A randomized, placebo-controlled trial of G-CSF administration to neonates with early-onset sepsis and neutropenia

Abstract

Our laboratory previously reported diminished granulocyte colony-stimulating factor (G-CSF) production in vitro and in vivo by human neonates and normal responsiveness of neonatal hematopoietic progenitors to recombinant G-CSF. We sought to determine whether G-CSF administration would enhance neutrophil production and recovery from illness in neonates with early-onset bacterial sepsis and neutropenia. Participants were < 3 days old, neutropenic by Manroe criteria, had an 1/T ratio of > 0.5, required ventilatory support, and were being treated for suspected sepsis. Infants were randomized in double-blinded fashion to receive G-CSF (10 μg/kg) or placebo IV daily for three days. CBC's, cytokine levels, and clinical status were monitored. Gestational age, weight, gender, and culture/antigen positivity were similar in G-CSF- (n=10) and placebo-treated infants (n=10). Neutrophil counts increased fourfold in G-CSF-treated (p<0.05 vs baseline) and twofold in placebo-treated infants (N.S.) by 24 hours. Endogenous G-CSF concentration in plasma was 3889±2253 (X± s.d.) at enrollment, however, three of eight ELBW infants (5 26 wk GA) exhibited low levels of G-CSF despite significant neutropenia. While the severity of illness was greater in G-CSF-treated than placebo-treated infants at entry, 19±11 vs 13±7 (X±s.d.), as determined by Score for Acute Neonatal Physiology (SNAP), the rate of recovery by serial SNAP determinations was not significantly different between groups. Mortality was 20% in the G-CSF-treated vs 30% in placebo-treated infants. All four ELBW infants receiving G-CSF survived vs two of four placebo-treated infants. Morbidity associated with prematurity was higher in the G-CSF- than in the placebo-treated cohort: IVH (grades m & IV) 2 vs 1, BPD 6 vs 3, NEC 0 vs 1, ROP 5 vs 1. No acute toxicity was observed. In summary G-CSF shortened the duration of neutropenia, but it did not alter the rate of recovery from acute infection. A multicenter trial will be required to determine the efficacy of G-CSF in treatment of neonates with sepsis and neutropenia.