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1.
Blood Adv ; 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36375044

RESUMO

Platelets stored at 4oC exhibit equivalent or superior hemostatic function compared to 22oC platelets (PLTs), but have shorter circulation times and a decreased ability to modulate vascular permeability. These differences may be due to morphological changes and storage induced activation. Using a proteomics-based approach, we found that 4oC stored PLTs express decreased α-tubulin, a key PLT structural protein. PLT activation is characterized by α-tubulin de-acetylation, which is regulated by histone deacetylase-6 (HDAC-6). We hypothesized that inhibition of HDAC-6 in stored PLTs will improve their ability to regulate vascular permeability through reduced activation and α-tubulin deacetylation. In an in vivo model of vascular permeability, treatment of 4oC PLTs with the HDAC-6 inhibitor, tubacin, enhanced the vasculo-protective properties of untreated 4oC PLTs. 4oC PLT circulation, however, was unchanged by tubacin treatment, suggesting that circulation time may not be a critical factor in determining the vasculo-protective effects of PLTs. Assessing the factor content of stored PLTs revealed that angiopoietin-1 (Ang-1) increased in 4oC PLTs over time, which was further enhanced by tubacin treatment. In addition, angiopoietin-2 (Ang-2), an inducer of vascular leak and antagonist of Ang-1, inhibited PLT barrier protection, suggesting involvement of the Tie-2 pathway. This study demonstrates that HDAC-6 inhibition with tubacin attenuates the diminished vasculo-protective properties of 4oC PLTs, and these properties may be independent of PLT circulation time.

2.
Front Immunol ; 13: 991048, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36341368

RESUMO

Complementopathy, endotheliopathy, and coagulopathy following a traumatic injury are key pathophysiological mechanisms potentially associated with multiple-organ failure (MOF) and mortality. However, the heterogeneity in the responses of complementopathy, endotheliopathy, and coagulopathy to trauma, the nature and extent of their interplay, and their relationship to clinical outcomes remain unclear. Fifty-four poly-trauma patients were enrolled and divided into three subgroups based on their ISS. Biomarkers in blood plasma reflecting complement activation, endothelial damage, and coagulopathy were measured starting from admission to the emergency department and at 3, 6, 12, 24, and 120 hours after admission. Comparative analyses showed that severely injured patients (ISS>24) were associated with longer days on mechanical ventilation, in the intensive care unit and hospital stays, and a higher incidence of hyperglycemia, bacteremia, respiratory failure and pneumonia compared to mildly (ISS<16) or moderately (ISS=16-24) injured patients. In this trauma cohort, complement was activated early, primarily through the alternative complement pathway. As measured in blood plasma, severely injured patients had significantly higher levels of complement activation products (C3a, C5a, C5b-9, and Bb), endothelial damage markers (syndecan-1, sTM, sVEGFr1, and hcDNA), and fibrinolytic markers (D-dimer and LY30) compared to less severely injured patients. Severely injured patients also had significantly lower thrombin generation (ETP and peak) and lower levels of coagulation factors (I, V, VIII, IX, protein C) than less severely injured patients. Complement activation correlated with endothelial damage and hypocoagulopathy. Logistic regression analyses revealed that Bb >1.57 µg/ml, syndecan-1 >66.6 ng/ml or D-dimer >6 mg/L at admission were associated with a higher risk of MOF/mortality. After adjusting for ISS, each increase of the triadic score defined above (Bb>1.57 µg/ml/Syndecan-1>66.6 ng/ml/D-dimer>6.0mg/L) was associated with a 6-fold higher in the odds ratio of MOF/death [OR: 6.83 (1.04-44.96, P=0.046], and a 4-fold greater in the odds of infectious complications [OR: 4.12 (1.04-16.36), P=0.044]. These findings provide preliminary evidence of two human injury response endotypes (traumatized triad and non-traumatized triad) that align with clinical trajectory, suggesting a potential endotype defined by a high triadic score. Patients with this endotype may be considered for timely intervention to create a pro-survival/organ-protective phenotype and improve clinical outcomes.


