Abstract and Introduction
Abstract
Background: Septicemia activates coagulation and decreases activated protein C (APC). Low APC in adults is associated with multiorgan dysfunction and mortality, but such data in neonates are lacking. Being deficient in APC, neonates may be especially vulnerable to the effects of low APC.
Methods: This cohort study was conducted on 40 neonates with severe bacterial septicemia to determine the relationship between plasma APC values and mortality, time to mortality, and hazard of dying. Low birth weight neonates with sepsis, organ dysfunction, and systemic inflammatory response syndrome were enrolled after parental consent. Plasma APC was assayed at enrollment and subjects were followed for 14 days from enrollment. Low birth weight neonates, who had major malformations, severe birth asphyxia, or received blood products before APC assay, were excluded. Primary outcome: comparison of APC level between survivors and nonsurvivors. Secondary outcomes: survival with low versus normal APC; and hazard ratio of APC, adjusted for birth weight, Score for Neonatal Acute Physiology and number of affected organs.
Results: Forty of 74 eligible neonates were included. Twenty-five of the enrolled neonates died within 14 days. APC levels in nonsurvivors were lower than in survivors [median (interquartile range) %, 15 (4.5-21) versus 33 (18-55); P < 0.001]. Ten nonsurvivors versus 1 survivor had low APC (P = 0.03). Positive predictive value (PPV) of low APC values for mortality was 90.9%. Survival in the low APC group (n = 11) was shorter than in normal APC group [median (95% confidence interval) days, 3 (2.3-3.7) versus 10, P value <0.001]. APC value was independently associated with hazard of dying [adjusted risk 0.95 (95% confidence interval 0.92-0.99), P = 0.02]. Each 1% rise in APC decreased the hazard of dying by 5%.
Conclusions: Mortality was higher and duration of survival shorter in septic neonates with lower plasma ACP. The latter was an independent predictor of the hazard of dying.
Introduction
Organ dysfunction associated with septicemia results from a generalized inflammatory and procoagulant response to an infection. Endotoxins change the vascular endothelium to an antifibrinolytic and procoagulant state, resulting in multiple fibrin clots, hypoperfusion, tissue necrosis, and multiorgan dysfunction syndrome. Activated protein C (APC) can inactivate factor VIIIa and factor Va. By inhibiting these 2 rate-limiting steps of the coagulation cascade, APC limits thrombin formation, downregulates the coagulation pathway and thus, reduces the risk of multiorgan dysfunction.
Adult patients with severe sepsis have low APC values that can be associated with an increase in mortality. In children, APC matures slowly and the value of APC is only 30-40% of adult values at birth.
Being intrinsically deficient, neonates are likely to be especially vulnerable to the effects of low APC values. The role of APC deficiency in predicting mortality among severely septicemic newborns is not clearly understood. Previous studies have defined severe septicemia in neonates as sepsis with systemic inflammatory response syndrome (SIRS) and organ dysfunction. This study investigates the relationship between plasma APC levels and mortality, time to mortality, organ dysfunction, and the hazard of dying among neonates with severe sepsis.