Effect of an Interleukin-1 Receptor Antagonist on the Hemodynamic Manifestations of Group B Streptococcal Sepsis

Abstract

IL-1 is purported to be a proximal mediator in the cascade leading to septic shock. To characterize its hemodynamic effects and to ascertain whet her its block ade would ameliorat e the deleterious con sequences of sepsis, an IL-1 receptor antagonist (IL-1ra) was adminis tered to 16 anesthetized, mechanically ventilated piglets that rece ived a contin uous infusion of group B streptococci (GBS) (7.5 X 10 7 colony-forming units/kg/min ), Systemic (Psa), pulmonary artery (Ppa), and wedge (Pwp) pressures and cardiac output were measured pre-GBS and every 30 min during GBS infusion . After 15 min of bacteri al infusion the control group receiv ed norm al saline, whereas the treatment group rece ived a bolus of IL-1ra (40 mg/kg) followed by a con tinuo us infusion of IL-1ra (60 J-Lglkglmin). In comparing IL-lra-treated animals with controls from the IS-min GBS baseline to the succe eding septic study period (45-120 min), the following treatment effects were noted (120-min valu es shown) : mean Psa remained eleva ted in treatmen t compared with control animals (12.7 ::' ::: 2.5 versus 9 ::' ::: 3.5 kPa; p < 0.001) as did CO (0.21 ::' ::: 0.07 versus 0.13 ::' ::: 0.08 L'min/kg; p < 0.001) . Pwp decreased in the treatment comp ared to the con trol group over the study period (1 ::' ::: 0.3 versus 1.6 ::' ::: 0.7 kPa; p < 0.02). Mean IL-l is a cytokine thought to occupy a proximal position in the inflammatory cascade leading to tissue injury during sepsis (1, 2). After its release, IL-l influences the metabolism of arachidonic acid and results in increased synthesis of leukotrienes, prostaglandins, and thrombo xane A 2 (2). In addition, IL-l acts synergistica lly with other cytokines , such as TNFo:, to potentiate the inflammatory response (3).Investigators have focused on the role of IL-l as a prominent Ppa and mean Pra were not different between group s ove r time. Median length of sur vival was significantly longer (p = 0.04) in treated (226 min) comp ared with control animals (150 min). The se data suggest that IL-1 plays an impo rtant role in GBS sepsis and septic shock, and that IL-1ra may in part ameliorate the cardiovascular alterations associated with GBS sepsis in the neonate. (Pediatr Res 38: 704-708, 1995)

Recent advances in understanding the molecular basis of group BStreptococcusvirulence

“…Treatment with an IL-1 receptor antagonist improves cardiac output and mean arterial pressure and increases survival in piglets receiving a continuous infusion of GBS (Ref. 79). Conversely, the cytokine IL-12, which is elevated 12–72 hours after challenge in animal models, has an important role in regulating the systemic response to GBS infection.…”

Induction and termination of inflammatory signaling in group B streptococcal sepsis

“…In accordance with the concept of overwhelming inflammation, all clinical sequels of a cytokine storm, such as coagulation disorders, cardio‐respiratory depression, and multiorgan failure, can be observed in septic newborn infants. Finally, anti‐inflammatory cytokines (IL‐10, IL‐1ra), anti‐bacterial mediators (type I and II IFNs), or antibodies directed against inflammatory cytokines (TNF, IL‐6, IL‐12) protect neonatal mice and piglets from GBS sepsis (26–30, 98). Accordingly, the following sections explore whether neonatal immunity lacks regulation of the inflammatory response in the form of signal termination rather than signal induction.…”

Group B Streptococcal Infections

“…Elevation of IL-12 occurs 12 to 72 hours after challenge in the neonatal rat. Treatment with an IL-1 receptor antagonist improves cardiac output and mean arterial pressure, and increases duration of survival in piglets receiving a continuous infusion of GBS [297]. By contrast, IL-1, a known stimulator of cyclooxygenase and lipoxygenase pathways, seems to occupy a proximal position in the deleterious cytokine cascade of septic shock [296].…”