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Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

ABSTRACT: BACKGROUND:Although damage control resuscitation (DCR) is routinely performed for short durations, prolonged DCR may be required in military conflicts as a component of prolonged field care. Valproic acid (VPA) has been shown to have beneficial properties in lethal hemorrhage/trauma models. We sought to investigate whether the addition of a single dose of VPA to a 72-hour prolonged DCR protocol would improve clinical outcomes. METHODS:Fifteen Yorkshire swine (40-45 kg) were subjected to lethal (50% estimated total blood volume) hemorrhagic shock (HS) and randomized to three groups: (1) HS, (2) HS-DCR, (3) HS-DCR-VPA (150 mg/kg over 3 hours) (n = 5/cohort). In groups assigned to receive DCR, Tactical Combat Casualty Care guidelines were applied (1 hour into the shock period), targeting a systolic blood pressure of 80 mm Hg. At 72 hours, surviving animals were given transfusion of packed red blood cells, simulating evacuation to higher echelons of care. Survival rates, physiologic parameters, resuscitative fluid requirements, and laboratory profiles were used to compare the clinical outcomes. RESULTS:This model was 100% lethal in the untreated animals. DCR improved survival to 20%, although this was not statistically significant. The addition of VPA to DCR significantly improved survival to 80% (p < 0.01). The VPA-treated animals also had significantly (p < 0.05) higher systolic blood pressures, lower fluid resuscitation requirements, higher hemoglobin levels, and lower creatinine and potassium levels. CONCLUSION:VPA administration improves survival, decreases resuscitation requirements, and improves hemodynamic and laboratory parameters when added to prolonged DCR in a lethal hemorrhage model.

SUBMITTER: Williams AM

PROVIDER: S-EPMC6660397 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

Williams Aaron M AM Bhatti Umar F UF Biesterveld Ben E BE Graham Nathan J NJ Chtraklin Kiril K Zhou Jing J Dennahy Isabel S IS Kathawate Ranganath G RG Vercruysse Claire A CA Russo Rachel M RM Li Yongqing Y Alam Hasan B HB

The journal of trauma and acute care surgery 20190801 2

<h4>Background</h4>Although damage control resuscitation (DCR) is routinely performed for short durations, prolonged DCR may be required in military conflicts as a component of prolonged field care. Valproic acid (VPA) has been shown to have beneficial properties in lethal hemorrhage/trauma models. We sought to investigate whether the addition of a single dose of VPA to a 72-hour prolonged DCR protocol would improve clinical outcomes.<h4>Methods</h4>Fifteen Yorkshire swine (40-45 kg) were subjec ...[more]

PMID: 31206419

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Project description:BackgroundDamage-control resuscitation (DCR) improves survival in severely bleeding patients. However, deviating from balanced transfusion ratios during a resuscitation may limit this benefit. We hypothesized that maintaining a balanced resuscitation during DCR is independently associated with improved survival.MethodsThis was a secondary analysis of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Patients receiving >3 U of packed red blood cells (PRBCs) during any 1-hour period over the first 6 hours and surviving beyond 30 minutes were included. Linear regression assessed the effect of percent time in a high-ratio range on 24-hour survival. We identified an optimal ratio and percent of time above the target ratio threshold by Youden's index. We compared patients with a 6-hour ratio above the target and above the percent time threshold (on-target) with all others (off-target). Kaplan-Meier analysis assessed the combined effect of blood product ratio and percent time over the target ratio on 24-hour and 30-day survival. Multivariable logistic regression identified factors independently associated with 24-hour and 30-day survival.ResultsOf 1,245 PROMMTT patients, 524 met the inclusion criteria. Optimal targets were plasma/PRBC and platelet/PRBC of 0.75 (3:4) and ≥40% time spent over this threshold. For plasma/PRBC, on-target (n = 213) versus off-target (n = 311) patients were younger (median, 31 years; interquartile range, [22-50] vs. 40 [25-54]; p = 0.002) with similar injury burdens and presenting physiology. Similar patterns were observed for platelet/PRBC on-target (n = 116) and off-target (n = 408) patients. After adjusting for differences, on-target plasma/PRBC patients had significantly improved 24-hour (odds ratio, 2.25; 95% confidence interval, 1.20-4.23) and 30-day (odds ratio, 1.97; 95% confidence interval, 1.14-3.41) survival, while on-target platelet/PRBC patients did not.ConclusionMaintaining a high ratio of plasma/PRBC during DCR is independently associated with improved survival. Performance improvement efforts and prospective studies should capture time spent in a high-ratio range.Level of evidenceEpidemiologic/prognostic study, level II; Therapeutic, level IV.

