Tara Benton, MD Pediatric Critical Care Fellow October 24, 2011 Sepsis

Objectives Definitions Epidemiology Microbiology Pathophysiology Guidelines for treatment Prevention

Sepsis “clinical syndrome that complicates severe infection and is characterized by systemic inflammation and widespread tissue injury ”

Definitions SIRS (systemic inflammatory response syndrome) At least 2 of the 4 following criteria (abnormal temp or WBC must be one of them) Temperature >38.5 or <36C Tachycardia (>2 SD above normal for age in absence of external stimulus, chronic drugs or painful stimuli) OR otherwise unexplained persistent elevation over a hr period OR for children <1 yr old: bradycardia, defined as a mean HR <10 th % for age Mean tachypnea>2 SD above normal for age or mechanical ventilation for an acute process WBC elevated or depressed for age or >10% neutrophils International Consensus Conference on Pediatric Sepsis 2005

Definitions Infection defined as a suspected or proven (by positive culture, tissue stain or PCR test) infection caused by any pathogen OR a clinical syndrome associated with a high probability of infection Sepsis = SIRS + infection Severe Sepsis = SEPSIS + CV dysfunction OR ARDS OR 2 other organ dysfunctions Septic Shock = SEPSIS + CV dysfunction International Consensus Conference on Pediatric Sepsis 2005

Definitions Shock Inadequate perfusion and oxygenation of the body and its organs Delivery of substrate ≠ demand

Epidemiology Bacterial sepsis is the leading cause of medical admissions to the PICU Worldwide, sepsis is the most common cause of death in infants In 1995 Watson et al published a large population based study evaluating severe sepsis cases per 1000 children (total of 40,000 cases each year) More common in infants especially low-birth-weight, least common in 10-14yr Half of all patients in this study had underlying medical conditions Respiratory infection and primary bacteremia encompasses >40% of all causes

Epidemiology Mortality is consistent at ~10% across age groups Severity of illness does correlate with mortality (in adults) SIRS – 7% Sepsis – 16% Severe Sepsis – 20% Septic Shock - 46%

Microbiology Most common pathogen overall is Staphylococcus of all types In the population study previously discussed, 18% of cases overall and 26% of neonatal infections An international study from 2007, 44% of all cases were caused by Staph Most common isolate overall is Staph aureus Other organisms noted in above studies: Streptococcus and Pseudomonas aeruginosa Viral sepsis may be indistinguishable from bacterial sepsis HSV in neonates

Risk factors Genetic Study in adopted children by Sorensen et all in 1988 – more likely to die from an infectious etiology if biologic parent died from infection before age 50. Not associated with death from infection in adoptive parents Polymorphisms identified in multiple inflammatory molecules but unclear effect on host response Gender: M>F

Risk Factors Comorbidity Nearly half of all children with sever sepsis have an underlying comorbidity (neuromuscular, CV, respiratory) Neoplasm associated with greatest number of sepsiis-related deaths among all children In older children, CV conditions have the highest case fatality rate of all comorbid conditions Risk of death increases with increasing number of organ dysfunction

Risk Factors Environmental risk factors Surgical site infections 1/3 most commonly reported infection (~15%) Contaminated procedure, surgery >2hrs, abd or thoracic procedure, present of ≥ 3 discharge diagnoses Central venous lines Most often gram + bacteria (staph aureus, staph epi) GNR 21% Very young, chronically ill, poor nutritional status, loss of skin integrity, neutropenia Endocarditis, Urosepsis, Hemodialysis, Osteomyelitis

Pathophysiology Widespread tissue injury Massive and uncontrolled release of proinflammatory mediators Host inflammatory response

Pathophysiology What the bacteria do to us: Depends on the bacteria Gram-negative Lipopolysaccharide (LPS) endotoxin – found in cell wall Rapidly triggers an inflammatory response from host Gram-positive Exotoxins (tetanus, diptheria, botulism) Endotoxin –like cell wall components (lipoteichoic acid (LTA), peptidoglycan) Soluble toxins (super antigens) – toxic shock syndrome

