Treatment with a platelet-activating factor receptor antagonist improves hemodynamics and reduces epinephrine requirements, in a lethal rodent model of anaphylactic shock.

Abstract

In some cases, anaphylactic shock (AS) is still lethal, despite rapid use of epinephrine. High doses of epinephrine are associated with severe complications. Platelet-activating factor (PAF) is secreted in massive amounts during AS, and a high plasma level is correlated with increased AS severity. To assess the effect of ABT-491, a PAF-receptor antagonist and possible adjunct treatment, alone or in combination with epinephrine during AS. AS was induced by intravenous injection of 1mg ovalbumin into ovalbumin-sensitized rats. Rats were then randomly assigned to 5 groups (n=10 per group): SHAM (vehicle only), SHOCK (no treatment), ABT (ABT-491 1mg/kg), EPI (epinephrine 5µg as a bolus then 10µgkg-1 min-1 by continuous infusion, followed by a reducing protocol) and EPI-ABT (both treatments). Ovalbumin injection resulted in a severe decrease in mean arterial pressure, left ventricular inotropy (max dP/dt) and left ventricular shortening fraction (LVSF). All rats from the ABT group survived until the end of the experiment. ABT-491 prevented the LVSF decrease observed in the SHOCK group (at T15: ABT 50%±11% vs SHOCK 36%±9%, P=.01), significantly reduced the dose of epinephrine needed to treat anaphylactic shock (EPI-ABT 314±67µg/kg vs EPI 475±69µg/kg, P<.001) and reduced the time to restore basal MAP (ABT 23±7minutes vs EPI-ABT 13±5minutes, P<.01). AS was characterized by early cardiac dysfunction in our model. Treatment with ABT-491 allowed survival until the end of the experiment and reduced cardiac dysfunction. Use of the PAF-R antagonist had a synergistic effect with epinephrine and allowed a significant reduction in epinephrine consumption. Use of PAF-R antagonists during AS could reduce epinephrine-related complications and improve the treatment of epinephrine refractory cases.