Anti-ovine interleukin-1beta monoclonal antibody immunotherapy in an ovine model of gram-negative septic shock.
OBJECTIVE
To investigate the efficacy of an anti-ovine interleukin-1beta monoclonal antibody to ameliorate pathophysiological derangements and improve survival in an ovine model of gram-negative septic shock.


METHODS
Prospective, placebo-controlled, interventional study (24-hr study period).


METHODS
University hospital animal research laboratory.


METHODS
Ten awake, mature female sheep.


METHODS
Seven milligrams per kilogram of intravenous anti-ovine interleukin-1beta immunoglobin G1 monoclonal antibody (anti-interleukin-1beta group, n = 5) or equivalent amount of protein (5% human albumin; control group, n = 5) was infused over 1 hr (time-zero minus 1 hr to time-zero) and followed by an intravenous LD100 live Escherichia coli infusion (time-zero to time-zero plus 1 hr). Normal saline, maintenance and boluses to maintain baseline filling pressures, and gentamicin, 3 mg/kg intravenous, at time-zero plus 2 and time-zero plus 13 hrs.


RESULTS
Hemodynamic and oxygen transport indexes as well as hematological, biochemical, cytokine (interleukin-1beta, tumor necrosis factor-alpha), and endotoxin measurements were performed at baseline (time-zero minus 1 hr), on completion of the monoclonal antibody/placebo (time-zero) and E. coli (time-zero plus 1 hr) infusions, and at multiple time points thereafter (time-zero plus 1.5 hrs to time-zero plus 24 hrs). Baseline data were not different between the treatment groups. From time-zero plus 1.5 hrs onward, in the anti-interleukin-1beta group, there was a sustained increase in mean arterial pressure, decreased peripheral vasodilation, and an attenuated metabolic acidosis, relative to the control group (p < or = .01, repeated-measures analysis of variance). Predicted percentage increases in mean arterial pressure and systemic vascular resistance index relative to the control group were 35% and 40%, respectively. Resuscitation fluid requirements were also decreased: anti-interleukin-1beta group, 4.1 +/- 2.9 mL x kg(-1) x hr(-1); control group, 10.6 +/- 1.8 mL x kg(-1) x hr(-1) (p < or = .01, Student's t-test). Survival was not different (anti-interleukin-1beta group, 40%; control group, 0%; p > .01, log-rank test).


CONCLUSIONS
Adjunctive therapy with anti-ovine interleukin-1beta monoclonal antibody in ovine gram-negative septic shock was associated with improved hemodynamic performance. However, the beneficial effects were incomplete and survival was not significantly improved.
Peake
Sandra L
SL
Transplant Immunology Laboratory, Queen Elizabeth Hospital, Woodville, South Australia, Australia. sandra.peake@nwahs.sa.gov.au
Pierides
John
J
Leppard
Phillip I
PI
Russ
Graeme R
GR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001794:Blood Pressure / Q000502:physiology; D016207:Cytokines / Q000032:analysis; D004927:Escherichia coli Infections / Q000628:therapy; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000503:physiopathology / Q000628:therapy*; D007375:Interleukin-1 / Q000276:immunology*; D011446:Prospective Studies; D012756:Sheep; D012772:Shock, Septic / Q000503:physiopathology / Q000628:therapy*; D014655:Vascular Resistance; D014664:Vasodilation / Q000502:physiology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007375:Interleukin-1