Sepsis Pathophysiology How Kids Differ From Adults Steve Standage Pediatric Critical Care Medicine Seattle Children's Hospital University of Washington School of Medicine Disclosures & Preamble No agenda, no special interests Research funding from the American Heart Association, NIH, Seattle Children s Research Institute No other conflicts Learning Objectives Review basic sepsis pathophysiology Preview recent developments Discuss differences between kids and big people What is sepsis? Sepsis is defined as life threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is not a specific illness but rather a syndrome encompassing a still uncertain pathobiology. 1
Old Definitions Systemic Inflammatory Response Syndrome Sepsis Severe Sepsis Septic Shock Classical paradigm Local infection Generalized infection/inflammatory dysregulation Hyperinflammatory cytokine storm Endothelial dysfunction Capillary leak Vasodilatation Leukocyte tissue infiltration and damage Dysregulated clotting cascade (DIC) Myocardial depression Shock (DO 2 failure) & tissue hypoxia Organ system dysfunction Classical paradigm Interventions targeted at hyperinflammatory state: High dose steroids Anti TNFα antibodies TNFα receptor:fc fusion protein IL 1 receptor antibodies Anti endotoxin antibodies Activated protein C TLR4 antagonists All these interventions have FAILED! 2
Problems with the classical paradigm CARS There is significant immunosuppression associated with sepsis Opposite SIRS is CARS the Compensitory Anti inflammatory Response Syndrome. Many septic patients die with signs of profound immunoparalysis, secondary infections, and reactivation of latent infections. Current conceptual model Few patients die of fulminant hyperinflammatory sepsis. Those who recover return inflammatory and anti inflammatory systems to baseline. Persistent, simultaneous inflammation and immunosuppression is an ongoing problem that contributes to sepsis morbidity and mortality. New therapies aimed at restoring immune function. Problems with the current model Metabolism Septic people don t die of hypercytokinemia, they die of organ system failure. Organ system function is dependent upon cellular function, which is paid for with the currency of ATP. Metabolism is essential! Accumulating evidence points to metabolic failure in sepsis as an important cause of morbidity and mortality. 3
Kids Adults but some things are the same! Timely attention Early warning systems Code Sepsis criteria in ED triage Prompt response Aggressive fluid resuscitation But not too much Start vasoactive medications through the peripheral IV if necessary Rapid source control Timely antibiotics Surgical intervention Children differ in cardiovascular response Sepsis induces cardiac dysfunction Decreased ejection fraction Ventricular dilation Kids seem to have more dysfunction than adults Children lack sufficient physiologic reserve Decreased ability to augment contractility Cardiac output is heart rate dependent But they can t increase it as much as adults due to low diastolic filling time Often present in Cold Shock Increased systemic vascular resistance Inotropes (epi) rather than pressors (norepi) Neonates and infants Sepsis associated acidosis and hypoxia can induce: Increased pulmonary vascular resistance Persistent fetal circulation Therapies directed towards reducing pulmonary artery pressures are likely to benefit. Correction of acidosis / hypercapnia Supplemental oxygen Consider sedation / paralysis Nitric oxide 4
Kids more susceptible to respiratory failure Anatomic differences predispose children to acute respiratory failure Narrow airways increase resistance Thoracic geometry and soft chest wall increase work of breathing in situations of poor lung compliance Fewer alveoli and pathways of collateral ventilation lead decreased surface area and atelectasis, impairing gas exchange Neurologic immaturity can lead to frank apnea in sick neonates Miscellany Possible increased propensity to bleed Amount of clotting factors decreased compared to adults Pediatric platelets are relatively hyporesponsive The immature immune system leaves infants and toddlers more susceptible to sepsis Children more prone to immunoparalysis in sepsis Full immunocompetence not achieved till adolescence Hemophagocytic Lymphohistiocytosis (HLH) Severe, hyperinflammatory disorder leading to rapid onset multisystem organ failure. Caused by dysfunctional NK and T effector cell mediated killing Two flavors: Familial HLH Secondary Requires aggressive supportive care Will not abate without immunosuppressive therapies 5
Pediatric outcomes are much better Pediatric mortality about 10 15% Adult mortality about 20 30% 6