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A randomized, placebo-controlled trial of recombinant human granulocyte
colony-stimulating factor administration in newborn infants with presumed
sepsis: significant induction of peripheral and bone marrow neutrophilia
ER Gillan, RD Christensen, Y Suen, R Ellis, C van de Ven and MS Cairo
Children's Hospital of Orange County, CA.
Host defenses in the human neonate are limited by immaturity in phagocytic
immunity. Such limitations seem to predispose infected newborns to
neutropenia from an exhaustion of the neutrophil reserve. Among the
critical defects thus far identified in neonatal phagocytic immunity is a
specific reduction in the capacity of mononuclear cells to express
granulocyte colony-stimulating factor (G-CSF) after stimulation. However,
the safety, pharmacokinetics, and biological efficacy of administration of
recombinant human (rh)G-CSF to infected human newborns to compensate for
this deficiency is unknown. Forty-two newborn infants (26 to 40 weeks of
age) with presumed bacterial sepsis within the first 3 days of life were
randomized to receive either placebo or varying doses of rhG-CSF (1.0, 5.0
or 10.0 micrograms/kg every 24 hours [36 patients] or 5.0 or 10.0
micrograms/kg every 12 hours [6 patients]) on days 1, 2, and 3. Complete
blood counts with differential and platelet counts were obtained at hours
0, 2, 6, 24, 48, 72, and 96. Circulating G-CSF concentrations were
determined at hours 0, 2, 6, 12, 14, 16, 18, 24, and 36. Tibial bone marrow
aspirates were obtained after 72 hours for quantification of the bone
marrow neutrophil storage pool (NSP), neutrophil proliferative pool,
granulocyte progenitors, and pluripotent progenitors. Functional activation
of neutrophils (C3bi expression) was determined 24 hours after rhG-CSF or
placebo administration. Intravenous rhG-CSF was not associated with any
recognized acute toxicity. RhG-CSF induced a significant increase in the
blood neutrophil concentration 24 hours after the 5 and 10 micrograms/kg
doses every 12 and 24 hours and it was sustained as long as 96 hours. A
dose-dependent increase in the NSP was seen following rhG-CSF. Neutrophil
C3bi expression was significantly increased at 24 hours after 10
micrograms/kg every 24-hour dose of rhG- CSF. The half-life of rhG-CSF was
4.4 +/- 0.4 hours. The rhG-CSF was well tolerated at all gestational ages
treated. The rhG-CSF induced a significant increase in the peripheral blood
and bone marrow absolute neutrophil concentration and in C3bi expression.
Future clinical trials aimed at improving the outcome of overwhelming
bacterial sepsis and neutropenia in newborn infants might include the use
of rhG-CSF.
Volume 84,
Issue 5,
pp. 1427-1433,
09/01/1994
Copyright © 1994 by The American Society of Hematology
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