Project description:BackgroundDespite the benefits of extracorporeal cardiopulmonary resuscitation (ECPR) in cohorts of selected patients with cardiac arrest (CA), extracorporeal membrane oxygenation (ECMO) includes an artificial oxygenation membrane and circuits that contact the circulating blood and induce excessive oxidative stress and inflammatory responses, resulting in coagulopathy and endothelial cell damage. There is currently no pharmacological treatment that has been proven to improve outcomes after CA/ECPR. We aimed to test the hypothesis that administration of hydrogen gas (H2) combined with ECPR could improve outcomes after CA/ECPR in rats.MethodsRats were subjected to 20 min of asphyxial CA and were resuscitated by ECPR. Mechanical ventilation (MV) was initiated at the beginning of ECPR. Animals were randomly assigned to the placebo or H2 gas treatment groups. The supplement gas was administered with O2 through the ECMO membrane and MV. Survival time, electroencephalography (EEG), brain functional status, and brain tissue oxygenation were measured. Changes in the plasma levels of syndecan-1 (a marker of endothelial damage), multiple cytokines, chemokines, and metabolites were also evaluated.ResultsThe survival rate at 4 h was 77.8% (7 out of 9) in the H2 group and 22.2% (2 out of 9) in the placebo group. The Kaplan-Meier analysis showed that H2 significantly improved the 4 h-survival endpoint (log-rank P = 0.025 vs. placebo). All animals treated with H2 regained EEG activity, whereas no recovery was observed in animals treated with placebo. H2 therapy markedly improved intra-resuscitation brain tissue oxygenation and prevented an increase in central venous pressure after ECPR. H2 attenuated an increase in syndecan-1 levels and enhanced an increase in interleukin-10, vascular endothelial growth factor, and leptin levels after ECPR. Metabolomics analysis identified significant changes at 2 h after CA/ECPR between the two groups, particularly in D-glutamine and D-glutamate metabolism.ConclusionsH2 therapy improved mortality in highly lethal CA rats rescued by ECPR and helped recover brain electrical activity. The underlying mechanism might be linked to protective effects against endothelial damage. Further studies are warranted to elucidate the mechanisms responsible for the beneficial effects of H2 on ischemia-reperfusion injury in critically ill patients who require ECMO support.

Project description:BackgroundUp to 40% of combat casualties with a truncal injury die of massive hemorrhage before reaching a surgeon. This hemorrhage can be prevented with damage control resuscitation (DCR) methods, which are focused on replacing shed whole blood by empirically transfusing blood components in a 1:1:1:1 ratio of platelets:fresh frozen plasma:erythrocytes:cryoprecipitate (PLT:FFP:RBC:CRYO). Measurement of hemostatic function with rotational thromboelastometry (ROTEM) may allow optimization of the type and quantity of blood products transfused. Our hypothesis was that incorporating ROTEM measurements into DCR methods at the US Role 3 hospital at Bagram Airfield, Afghanistan would change the standard transfusion ratios of 1:1:1:1 to a product mix tailored specifically for the combat causality.MethodsThis retrospective study collected data from the Department of Defense Trauma Registry to compare transfusion practices and outcomes before and after ROTEM deployment to Bagram Airfield. Over the course of six months, 134 trauma patients received a transfusion (pre-ROTEM) and 85 received a transfusion and underwent ROTEM testing (post-ROTEM). Trauma teams received instruction on ROTEM use and interpretation, with no provision of a specific transfusion protocol, to supplement their clinical judgment and practice.ResultsThe pre and post groups were not significantly different in terms of mortality, massive transfusion protocol activation, mean injury severity score, or coagulation measurements. Despite the difference in size, each group received an equal total number of transfusions. However, the post-ROTEM group received a significant increase in PLT and CRYO transfusions ratios, 4× and 2×, respectively.ConclusionThe introduction of ROTEM significantly improved adherence to DCR practices. The transfusion differences suggest that aggressive DCR without thromboelastometry data may result in reduced hemostatic support and underestimate the need for PLT and CRYO. Thus, future controlled trials should include ROTEM-guided coagulation management in trauma resuscitation.Level of evidenceTherapeutic, level IV.

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Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

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Valproic acid improves survival and decreases resuscitation requirements in a swine model of prolonged damage control resuscitation.

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