[show abstract][hide abstract] ABSTRACT: Trauma-associated coagulopathy carries an extremely high mortality. Fresh-frozen plasma (FFP) is the mainstay of treatment; however, its availability in the battlefield is limited. We have already shown that lyophilized, freeze-dried plasma (FDP) reconstituted in its original volume can reverse trauma-associated coagulopathy. To enhance the logistical advantage (lower volume and weight), we developed and tested a hyperoncotic, hyperosmotic spray-dried plasma (SDP) product in a multiple injuries/hemorrhagic shock swine model.
Plasma separated from fresh porcine blood was stored as FFP or preserved as FDP and SDP. In in vitro testing, SDP was reconstituted in distilled water that was either equal (1 × SDP) or one-third (3 × SDP) the original volume of FFP. Analysis included measurements of prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen levels, and activity of selected clotting factors. In in vivo testing, swine were subjected to multiple injuries (femur fracture and grade V liver injury) and hemorrhagic shock (60% arterial hemorrhage, with the "lethal triad" of acidosis, coagulopathy, and hypothermia) and were treated with FFP, FDP, or 3 × SDP (n=4-5/group). Coagulation profiles (PT, PTT, and thromboelastography) were measured at baseline, post-shock, post-crystalloid, treatment (M0), and during 4 hours of monitoring (M1-4).
In vitro testing revealed that clotting factors were preserved after spray drying. The coagulation profiles of FFP and 1 × SDP were similar, with 3 × SDP showing a prolonged PT/PTT. Multiple injuries/hemorrhagic shock produced significant coagulopathy, and 3 × SDP infusion was as effective as FFP and FDP in reversing it.
Plasma can be spray dried and reconstituted to one-third of its original volume without compromising the coagulation properties in vivo. This shelf-stable, low-volume, hyperoncotic, hyperosmotic plasma is a logistically attractive option for the treatment of trauma-associated coagulopathy in austere environments, such as a battlefield.
The Journal of trauma 03/2011; 70(3):664-71. · 2.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have previously demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, and spray-dried plasma (SDP) improve early survival after lethal hemorrhage and polytrauma, but their effect on long-term survival and organ function remains untested.
Yorkshire swine (n=27; 6-8/group) underwent a protocol simulating different phases of trauma care: (1) prehospital-rib fracture, soft-tissue injury, hemorrhage (50% blood volume), 30 minutes of shock, and infusion of 0.9% saline (3× shed blood); (2) early hospital/treatment-grade IV liver (partial amputation of the median lobe) and grade V splenic (transection of spleen into three pieces) injuries to simulate rupture of contained hematomas, followed by 30 minutes of uncontrolled hemorrhage. Animals were treated with (a) Hextend (6% hetastarch), (b) fresh whole blood (FWB), (c) SDP, and (d) VPA (300 mg/kg) plus Hextend. VPA was given during the prehospital phase, and the volumes of Hextend, FWB and SDP (reconstituted in water) matched shed blood; (3) repair/resuscitation-liver injury was controlled by suture control of the transected edge, and splenic injury was treated by partial splenectomy; 1 hour after repair of injuries, surviving animals were fully resuscitated with packed red blood cells; and (4) monitoring-survival was monitored for 7 days (primary endpoint), and blood samples were drawn serially to measure organ function.
Only 25% of the Hextend-treated animals survived. Addition of VPA improved survival to only 50% (p=0.28), whereas treatment with SDP and FWB increased survival significantly to 83% and 100%, respectively (p<0.05). Surviving animals showed no long-term organ dysfunction, postoperative hemorrhage, and delayed complications.
In a clinically relevant lethal polytrauma model, administration of SDP significantly improves survival without any long-term organ dysfunction or complications.
The Journal of trauma 03/2011; 70(3):636-45. · 2.35 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hemorrhage is the leading cause of preventable trauma-related deaths, and histone deacetylase inhibitors (HDACI) such as valproic acid (VPA) can improve survival following lethal hemorrhage. HDACI acetylate proteins, and acetylation regulates many cellular functions. Here we have investigated the effects of VPA treatment on extracellular signal-regulated kinase 1/2 (ERK) activation, as ERK is well known to modulate cell death, gene expression, and inflammation.
Anesthetized Wistar-Kyoto rats were subjected to lethal (60%) blood loss, and then randomized (n = 5-6/group) to (1) VPA 300 mg/kg or (2) vehicle control. Survival was monitored for 24 h. A separate group of rats were subjected to sublethal (40%) hemorrhage and were treated with VPA or vehicle. Rats were sacrificed at 1, 4, and 20 h, and lung tissue was assessed for the degree of acetylation of histone 3, and activation (phosphorylation) of ERK. Sham animals served as normal controls.
Sixty percent hemorrhage resulted in severe shock. Only 17% of the vehicle-treated animals survived (most died within 1 h), whereas 80% of the VPA-treated animals survived (P < 0.05). Hemorrhage resulted in a significant increase in phosphorylated ERK (activated form) compared with sham at the 1 and 4 h time points, but not at the 20 h time point. VPA treatment significantly attenuated these changes, while increasing histone protein acetylation.
VPA treatment significantly improves survival following lethal hemorrhagic shock. Hemorrhage induces ERK activation, which is significantly attenuated by VPA treatment. This may represent one mechanism through which VPA promotes survival in otherwise lethal hemorrhagic shock.
Journal of Surgical Research 09/2010; 163(1):118-26. · 2.02 Impact Factor