Pathophysiology What we do to fight the bacteria: First the pathogen is identified by our innate immune system (macrophages, neutrophils) by specific receptors (Toll- like receptors) These receptors trigger production of proinflammatory gene elements Activation of innate immune cells and enhancement of pathogen internalization and intracellular killing

Pathophysiology What we do to fight the bacteria: Release of cytokines (TNF- α, IL-1) and chemokines which modulate the inflammatory response Of interest – anti-inflammatory cytokines are produced as well (TGF- β, IL-1 receptor antagonist, IL10 ) Activation of adaptive immune system (T- and B-lymphocytes) More cytokines released (able to produce both pro- and anti-inflammatory) Activation of the endothelium results in more cytokine release

Pathophysiology End organ results Endothelium Increase in vascular permeability -> capillary leak Vasodilation Coagulation cascade DIC – both bleeding and microvascular clots Myocardial dysfunction Temperature regulation Fever

Clinical presentation of Sepsis Classically early sepsis presents as: Hyperdynamic and high cardiac output Warm extremities Flash cap refill Widened pulse pressure Fever Ill appearing Progression to shock will have findings of end organ dysfunction Mental status changes (may just be irritability in infants) Grunting or other signs of impending respiratory failure Poor urine output Physical exam and history can give you clues to sites of infection

Clinical presentation of septic shock Surviving Sepsis Campaign 2007 Guidelines for Pediatric Septic Shock

Treatment of sepsis Early recognition “Goal directed therapy” to restore tissue perfusion In 2002 – the first set of clinical practice parameters were published Updated guidelines were published in 2007 and are what we use today

Goal Directed Therapy – pediatric patients

Goal Directed Therapy

Goal directed therapy - neonates

Initial Antimicrobial Therapy As noted in the algorithm, antimicrobial therapy should be initiated EARLY Complex decision for choosing antibiotics and history of child is key Overall need to start broad spectrum Should cover MRSA for all children now If immunosuppressed or at risk like CF, should cover for Pseudomonas Listeria monocytogenes and HSV coverage for infants <28 days

Initial Antimicrobial Therapy Children >28 days of age and normal hosts Vancomycin PLUS cefotaxime Consider clinda or metronidazole if suspected GI/GU source Children >28 days and immunosuppressed Vancomycin PLUS ceftazidime (or cefepime) Consider adding aminoglycoside like tobramycin For Penicillin allergic: Vancomycin PLUS meropenem For infants <28 days Typical is Ampicillin, Gentamicin, and Acyclovir Think about whether Vancomycin is needed for MRSA coverage

Initial Inotropic Therapy No one right answer for this Warm, vasodilated, no known cardiac disease -> NOREPI or EPI Cool, mottled -> DOPAMINE or EPINEPHRINE Cardiac disease -> DOPAMINE OR EPINEPHRINE If one isn’t working, add another Think about vasopressin if not responding to the catecholamines (Dopa, Epi, Norepi)

Summary of therapy Keep in mind goals up front SvO2 70% Perfusion pressure CVP ~10-12 Follow lactate Early antibiotics Fluid Inotrope Additional Inotrope Hydrocortisone ECMO

ICU monitoring and continued care Intubation with lung protective mechanical ventilation if necessary Fluid removal Diruetics CRRT or PD Hemoglobin - >10gm/dl Now being debated Glycemic control – start insulin if necessary to keep glucose Nutritional support utilizing enteral route if possible (transpyloric if gastroparesis) Identifying source of infection and addressing this if possible

Prevention Vaccination Following recommendations for reducing CLABSI Insertion bundle Meticulous sterile technique went entering line GET THE LINE OUT Follow VAP prevention bundle while intubated Remove all plastic as soon as possible Talk about lines/tubes/drains every day on rounds and engage bedside nursing to facilitate the above

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