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Granulocyte colony-stimulating factor versus placebo in addition to
penicillin G in a randomized blinded study of gram-negative pneumonia
sepsis: analysis of survival and multisystem organ failure
WS Smith, GE Sumnicht, RW Sharpe, D Samuelson and FE Millard
Department of Internal Medicine (Hematology/Oncology Division), Naval
Medical Center, San Diego, CA 92134-5000, USA.
Sepsis is a common cause of morbidity and mortality. Neutrophils are the
major defense against bacterial invasion, and granulocyte colony-
stimulating factor (G-CSF) augments both neutrophil number and function. In
our study, 160 rabbits were inoculated transtracheally with 0.5 mL of a
solution containing 10(4) colony forming units per milliliter of
Pasteurella multocida. Twenty-four hours later, chest x- rays and
quantitative blood cultures demonstrated pneumonia and bacteremia. Therapy
was then begun with penicillin G and either recombinant human G-CSF
(rG-CSF; 5 to 8 micrograms/kg subcutaneously) or placebo every day for 5
days. Arterial blood gases and 23 other parameters of organ function were
performed before inoculation and serially thereafter. All rabbits underwent
histologic examination of organs at the time of septic death or when
sacrificed on day 6. A total of 149 rabbits survived long enough to
initiate therapy. A significant increase in leukocytes by day 4 was found
in the rG-CSF-treated group. There was a trend towards improved survival in
the rG-CSF group (77% v 67%; P = .13, n = 149). Analysis of pretreatment
variables revealed sepsis-induced leukopenia (< or = 2,800/microL) as
the only predictor of significantly improved survival with rG-CSF treatment
(57% v 39%; P = .04, n = 73). The majority of the survival benefit occurred
within the first 24 hours of treatment. This was before the time that a
significant difference in mean white blood cell (WBC) count was observed
between the study groups, making intravascular leukocytosis an unlikely
explanation for the survival advantage in the rG-CSF group. No significant
difference in laboratory variables reflecting organ function was
demonstrated between the groups. Histologic grading of inflammation (0,
normal, to 6, necrosis) in seven organs revealed that the surviving rabbits
had mild but statistically significant increased inflammation in the liver,
spleen, and noninoculated lung in the rG-CSF versus placebo groups (liver:
2.6 v 1.5, P < or = .0001; spleen: 3.2 v 2.3, P < or = .0001; and
noninoculated lung: 2.9 v 2.5, P = .04). Administration of rG-CSF, in
addition to penicillin G, in immune competent rabbits with gram-negative
sepsis complicated by leukopenia significantly improved survival over
antibiotics alone. The administration of rG-CSF in early sepsis for a short
therapeutic duration was not associated with any clinically evident
toxicity. Clinical trials using rG-CSF in septic patients with leukopenia
are indicated.
Volume 86,
Issue 4,
pp. 1301-1309,
08/15/1995
Copyright © 1995 by The American Society of Hematology
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