Pathophysiology and Treatment of Septic Shock in Neonates

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Definitions of the sepsis continuum

In 2005, definitions for pediatric infection, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and organ dysfunction were suggested that included term neonates (0–7 days), newborns (1 week to 1 month) and infants (1 month to 1 year) (Tables 1 and 2).25 Working definitions for the sepsis continuum specific for preterm neonates are needed to provide a uniform basis for clinicians and researchers to study and diagnose severe sepsis in this particularly

Risk factors for development of neonatal septic shock

Risk factors for a neonate developing sepsis have been well described. Although risk factors for septic shock overlap those for sepsis, specific antenatal and postnatal risks for the development of neonatal septic shock have not been described in detail.

Maternal factors contributing to the risk of neonatal sepsis are shown in Box 1 and include prematurity, low birth weight, rectovaginal colonization with group B streptococcus (GBS), prolonged rupture of membranes, maternal intrapartum fever,

Microbiology of sepsis and septic shock in neonates

Several pathogens have been associated with sepsis in the neonatal period. The predominant agents are bacterial, but viruses including herpes simplex and enteroviruses have been associated with fulminant neonatal sepsis with high mortality.57, 58, 59 In 1 study, gram-negative infection accounted for 38% of cases of septic shock and 62.5% of sepsis mortality.7 These results are similar to those from a previous study that showed gram-negative infection was associated with 69% of cases of

Molecular Signaling: Pattern Recognition Receptors, Pathogen-associated Molecular Patterns, and Damage- or Danger-associated Molecular Patterns

Pathogen recognition by local immune sentinel cells is the first step toward the development of an immune response once local barrier function has been compromised (Fig. 1). Recognition is initiated via the activation of pattern recognition receptors (PRRs)65 including Toll-like receptors (TLRs). There are 10 known TLRs in humans, and each receptor has a specific molecular activation trigger.66, 67 TLRs, present on and within multiple cell types, recognize extracellular and intracellular

Cardiovascular Effects

The hemodynamic response to sepsis has been less well characterized in premature and term neonates compared with children and adults, and the hemodynamic abnormalities are significantly more variable.219 Factors contributing to developmental differences in hemodynamic responses include altered structure and function of cardiomyocytes, limited ability to increase stroke volume and contractility, and contributions of the transition from fetal to neonatal circulation.220 A patent ductus arteriosus

Initial Resuscitation

Treatment guidelines for the management of severe sepsis and septic shock have been established for adults,254 children, and term neonates,255 but no such consensus guidelines exist for preterm neonates. The authors have attempted to incorporate the special circumstances related to premature physiology into the framework of treatment guidelines for term infants (Fig. 4). Development, testing, and acceptance of consensus guidelines for classification and management of preterm neonates with

Other supportive care of neonates with septic shock

Avoidance of hypothermia and hypoglycemia is important in neonates with septic shock. With the exception of patients with acute perinatal hypoxic ischemic encephalopathy,290 normothermia should be maintained on a radiant warmer. Use of a 10% glucose solution delivering 4 to 6 mg/kg/min of glucose combined with frequent monitoring to ensure normoglycemia is recommended. Correction of a significant coagulopathy and anemia (hemoglobin ≤10 g/dL) through the transfusion of fresh frozen plasma or

Alternative immunologic and pharmacotherapies for neonatal sepsis/shock

There have been many attempts directed at improving outcomes of sepsis and septic shock in neonates via immunomodulation. A complete review of adjunct immunologic therapies in neonatal sepsis, see the article by Tarnow-Mordi and colleagues elsewhere in this issue for further exploration of this topic.

Outcomes with sepsis and septic shock

The outcome of septic shock in the neonate is dismal. One study reported death or severe sequelae in 52% of infants, with only 28% of infants less than 1000 g alive and free of disability at 18 months of age.7 Variables predictive of mortality include cardiac dysfunction manifested as refractory shock, acute renal failure, neutropenia, increased prothrombin time, excessive bleeding, metabolic acidosis, and hypothermia.231, 297

Neurodevelopmental outcomes following neonatal sepsis, without

Future considerations

Neonatal sepsis requires translational and clinical research. Definitions for the sepsis continuum and treatment algorithms specific for preterm infants should be developed to improve the quality of clinical trials and facilitate meta-analyses of prophylactic and therapeutic interventions. Systems biology and genomic and proteomic studies have yielded important data on septic shock in older populations304, 305, 306, 307, 308, 309, 310, 311, 312 and the use of these modern techniques in the

Summary

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

Acknowledgments

The authors thank Associate Professor C. Michael Cotten, MD, MHS for his review of this manuscript.

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