Assuntos
Transtornos da Coagulação Sanguínea , Traumatismo Múltiplo , Humanos , Sindecana-1 , Escala de Gravidade do Ferimento , Estudos Prospectivos , Transtornos da Coagulação Sanguínea/etiologia , Biomarcadores , Traumatismo Múltiplo/complicações , Insuficiência de Múltiplos Órgãos
3.
Trauma Surg Acute Care Open ; 7(1): e000927, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36117727

RESUMO

Objectives: Early complementopathy and coagulopathy are shown often after trauma. However, the prevalence of any interplay between complement cascade (ComC) and coagulation cascade (CoaC) after trauma remains unclear. This study intended to explore whether complement-coagulation crosstalk exists, which may provide a reliable guide to clinical implications in trauma patients. Methods: This single-center cohort study of trauma patients enrolled 100 patients along with 20 healthy volunteers. Blood samples from patients were collected at admission, 45, 90, 135 minutes, and 18 hours after admission. Demographic characteristics were recorded, blood levels of ComC and CoaC factors, and inflammatory cytokines were measured by ELISA, clot-based assays, or luminex multiplex assay, and partial thromboplastin (PT) and partial thromboplastin time (PTT) were assessed using a Behring blood coagulation system. Results: Compared with the healthy controls, plasma levels of complement factors (C5b-9 and Bb) and 11 tested inflammatory cytokines increased in moderately and severely injured patients as early as 45 minutes after admission and sustained higher levels up to 18 hours after admission. C5b-9 correlated positively to patients' hospital stay. In parallel, the consumption of coagulation factors I, II, X, and XIII was shown throughout the first 18 hours after admission in moderately and severely injured patients, whereas PT, PTT, D-dimer, factor VII, and factor VIII values significantly increased from the admission to 135 minutes in moderately and severely injured patients. Along with an inverse correlation between plasma Bb, factors I and II, a positive correlation between C5b-9, Bb, D-dimer, PT, and PTT was evident. Conclusions: This study demonstrates trauma-induced early activation of plasma cascades including ComC, CoaC, and fibrinolytic cascade, and their correlation between plasma cascades in severe trauma patients. Our study suggests that the simultaneous modulation of plasma cascades might benefit clinical outcomes for trauma patients. Level of evidence: Prospective study, level III.

5.
Prehosp Emerg Care ; : 1-7, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36037100

RESUMO

BACKGROUND: The MARCH (Massive hemorrhage, Airway, Respirations, Circulation, and Hypothermia/Head injuries) algorithm taught to military medics includes interventions to prevent hypothermia. As possible sequelae from major trauma, hypothermia is associated with coagulopathy and lower survival. This paper sought to define hypothermia within our combat trauma population using an outcomes-based method, and determine clinical variables associated with hypothermia. METHODS: This is a secondary analysis of a previously described dataset from the Department of Defense Trauma Registry focused on casualties who received prehospital care. A receiver operating curve was constructed and Youden's index was used to define hypothermia within the predetermined population based on mortality risk. A multivariable regression model was used to identify associations. RESULTS: There were 23,243 encounters that met the inclusion criteria for this study with patients having received prehospital care and documentation of at least one emergency department temperature. An optimal threshold of 36.2° C was found to predict mortality; 3,159 casualties had temperatures below this threshold (14%). Survival to discharge was lower among casualties with hypothermia (91% versus 98%). Hypothermic casualties were less likely to undergo blanket application (38% versus 40%). However, they had higher proportions with Hypothermia Prevention and Management Kit application (11% versus 7%) and radiant warming (2% versus 1%). On multivariable regression modeling, none of the hypothermia interventions were associated with a decreased likelihood of hypothermia. Non-hypothermia interventions associated with hypothermia included prehospital intubation (OR 1.57, 95% CI 1.45-1.69) and blood product administration. CONCLUSIONS: Hypothermia, including a single recorded low temperature in the patient care record, was associated with worse outcomes in this combat trauma population. Prehospital intubation was most strongly associated with developing hypothermia. Prehospital warming interventions were not associated with a reduction in hypothermia risk. Our dataset suggests that current methods for prehospital warming are inadequate.

