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SEPSIS SEVERE SEPSIS SEPTIC SHOCK Rontgene M. Solante,M.D.,FPCP,FPSMID Internal Medicine – Infectious Diseases SEPSIS: WHAT DO WE KNOW? Sepsis (Greek): “rotten flesh and putrefaction” “complex medical condition that begins with an infectious stimulus and results in an exaggerated immune response” European Study: >35% of patients develop sepsis at some point during their ICU stay; 30% severe sepsis; mortality- 27% sepsis and >50% if septic shock - Jean-Louis Vincent, et al. Sepsis in European Intensive Care Units: Results of SOAP Study. 2006 Sepsis: A Complex Disease This Venn diagram provides a conceptual framework to view the relationships between various components of sepsis. The inflammatory changes of sepsis are tightly linked to disturbed hemostasis. Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Opal SM et al. Crit Care Med. 2000;28:S81-2. Sepsis: ACCP/SCCM Definitions Infection – Inflammatory response to microorganisms, or – Invasion of normally sterile tissues Systematic Inflammatory Response Syndrome(SIRS) – – – – > 2 of the following: Core temperature >38o C or <36oC (>100.4o F or <96.8o F) Elevated heart rate (>90 beats/min) Respiratory rate >20 breaths/min or PACO2 <32 mm Hg or mechanical ventilation for acute respiratory process WBC count > 12,000 cells/mm3 or <4,000 cells/mm3 or >10% immature neutrophils Sepsis: ACCP/SCCM Definitions Known or suspected infection, plus >2 SIRS criteria: – Core temperature >38o C or <36oC (>100.4o F or <96.8o F) – Elevated heart rate (>90 beats/min) – Respiratory rate >20 breaths/min or PACO2 <32 mm Hg or mechanical ventilation for acute respiratory process – WBC count > 12,000 cells/mm3 or <4,000 cells/mm3 or >10% immature neutrophils Severe Sepsis: Acute Organ Dysfunction and Disordered Hemostasis Severe Sepsis: Sepsis with signs of organ dysfunction in 1 of the following systems: – – – – – – – Cardiovascular Renal Respiratory Hepatic Hemostasis CNS Unexplained metabolic acidosis Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Severe Sepsis (Sepsis syndrome) 1. Cardiovascular: Arterial systolic BP< 90 mmHg or mean arterial pressure (MAP) <70 mmHg that responds to administration of fluid 2. Renal: Urine output < 0.5 ml/kg per hour for 1 hr despite adequate fluid resuscitation 3. Respiratory: PaO2 /FiO2 <250 or, if the lung is the only dysfunctional organ, <200 4. Hematologic: Platelet count <80,000/uL or 50% decrease in platelet count from highest value recorded over previous 3 days Septic Shock -Sepsis with hypotension despite adequate fluid resuscitation accompanied by perfusion abnormalities Systemic Inflammatory Response Syndrome (SIRS) INFECTION Inflammatory response to the presence of or invasion of normally sterile host tissue by microorganisms SEPSIS Systemic response to infection with Same manifestation as SIRS BACTEREMIA The presence of live bacteria in the blood SEVERE SEPSIS Sepsis associated with organ dysfunction, hypopefusion or hypotension. Perfusion abnormalities may include but are not limited to: • Lactic acidosis • Oliguria • Acute mental status changes 2º MODS Altered organ function in acutely ill patient requiring intervention SEPTIC SHOCK Sepsis with hypotension despite adequate fluid resuscitation accompanied by perfusion abnormalities HYPOTENSION Systolic BP < 90 or ↓ from baseline > 40 mmHg Severe Sepsis: A Complex and Unpredictable Clinical Syndrome Sepsis-induced organ failure: -? Cause (autopsies): discordant findings - tissue hypoxia (microvascular blood flow studies in mucosal membranes) Alterations in cell metabolisms- oxidative modifications of proteins, lipids, DNAs SEPSIS ACUTE ORGAN DYSFUNCTION (Severe Sepsis) DEATH - Vincent JL and Abraham E. The Last 100 Years of Sepsis. AJRCCM 2006; 173:256-63. PATHOPHYSIOLOGY: Microcirculatory dysfunction Cytopathic hypoxia –diminished production of ATP despite normal PO2 values in the vicinity of mitochondria within cells ↓ Activation or Injury of the vascular endothelium Secondary to alteration of vascular tone, vascular permeability and coagulation ↓ ↓ Activation of cytokines and other mediators ↓ Complement Activation ↓ Coagulopathy ↓ Immunosuppression Microorganisms Involved in Episodes of Severe Sepsis Episodes with bloodstream infection, % (n=436) Gram negative bacteria Gram positive bacteria Fungi Polymicrobial Classic Pathogens 35 40 7 11 <5 Episodes with Documented Infection But No Bloodstream infection, % (n= 430) 44 24 5 21 <5 Total Episodes, % (n= 866) 40 31 6 16 <5 Balance between proinflammatory and counter-regulatory events in response to infection determines clinical outcome Outcome Proinflammatory cytokine, coagulation