Objective:

We have recently shown that administration of human inter-α inhibitor proteins (IαIp) very early after the onset of sepsis maintains cardiovascular stability and reduced mortality. However, it remains unknown whether injection of IαIp at later time points of sepsis has any beneficial effects. We therefore hypothesized that IαIp and its active component bikunin are reduced in sepsis and that the delayed administration of IαIp also improves survival rate.

Design:

Prospective, controlled, and randomized animal study.

Setting:

A research institute laboratory.

Subjects:

Male adult Sprague-Dawley rats.

Interventions:

Rats were subjected either to polymicrobial sepsis by cecal ligation and puncture (CLP) or to sham operation followed by the administration of normal saline solution (ie, fluid resuscitation).

Measurements and Main Results:

Bikunin gene expression in the liver was measured by reverse transcription polymerase chain reaction. Plasma concentrations of IαIp were determined by Western blot at 5 and 20 hrs after CLP. IαIp clearance was assessed by injecting radioactive IαIp at 12 hrs post-CLP, and the half-life was determined. In addition, IαIp (30 mg/kg of body weight) or vehicle was administered at 1, 5, or 10 hrs (single treatment) or at both 10 and 20 hrs (double treatment) post-CLP. The necrotic cecum was excised at 20 hrs post-CLP, and 10-day survival was recorded. The results indicate that bikunin gene expression decreased significantly at 20 hrs post-CLP. Moreover, IαIp concentrations decreased significantly at 5 and 20 hrs post-CLP, and its half-life increased from 5.6±0.3 hrs to 11.8±2.7 hrs (p<. 05), suggesting down-regulation of IαIp in sepsis despite the decreased clearance. Administration of IαIp at 1 hr post-CLP improved the survival rate from 50% to 92%(p<. 05), whereas there was no significant improvement when IαIp was administrated at 5 or 10 hrs post-CLP. However, double injection of IαIp at 10 and 20 hrs post-CLP (ie, severe sepsis) increased the survival rate from 44% to 81%(p<. 05).

Conclusion:

Since delayed but repeated administration of human IαIp improves survival after CLP, this compound appears to be a useful agent for the treatment of severe sepsis.