8.
J Trauma Acute Care Surg ; 93(2S Suppl 1): S12-S15, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35667094

RESUMO

BACKGROUND: Battlefield pain occurs in combat casualties who experience multiple severe injuries. The nature of battlefield scenarios requires a distinct approach to battlefield pain research. A battlefield pain summit was thus convened to identify shortcomings in the current understanding of battlefield pain management, review the current state of battlefield pain research, and shape the direction of future research. METHODS: On January 10 to 11, 2022, a hybrid in-person and virtual meeting hosted by the US Army Institute of Surgical Research defined research priorities for the Combat Casualty Care Research Program's Battlefield Pain research portfolio. Summit participants identified the following key focus areas under the umbrella of battlefield pain research: battlefield injury patterns; use of ketamine and nonopioid analgesics; analgesic delivery systems; the impact of analgesia on performance, cognition, and survival; training methods; battlefield regional anesthesia; and research models. Preliminary statements presented during the summit were refined and rank ordered through a Delphi process. RESULTS: Consensus was achieved on 7 statements addressing ideal analgesic properties, delivery systems, operational performance concerns, and pain training. Ketamine was identified as safe and effective for battlefield use, and further research into nonopioid analgesics represented a high priority. CONCLUSION: The 7 consensus statements that emerged from this battlefield pain summit serve as a template to define the near-term research priorities for military-specific battlefield pain research.


Assuntos
Analgésicos não Narcóticos , Ketamina , Medicina Militar , Analgésicos/uso terapêutico , Humanos , Ketamina/uso terapêutico , Medicina Militar/métodos , Dor/tratamento farmacológico , Manejo da Dor/métodos
10.
Transfusion ; 62 Suppl 1: S12-S21, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35730720

RESUMO

BACKGROUND: Mass casualty incidents (MCIs) create an immediate surge in blood product demand. We hypothesize local inventories in major U.S. cities would not meet this demand. STUDY DESIGN AND METHODS: A simulated blast in a large crowd estimated casualty numbers. Ideal resuscitation was defined as equal amounts of red blood cells (RBCs), plasma, platelets, and cryoprecipitate. Inventory was prospectively collected from six major U.S. cities at six time points between January and July 2019. City-wide blood inventories were classified as READY (>1 U/injured survivor), DEFICIENT (<10 U/severely injured survivor), or RISK (between READY and DEFICIENT), before and after resupply from local distribution centers (DC), and features of DEFICIENT cities were identified. RESULTS: The simulated blast resulted in 2218 injured survivors including 95 with severe injuries. Balanced resuscitation would require between 950 and 2218 units each RBC, plasma, platelets and cryoprecipitate. Inventories in 88 hospitals/health systems and 10 DCs were assessed. Of 36 city-wide surveys, RISK inventories included RBCs (n = 16; 44%), plasma (n = 24; 67%), platelets (n = 6; 17%), and cryoprecipitate (n = 22; 61%) while DEFICIENT inventories included platelets (n = 30; 83%) and cryoprecipitate (n = 12; 33%). Resupply shifted most RBC and plasma inventories to READY, but some platelet and cryoprecipitate inventories remained at RISK (n = 24; 67% and n = 12; 33%, respectively) or even DEFICIENT (n = 11; 31% and n = 6; 17%, respectively). Cities with DEFICIENT inventories were smaller (p <.001) with fewer blood products per trauma bed (p <.001). DISCUSSION: In this simulated blast event, blood product demand exceeded local supply in some major U.S. cities. Options for closing this gap should be explored to optimize resuscitation during MCIs.


