A Novel Swine Model for Evaluation of Potential Intravascular Hemostatic Agents

摘要

Becauseuncontrolledhemorrhageisaleadingcauseofbattlefieldmortality,findinganintravenoustreatmentthatcouldassistendogenousclottingmechanismsisamajormissionformilitaryresearchers.Evaluationofpotentialintravenoushemostaticagentsrequiresbothinvitroandinvivotests.Forinvivoevaluation,wehavedevelopedanovelswinemodelinwhich1)bleedingtimes(BT)andcoagulationfunctioncouldbeascertainedaftermultipledosesofhemostaticdrugadministrationand2)asubsequentexsanguinatinginjurycouldbeperformedinthesameanimal,yieldingscreeninginformationregardingtheeffectsofdrugpretreatmentonbloodlossandsurvival.TransectionofsmallmesentericarteriesandveinsallowedformultipleandreproducibleBTmeasuresthatcorrelatedwithcoagulationfunction.Subsequentexcisionofdefinedareasoftheliverproducedbleedingpredominantlyfromsmallvessels(diameter,lessthan2mm)andparenchymawhileresultingin62%mortalitywithouttheuseofeitherheparinizationoraggressivefluidinfusion.Thisswinemodelallowsformultiple,repeatableBTmeasuresinthesameanimalinexperimentsalreadyinvolvinglaparotomy.SuchamodeliswellsuitedforterminalstudiestotesteffectsofmultipledosesofthesamedrugormultipledrugsonBTandallowsformultiple,easilyvisualizedmeasuresthatpermitenhancedrepeatability.Theliverinjuryprovidesfornumeroussmallvessellesionsthatcouldbeamenabletoclosurebycoagulation.Therefore,drugsormechanismsthatenhancecoagulationandconcomitantlydecreasebloodlossandincreasesurvivaltimemaybeaccuratelyevaluatedinthisnewmodel.