium and subsequent tissue edema.• Plugging of select microvascular beds with neutrophils, fibrin aggregates, and microthrombi impair microvascular perfusion.• Organ-specific vasoconstriction.
Infection Inflammatory Endothelial Vasodilation Mediators DysfunctionHypotension Microvascular Plugging Vasoconstriction Edema Maldistribution of Microvascular Blood Flow Ischemia Cell Death Organ Dysfunction
• Loss of Sympathetic Responsiveness: • Down-regulation of adrenergic receptor number and sensitivity, possible altered signal transduction.• Vasodilatory Inflammatory Mediators.• Endotoxin has direct vasodilatory effects.• Increased Nitric Oxide Production.
• Decreased red cell deformability in inflammatory states.• Microvascular sequestration of activated leukocytes and platelets.• Sepsis is a Procoagulant State. • The extrinsic pathway may be activated in sepsis by upregulation of Tissue Factor on monocytes or endothelial cells. • Fibrinolysis appears to be inhibited in sepsis by upregulation of Plasminogen Activator Inhibitor. • A variety of pathways result in reduced Protein C activity in sepsis.
• Endothelial cell expression of Selectins and ICAM / ELAM is upregulated in Sepsis due to inflammatory activation. • Selectins bind carbohydrate ligands on the surfaces of PMN’s. • ICAM bind Integrins on the surfaces of PMN’s. • The Selectins initiate a weak bond between the PMN and the endothelial cell causing PMN’s to tumble along the vessel wall.
• Binding of leukocytes to ICAM leads to transmigration of PMN’s into interstitium.• Transmigration disrupts normal cell-cell adhesions resulting in increased vascular permeability and tissue edema.• Vascular permeability is also increased by several types of inflammatory cytokines.
• A physiologic process of homeostatically- regulated programmed cell death to eliminate dysfunctional or excessive cells.• A number of inflammatory cytokines, NO, low tissue perfusion, oxidative injury, LPS, and glucocorticoids all are known to increase apoptosis in endothelial and parenchymal cells.• Levels of circulating sfas (circulating apoptotic receptor) and nuclear matrix protein (general cell death marker) are both elevated in MODS.
• Transmigration and release of elastase and other degradative enzymes can disrupt normal cell-cell connections and normal tissue architecture required for organ function.• Reactive oxygen species cause direct cellular DNA and membrane damage and induce apoptosis.
• A defect of cellular oxygen utilization.• May be due to activation of PARP (poly-ADP- ribosylpolymerase-1).• Oxidative DNA damage activates PARP which consumes intracellular and mitochondrial NAD+.• NAD+ depletion leads to impaired respiration and a shift to anaerobic metabolism.• Affected cells may suspend normal cell- specific activities in favor of preservation of cell viability.
• Control Infection Source • Drainage • Surgical • Radiologically-guided • Culture-directed antimicrobial therapy • Support of reticuloendothelial system • Enteral / parenteral nutritional support • Minimize immunosuppressive therapies
• Support Dysfunctional Organ Systems • Renal replacement therapies (CVVHD, HD). • Cardiovascular support (pressors, inotropes). • Mechanical ventilation. • Transfusion for hematologic dysfunction. • Minimize exposure to hepatotoxic and nephrotoxic therapies.
• Modulation of Host Response Targeting Endotoxin •Anti-endotoxin monoclonal antibody failed to reduce mortality in gram negative sepsis. Neutralizing TNF •Excellent animal data. •Large clinical trials of anti-TNF monoclonal antibodies showed a very small reduction in mortality (3.5%).
• Modulation of Host Response • IL-1 Antagonism Three randomized trials: Only 5% mortality improvement. • PAF-degrading enzyme Great phase II trial. Phase III trial stopped due to no demonstrable efficacy. • NO Antagonist (LNMA) Increased mortality (? Pulmonary Hypertension).
• Modulation of Host Response • Antithrombin III No therapeutic effect. Subset of patients with effect when concomitant heparin not given. • Activated Protein C (Drotrecogin alpha / Xigris) Statistically significant 6% reduction in mortality. Well-conducted multicenter trial (PROWESS). FDA-approved for use in reduction of mortality in severe sepsis (sepsis with organ failure).
• Modulation of Host Response •Corticosteroids Multiple studies from 1960’s – 1980’s: Not helpful, possibly harmful. Annane, et al. (2002): 10% mortality reduction in vasopressor-dependent septic shock (relative adrenal insufficiency, ACTH nonresponders).
• 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
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