Screening of potential small volume resuscitation products using a severe hemorrhage sedated swine model

Small volumes of resuscitation products to sustain survival until definitive care are desired in extreme environments due to limited resources. A severe controlled hemorrhage model in sedated, sexually mature miniature swine has been developed to evaluate these products. Valproic Acid (VPA) and Pentoxifylline (PTX) have been suggested as potential products for small volume resuscitation following hemorrhage predominately in anesthetized small animal models. We evaluated the survival time of VPA and PTX in the swine model.

Fifteen male miniature swine weighing 41.1 ± 2.9 kg were sedated and hemorrhaged 60% of estimated blood volume over 1 hr and treated with one of the following: 1) VPA at 400 mg/kg in a volume of 1.33 ml/kg over 2 min (n=4); 2) VPA at 300 mg/kg in a volume of 2 ml/kg over 30 min (n=3); 3) PTX at 50 mg/kg in a volume of 2 ml/kg over 2 min (n=4); 4) saline vehicle at 2 ml/kg over 2 min (n=4). Survival times were compared to non-resuscitated historic controls (n=16). Survival was determined from the end of hemorrhage/initiation of treatment.

Median (95% CI) survival times were: Control 55.7 (17.5 - 86) min; VPA (400 mg/kg) 6 (4 - 8) min; VPA (300 mg/kg) 17.5 (12 - 24.5) min; PTX 60.8 (21 - 75) min; and vehicle 92 (15 - 180) min. No treatment increased survival time compared to controls and there were no significant differences in percent survival among groups.

In this sedated severe hemorrhage model VPA and PTX were unacceptable as small volume resuscitation products at the concentrations and delivery rates used because of early deaths. Considering that these drugs are FDA approved for other indications at lower doses the present data suggest that further investigation of mechanisms involved are warranted.