Assuntos
Incidentes com Feridos em Massa , Ferimentos e Lesões , Cidades , Humanos , Plasma , Ressuscitação/métodos
11.
Transfusion ; 62 Suppl 1: S167-S176, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35748678

RESUMO

BACKGROUND: The United States Armed Services Blood Program (ASBP) faced complex blood supply challenges during two decades of military operations in the U.S. Central Command (CENTCOM) and through an adaptive, responsive, and agile system, gained valuable insights on blood product usage in combat casualty care. STUDY DESIGN AND METHODS: A retrospective review of blood product introduction and utilization trends was compiled from ASBP data collected during CENTCOM operations from 2014 through 2021. RESULTS: During the study period, several blood products were introduced to the CENTCOM area of operations including Low Titer O Whole Blood (LTOWB), Cold-Stored Platelets (CSP), Liquid Plasma (LP), and French Freeze Dried Plasma (FDP) manufactured from U.S. sourced donor plasma, all while expanding Walking Blood Bank capabilities. There was a gradual substitution of component therapy for whole blood; blood utilization peaked in 2017. Transfusion of Fresh Whole Blood (FWB) from Walking Blood Banks decreased as fully pre-tested LTOWB was supplied by the ASBP. LTOWB was initially supplied in citrate-phosphate-dextrose (CPD) anticoagulant (21-day shelf life) but was largely replaced with LTOWB in citrate-phosphate-dextrose-adenine (CPDA-1) anticoagulant (35-day shelf life) by 2019. Implementation of prehospital transfusion and expansion of surgical and resuscitation teams led to an increase in the number of sites receiving blood. DISCUSSION: ASBP introduced new products to its inventory in order to meet changing blood product demands driven by changes in the Joint Trauma System Clinical Practice Guidelines and operational demands. These products were adopted into clinical practice with a resultant evolution in transfusion strategies.


Assuntos
Ressuscitação , Ferimentos e Lesões , Anticoagulantes , Citratos , Glucose , Humanos , Fosfatos , Estados Unidos , Ferimentos e Lesões/terapia
13.
Transfusion ; 62 Suppl 1: S218-S223, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35748693

RESUMO

BACKGROUND: Hemorrhagic shock is a clinically challenging disease process with high mortality. When conventional blood products are unable to be administered, oxygen-carrying blood alternatives are sometimes utilized. The international experience with this scenario is limited. We aim to add to this body of literature. STUDY DESIGN AND METHODS: This is a case report of the administration of bovine hemoglobin-based oxygen-carrying red blood cell (RBC) substitute HBOC-201 (HemoPure®) to a patient with post-partum bleeding and hemorrhagic shock because the patient declined RBC transfusion. HBOC-201 was administered with consent under a one-time Emergency Investigational New Drug (eIND) approval from the Food and Drug Administration with appropriate notification of the Institutional Review Board. RESULTS: The patient was successfully resuscitated with HBOC-201 from hemorrhagic shock. She was weaned off of vasopressor support and extubated with the recovery of her baseline mental status within 4 h. However, approximately 36 h after this, the patient developed multi-organ system dysfunction, volume overload, right heart failure and ultimately expired early on post-partum day 4. DISCUSSION: Resuscitation from hemorrhagic shock with HBOC-201 as an RBC alternative is feasible, but significant challenges remain with the management of sequelae resulting from prolonged low-flow, ischemic states as well as the significant colloid pressure and volume overload experienced after massive transfusion with an acellular colloid oxygen carrier.


Assuntos
Substitutos Sanguíneos , Obstetrícia , Choque Hemorrágico , Substitutos Sanguíneos/uso terapêutico , Feminino , Hemoglobinas/uso terapêutico , Humanos , Oxigênio , Ressuscitação/métodos , Choque Hemorrágico/terapia
14.
Transfusion ; 62 Suppl 1: S139-S150, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35765921

