Pathophysiology and treatment of septic shock in neonates

Abstract

Neonatal septic shock is a devastating condition associated with high morbidity and mortality. Definitions for the sepsis continuum and treatment algorithms specific for premature neonates are needed to improve studies of septic shock and assess benefit from clinical interventions. Unique features of the immature immune system and pathophysiologic responses to sepsis, particularly those of extremely preterm infants, necessitate that clinical trials consider them as a separate group. Keen clinical suspicion and knowledge of risk factors will help to identify those neonates at greatest risk for development of septic shock. Genomic and proteomic approaches, particularly those that use very small sample volumes, will increase our understanding of the pathophysiology and direct the development of novel agents for prevention and treatment of severe sepsis and shock in the neonate. Although at present antimicrobial therapy and supportive care remain the foundation of treatment, in the future immunomodulatory agents are likely to improve outcomes for this vulnerable population.

Figures

Figure 1. Activation of sentinel immune cells

Sentinel cells (e.g.. monocyte, macrophage) sense pathogens via PAMPs or DAMPs binding to PRRs. Pathogen recognition receptors (PRRs) include TLRs (Toll-like receptor), RLRs (Rig-1-like receptors), and NLRs (NOD-like receptors). Pathogen associated molecular patterns (PAMPs) include LPS (lipopolysaccharide), LTA (lipotechoic acid), DNA, and RNA. Damage/Danger associated molecular patterns (DAMPs) can also be sensed through TLRs and include uric acid (UA), heat shock proteins (Hsp), and HMGB-1. Signaling occurs through a series of second messengers and results in transcription and translation of cytokines and chemokines that amplify the immune response.

Figure 2. Cellular recruitment and endothelial activation following pathogen detection

Pathogen-stimulated tissue/blood monocytes, dendritic cells (DC), and macrophages release proinflammatory cytokines that activate the surrounding endothelium. Endothelial activation results in upregulation of cell adhesion molecules (CAM), production of chemokines and vasoactive substances, activation of complement, and development of a procoagulant state. Recruitment of PMNs occurs along the chemokine gradient surrounding the area of inflammation. Anti-inflammatory cytokines counter the actions of proinflammatory cytokines to prevent excessive cellular activation and recruitment that can result in tissue damage and systemic inflammation. Endothelium can be damaged when PMNs release reactive oxygen intermediates (ROI). LTE-leukotriene, NO-nitric oxide, PMN-neutrophil.

Figure 3. Pathophysiology of neonatal sepsis and septic shock

PRR-Pattern recognition receptors; AEM-antimicrobial effector mechanisms; DAMP-Danger/damage-associated molecular patterns; SIRS-Systemic inflammatory response syndrome; DIC-disseminated intravascular coagulation; CV-cardiovascular.

Figure 4. ACCCM consensus guidelines for treatment of shock in term infants and suggested modifications for preterm infants

RDS-respiratory distress syndrome, NRP-Neonatal Resuscitation Program, CVP-central venous pressure, MAP-mean arterial pressure, ScvO2-central venous oxygen saturation, SVC-superior vena cava, CI-cardiac index, VLBWvery low birth weight, PDA-patent ductus arteriosus, PPHN-persistent pulmonary hypertension of the newborn.