system, neutrophil activation Excessive Response Fulminant SIRS Early Mortality Antiinflammatory Cytokine, natural inhibitor release, Stress hormones, immune cell activation Excessive Response Immunoparalysis Late Mortality Normal Host Responses to Infection Local Defenses: Walling Off and Killing Invading Microbes Systemic Responses: Keeping Infection and Inflammation localized a.) CNS Regulation of Systemic Response b.) Essential Roles of Liver and Spleen Acute Phase Responses a.) Anti-infective Responses b.) Anti-inflamatory responses c.) Metabolic responses d.) Procoagulant responses e.) Thermoregulatory Responses Walling off and Killing Invading Microbes Innate Immunity Senses microbes through proteins that bring highly conserved microbial molecules (lipopolysaccharides, peptiglycan) “Hard-wired” –inferited in the genome; shaped by evolution Responds rapidly to microbial invasion Elements: mannose-binding-lectin, alternative complement pathway, “natural” antibodies, pattern – recognition proteins, the “professional” phagocytes, mast cells, (NK) natural killer cells Systemic Responses: Keeping Infection and Inflammation localized a.) CNS Regulation of Systemic Response The CNS senses microbial invasion via: 1. afferent impulses along nociceptive and vagal nerves rapidly transmit signals from infected local tissues to the hypothalamus and brainstem where they can activate the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system and the hypothalamic thermoregulatory center 2. Blood-borne mediators (IL-Iβ, TNF, IL-6, interferons and prostaglandins) can cross the blood-brain barrier or be transported passively through capillaries in the circumventricular organs to reach the hypothalamus Systemic Responses: Keeping Infection and Inflammation localized Role of Liver and Spleen The liver acts as a blood filter that collects and kills blood-borne microbes, as a “listening station” that senses low concentration of circulating cytokines and transmits this information to the CNS, as a factory for the production of many elements of the systemic response, and as a major site of infection-associated metabolic adaptations. The spleen functions as the major filter for opsonized microorganisms. Acute Phase Responses A. Anti-infective responses - increases synthesis of complement factors, microbe pattern-recognition molecules (mannosebinding lectin, LBP, CRP, CD14 and others) - sequesters iron (lactoferrin) and zinc (metallothionein) B. Anti-inflammatory Responses - releases anti-inflammatory neuroendocrine hormones (cortisol, ACTH, epinephrine, MSH) - increases synthesis of proteins that help prevent inflammation within the systemic compartment . Cytokinase antagonists (IL-1Ra) . Anti-inflammatory mediators . Protease inhibitors . Antioxidants - reprograms circulating leukocytes (epinephrine, cortisol, PGE) C. Metabolic Responses - preserves euglycemia, mobilizes fatty acids, epinephrine, cortisol, glucagon, cytokines D. Procoagulant Responses - walls off infection, prevents systemic spread by: . increasing synthesis or release of fibrinogen, PAI-I, C4b . decreasing synthesis of protein C, antithrombin III E. Thermoregulatory Responses Inhibits microbial growth (fever) CLINICAL MANIFESTATIONS Identifying Acute Organ Dysfunction as a Marker of Severe Sepsis Altered Consciousness Confusion Psychosis Tachycardia Hypotension CVP PAOP Tachypnea PaO2 <70 mm Hg SaO2 <90% PaO2/FiO2 300 Oliguria Anuria Creatinine Jaundice Enzymes Albumin PT Platelets PT/APTT Protein C D-dimer Nervous and Neuroendocrine Systems a. Cerebral function - confusion and other subtle abnormalities in cognitive function - focal signs, seizures and cranial nerve palsies - encephalopathy is associated with poor prognosis b. Hypothalamic-Pituitary-Adrenal axis high plasma concentration of vasopressin are followed by relatively low levels, probably reflecting both loss of baroreflex feedback regulation and vasopressin depletion from the posterior pituitary c. Adrenal Insufficiency - due to anatomic damage to the adrenals or pituitary, hypoperfusion, cytokine-induced dysfunction of adrenals, drug induced steroid hypermetabolism, inhibitionof steroidogenesis and desensitization to glucocorticoid responsiveness at the cellular level - manifested as hypotension and hypoglycemia d. Autonomic dysfunction manifested as oscillations in heart rate, blood pressure, respiration e. Peripheral Nerves, Muscles polyneuropathy and myopathy manifested as difficulty in weaning from ventilator, generalized wasting of limbs and diffuse weakness THE BLOOD STREAM A. The Heart - reduced left and right ventricular ejection fractions - increased left and right ventricular end-diastolic volume - elevated heart rate and cardiac output SEPTIC SHOCK Phases of septic shock: 1. Vasoconstrictive (cold) shock low cardiac output and high peripheral resistance in hypovolemic pts. secondary to redistribution of blood flow, venous pooling, increased capillary permeability, increased insensible losses and poor fluid intake 2. Vasodilation Clinical hallmarks: decreased systemic vascular resistance high cardiac output. Lipids - decrease in levels of HDL and LDL - increase in levels of triglycerides, free acids and VLDL fatty Glucose - hypoglycemia is uncommon since the body can maintain glucose levels through gluconeogenesis, glycogenolysis and insulin resistance Lactate - increased blood lactate concentrations and increased lactate to pyruvate ratio due impaired hepatic lactate clearance and mitochondrial dysfunction Coagulopathy / DIC diagnostic criteria for DIC: 1. platelet count <100,000/mm3 or rapid decrease in platelet count; Acute Lung Injury Hyperventilation with respiratory alkalosis Diagnostic criteria: - arterial hypoxemia (PAO2/FIO2 <300) - bilateral infiltrates on chest radiograph in the absence of pneumonia and heart failure Renal Dysfunction Proteinuria- renal failure secondary to hypovolemia, hypotension, renal vasoconstriction and toxic drugs oliguria Gastrointestinal Tract injury Hypoperfusion of visceral organs leads to impairment of the gut barrier function allowing the translocation of bacteria into the lymph and blood stream Aspiration of the microbial and chemical contents of the upper GI tract GI bleeding Ileus Hepatic Dysfunction Cholestatic jaundice – elevation in conjugated and unconjugated bilirubin(<10mg/dl) Elevated alkaline phosphatase, bilirubin and aminotransferases are common Frank hepatic failure (“shock liver”) is uncommon Cutaneous Manifestations Cellulitis and thrombophlebitis Ecthyma gangrenosum or bullous lesions Symmetrical peripheral gangrene associated with DIC, fibrin thrombi are seen in small vessels, but neither inflammatory cells nor bacteria are found Diagnosis Timely diagnosis and early intervention are key factors in preventing morbidity and mortality 1. History a. Clinical History (Underlying diseases) immunosuppression – cell mediated vs. humoral diabetes mellitus – poor glycemic control ↑risk hormonal abnormalities chronic obstructive pulmonary disease- ↑risk pneumonia and bronchitis valvular and congenital heart disease - ↑risk of IE hyposplenism or asplenia Malignancy cirrhosis malnutrition Diagnosis b. Medication History (provides clues to infection type and severity) Prior antimicrobial therapy –alters disease epidemiology and warrants broadening microbiologic differential diagnosis (resistant and unusual pathogens) NSAIDS and corticosteroid therapy allergic reactions drug-related adrenal insufficiency Diagnosis 1. History c. Invasive procedure or surgery d. Obstetric and gynecologic history e. Social History - travel history, residence, occupation, recreational activities, alcoholism, smoking, sexual history Diagnosis 2. Physical examination a. Vital signs - temperature, Pulse, Blood pressure, respiratory rate b. General findings- apprehensive, tachypneic, toxic or illlooking c. Skin- petechiae, ecthyma gangrenosum, purpuric macules, rashes, cellulitis, furuncles, abscess, pustules d. heart murmurs e. lungs f. abdominal, rectal and pelvic examination g. extremities h. wound and soft tissues i. central nervous system Diagnosis 3. Diagnostic microbiology a. Blood cultures - blood volumes (10-20 ml adults) - blood culture set number – 2 to 3 sets - site selection- antecubital veins or upper extremities not from catheters b. Gram stains and other stains c. Cultures d. Hematology e. Coagulation studies f. Chemistries – electrolytes, hepatic and renal panels, CRP, cytokine levels g. Arterial blood gases h. Urinalysis Diagnosis 3. Diagnostic microbiology i. Serologic tests - acute and convalescent antibody titers j. Radiology k. CT and MRI l. ultrasonography m. Nuclear medicine imaging Severe Sepsis Therapy: Standard Care Source control Sedation/analgesia Antibiotics Ensure adequate Hemodynamic support Mechanical ventilation Renal replacement therapy Provide hematological support Other supportive measures nutrition Wheeler AP, Bernard GR. N Engl J Med. 1999;340:207-14. THANK YOU FOR YOUR ATTENTION! Other Sources: 1. Principles and Practice of Infectious Diseases 6th edition, 2005 (Mandel et al) 2. Approach to Infectious Diseases 5th edition, 2003 ( Reese and Betts) 3. Washington Manual on Infectious Diseases 2005 edition 4. Harrison’s Principle of Internal Medicine 17th edition 2008 5. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008 (Crit CareMed. 2008;36(1):296-327)