RESUMO

BACKGROUND: Screening for the risk of thromboembolism (TE) due to tranexamic acid (TXA) in patients with severe traumatic injury has not been performed in randomized clinical trials. Our objective was to determine if TXA dose was independently-associated with thromboembolism. STUDY DESIGN AND METHODS: This is a secondary analysis of a single-center, double-blinded, randomized controlled trial comparing placebo to a 2-g or 4-g intravenous TXA bolus dose in trauma patients with severe injury. We used multivariable discrete-time Cox regression models to identify associations with risk for thromboembolic events within 30 days post-enrollment. Event curves were created using discrete-time Cox regression. RESULTS: There were 50 patients in the placebo group, 49 in the 2-g, and 50 in the 4-g TXA group. In adjusted analyses for thromboembolism, a 2-g dose of TXA had an hazard ratio (HR, 95% confidence interval [CI]) of 3.20 (1.12-9.11) (p = .029), and a 4-g dose of TXA had an HR (95% CI) of 5.33 (1.94-14.63) (p = .001). Event curves demonstrated a higher probability of thromboembolism for both doses of TXA compared to placebo. Other parameters independently associated with thromboembolism include time from injury to TXA administration, body mass index, and total blood products transfused. DISCUSSION: In patients with severe traumatic injury, there was a dose-dependent increase in the risk of at least one thromboembolic event with TXA. TXA should not be withheld, but thromboembolism screening should be considered for patients receiving a dose of at least 2-g TXA intravenously for traumatic hemorrhage.


Assuntos
Antifibrinolíticos , Tromboembolia , Ácido Tranexâmico , Antifibrinolíticos/uso terapêutico , Método Duplo-Cego , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Tromboembolia/etiologia , Ácido Tranexâmico/efeitos adversos
15.
J Trauma Acute Care Surg ; 93(2S Suppl 1): S128-S135, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35583983

RESUMO

BACKGROUND: Valproic acid (VPA) has been extensively used for treatment of anxiety and seizure. Recent studies have shown that VPA has cellular protective effects in preclinical models following severe hemorrhage. This study investigated the effects of VPA on coagulation and survival in pigs after traumatic hemorrhage and hypotensive resuscitation. METHODS: Following baseline measurements, femur fracture was performed in 20 anesthetized and instrumented pigs (41 ± 2 kg), followed by hemorrhage of 55% of the estimated blood volume and a 10-minute shock period. Pigs were then resuscitated for 30 minutes with normal saline (NS) alone (NS group, n = 10, 4 mL/kg) or VPA solution (VPA group, n = 10, 90 mg/kg, 2 mL/kg of 45 mg VPA/mL, plus 2 mL NS/kg). All pigs were then monitored for 2 hours or until death. Hemodynamics were recorded, and blood samples were taken for blood and coagulation analysis (Rotem) at baseline, after hemorrhage, resuscitation, and 2 hours or death. RESULTS: Femur fracture and hemorrhage caused similar reductions in mean arterial pressure and cardiac output, and increase in heart rate in both groups. Resuscitation with NS or VPA did not return these measurements to baseline. No differences were observed in hematocrit, pH, lactate, base excess, or total protein between the groups. Compared with NS, resuscitation with VPA decreased platelet counts and prolonged activated partial thromboplastin time, with no differences in fibrinogen levels, prothrombin time, or any of the Rotem measurements between the two groups. Neither survival rates (NS, 7 of 10 pigs; VPA, 7 of 10 pigs) nor survival times after resuscitation (NS, 97 ± 40 minutes; VPA, 98 ± 43 minutes) differed between the groups. CONCLUSION: Following traumatic hemorrhage and hypotensive resuscitation in pigs, VPA provides no benefit toward improving coagulation function or survival times.


Assuntos
Choque Hemorrágico , Animais , Coagulação Sanguínea , Modelos Animais de Doenças , Hemorragia/tratamento farmacológico , Ressuscitação , Choque Hemorrágico/tratamento farmacológico , Choque Hemorrágico/metabolismo , Suínos , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico
17.
Artif Organs ; 46(6): 1181-1191, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35289412

RESUMO

BACKGROUND: Consumption of platelets and coagulation factors during extracorporeal carbon dioxide removal (ECCO2 R) increases bleeding complications and associated mortality. Regional infusion of lactic acid enhances ECCO2 R by shifting the chemical equilibrium from bicarbonate to carbon dioxide. Our goal was to test if regional blood acidification during ECCO2 R inhibits platelet function and coagulation. METHODS: An ECCO2 R system containing a hemofilter circulated blood at 0.25 L/min in eight healthy ewes (Ovis aries) for 36 h. Three of the sheep received ECCO2 R with no recirculation compared to five sheep that received ECCO2 R plus 12 h of regional blood acidification via the hemofilter, placed upstream from the oxygenator, into which 4.4 M lactic acid was infused. Blood gases, platelet count and function, thromboelastography, coagulation-factor activity, and von Willebrand factor activity (vWF:Ag) were measured at baseline, at start of lactic acid infusion, and after 36 h of extracorporeal circulation. RESULTS: Twelve hours of regional acid infusion significantly inhibited platelet aggregation response to adenosine diphosphate; vWF; and platelet expression of P-selectin compared to control. It also significantly reduced consumption of fibrinogen and of coagulation factors V, VII, IX, compared to control. CONCLUSIONS: Regional acidification reduces platelet activation and vitamin-K-dependent coagulation-factor consumption during ECCO2 R. This is the first report of a simple method that may enhance effective anticoagulation for ECCO2 R.


Assuntos
Dióxido de Carbono , Fator de von Willebrand , Animais , Plaquetas , Circulação Extracorpórea , Feminino , Concentração de Íons de Hidrogênio , Ácido Láctico/farmacologia , Ovinos
20.
Surgery ; 171(2): 518-525, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34253322

RESUMO

BACKGROUND: Death from uncontrolled hemorrhage occurs rapidly, particularly among combat casualties. The US military has used warm fresh whole blood during combat operations owing to clinical and operational exigencies, but published outcomes data are limited. We compared early mortality between casualties who received warm fresh whole blood versus no warm fresh whole blood. METHODS: Casualties injured in Afghanistan from 2008 to 2014 who received ≥2 red blood cell containing units were reviewed using records from the Joint Trauma System Role 2 Database. The primary outcome was 6-hour mortality. Patients who received red blood cells solely from component therapy were categorized as the non-warm fresh whole blood group. Non- warm fresh whole blood patients were frequency-matched to warm fresh whole blood patients on identical strata by injury type, patient affiliation, tourniquet use, prehospital transfusion, and average hourly unit red blood cell transfusion rates, creating clinically unique strata. Multilevel mixed effects logistic regression adjusted for the matching, immortal time bias, and other covariates. RESULTS: The 1,105 study patients (221 warm fresh whole blood, 884 non-warm fresh whole blood) were classified into 29 unique clinical strata. The adjusted odds ratio of 6-hour mortality was 0.27 (95% confidence interval 0.13-0.58) for the warm fresh whole blood versus non-warm fresh whole blood group. The reduction in mortality increased in magnitude (odds ratio = 0.15, P = .024) among the subgroup of 422 patients with complete data allowing adjustment for seven additional covariates. There was a dose-dependent effect of warm fresh whole blood, with patients receiving higher warm fresh whole blood dose (>33% of red blood cell-containing units) having significantly lower mortality versus the non-warm fresh whole blood group. CONCLUSION: Warm fresh whole blood resuscitation was associated with a significant reduction in 6-hour mortality versus non-warm fresh whole blood in combat casualties, with a dose-dependent effect. These findings support warm fresh whole blood use for hemorrhage control as well as expanded study in military and civilian trauma settings.


Assuntos
Transfusão de Sangue/métodos , Hemorragia/terapia , Medicina Militar/métodos , Ressuscitação/métodos , Adulto , Campanha Afegã de 2001- , Estudos de Coortes , Feminino , Hemorragia/etiologia , Humanos , Escala de Gravidade do Ferimento , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
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