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1.
Crit Care Med ; 2022 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-35120041

RESUMO

OBJECTIVES: Whether metformin exposure is associated with improved outcomes in patients with type 2 diabetes mellitus and sepsis. DESIGN: Retrospective cohort study. SETTING: Patients admitted to ICUs in 16 hospitals in Pennsylvania from October 2008 to December 2014. PATIENTS: Adult critical ill patients with type 2 diabetes mellitus and sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We conducted a retrospective cohort study to compare 90-day mortality in diabetic patients with sepsis with and without exposure to metformin during hospitalization. Data were obtained from the electronic health record of a large healthcare system in Pennsylvania from October 2008 to December 2014, on patients admitted to the ICU at any of the 16 hospitals within the system. The primary outcome was mortality at 90 days. The absolute and adjusted odds ratio (OR) with 95% CI were calculated in a propensity score-matched cohort. Among 14,847 patients with type 2 diabetes mellitus and sepsis, 682 patients (4.6%) were exposed to metformin during hospitalization and 14,165 (95.4%) were not. Within a total of 2,691 patients subjected to propensity score-matching at a 1:4 ratio, exposure to metformin (n = 599) was associated with decreased 90-day mortality (71/599, 11.9% vs 475/2,092, 22.7%; OR, 0.46; 95% CI, 0.35-0.60), reduced severe acute kidney injury (50% vs 57%; OR, 0.75; 95% CI, 0.62-0.90), less Major Adverse Kidney Events at 1 year (OR, 0.27; 95% CI, 0.22-0.68), and increased renal recovery (95% vs 86%; OR, 6.43; 95% CI, 3.42-12.1). CONCLUSIONS: Metformin exposure during hospitalization is associated with a decrease in 90-day mortality in patients with type 2 diabetes mellitus and sepsis.

2.
J Trauma Acute Care Surg ; 92(5): 839-847, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35081595

RESUMO

INTRODUCTION: Low titer group O whole blood (LTOWB) resuscitation is increasingly common in both military and civilian settings. Data regarding the safety and efficacy of prehospital LTOWB remain limited. METHODS: We performed a single-center, prospective, cluster randomized, prehospital through in-hospital whole blood pilot trial for injured air medical patients. We compared standard prehospital air medical care including red cell transfusion and crystalloids followed by in-hospital component transfusion to prehospital and in-hospital LTOWB resuscitation. Prehospital vital signs were used as inclusion criteria (systolic blood pressure ≤90 mm Hg and heart rate ≥108 beats per minute or systolic blood pressure ≤70 mm Hg for patients at risk of hemorrhage). Primary outcome was feasibility. Secondary outcomes included 28-day and 24-hour mortality, multiple organ failure, nosocomial infection, 24-hour transfusion requirements, and arrival coagulation parameters. RESULTS: Between November 2018 and October 2020, 86 injured patients were cluster randomized by helicopter base. The trial has halted early at 77% enrollment. Overall, 28-day mortality for the cohort was 26%. Injured patients randomized to prehospital LTOWB (n = 40) relative to standard care (n = 46) were similar in demographics and injury characteristics. Intent-to-treat Kaplan-Meier survival analysis demonstrated no statistical mortality benefit at 28 days (25.0% vs. 26.1%, p = 0.85). Patients randomized to prehospital LTOWB relative to standard care had lower red cell transfusion requirements at 24 hours (p < 0.01) and a lower incidence of abnormal thromboelastographic measurements. No transfusion reactions during the prehospital or in-hospital phase of care were documented. CONCLUSION: Prehospital through in-hospital LTOWB resuscitation is safe and may be associated with hemostatic benefits. A large-scale clinical trial is feasible with protocol adjustment and would allow the effects of prehospital LTOWB on survival and other pertinent clinical outcomes to be appropriately characterized. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level II.


Assuntos
Serviços Médicos de Emergência , Ressuscitação , Sistema ABO de Grupos Sanguíneos , Transfusão de Sangue , Humanos , Projetos Piloto , Estudos Prospectivos , Ressuscitação/métodos
3.
Blood Coagul Fibrinolysis ; 33(1): 14-24, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34889809

RESUMO

Acute kidney injury (AKI) is common after trauma, but contributory factors are incompletely understood. Increases in plasma von Willebrand Factor (vWF) with concurrent decreases in ADAMTS13 are associated with renal microvascular thrombosis in other disease states, but similar findings have not been shown in trauma. We hypothesized that molecular changes in circulating vWF and ADAMTS13 promote AKI following traumatic injury. VWF antigen, vWF multimer composition and ADAMTS13 levels were compared in plasma samples from 16 trauma patients with and without trauma-induced AKI, obtained from the Prehospital Air Medical Plasma (PAMPer) biorepository. Renal histopathology and function, vWF and ADAMTS13 levels were assessed in parallel in a murine model of polytrauma and haemorrhage. VWF antigen was higher in trauma patients when compared with healthy controls [314% (253-349) vs. 100% (87-117)] [median (IQR)], while ADAMTS13 activity was lower [36.0% (30.1-44.7) vs. 100.0% (83.1-121.0)]. Patients who developed AKI showed significantly higher levels of high molecular weight multimeric vWF at 72-h when compared with non-AKI counterparts [32.9% (30.4-35.3) vs. 27.8% (24.6-30.8)]. Murine plasma cystatin C and vWF were elevated postpolytrauma model in mice, with associated decreases in ADAMTS13, and immunohistologic analysis demonstrated renal injury with small vessel plugs positive for fibrinogen and vWF. Following traumatic injury, the vWF-ADAMTS13 axis shifted towards a prothrombotic state in both trauma patients and a murine model. We further demonstrated that vWF-containing, microangiopathic deposits were concurrently produced as the prothrombotic changes were sustained during the days following trauma, potentially contributing to AKI development.


Assuntos
Injúria Renal Aguda , Fator de von Willebrand , Proteína ADAMTS13 , Animais , Humanos , Rim , Camundongos , Peso Molecular , Plasma
5.
JAMA Surg ; 156(12): 1131-1139, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34550318

RESUMO

Importance: Prehospital plasma transfusion is lifesaving for trauma patients in hemorrhagic shock but is not commonly used owing to cost and feasibility concerns. Objective: To evaluate the cost-effectiveness of prehospital thawed plasma transfusion in trauma patients with hemorrhagic shock during air medical transport. Design, Setting, and Participants: A decision tree and Markov model were created to compare standard care and prehospital thawed plasma transfusion using published and unpublished patient-level data from the Prehospital Plasma in Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock (PAMPer) trial conducted from May 2014 to October 2017, health care and trauma-specific databases, and the published literature. Prehospital transfusion, short-term inpatient care, and lifetime health care costs and quality of life outcomes were included. One-way, 2-way, and Monte Carlo probabilistic sensitivity analyses were performed across clinically plausible ranges. Data were analyzed in December 2019. Main Outcomes and Measures: Relative costs and health-related quality of life were evaluated by an incremental cost-effectiveness ratio at a standard willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY). Results: The trial included 501 patients in the modified intention-to-treat cohort. Median (interquartile range) age for patients in the thawed plasma and standard care cohorts were 44 (31-59) and 46 (28-60) years, respectively. Overall, 364 patients (72.7%) were male. Thawed plasma transfusion was cost-effective with an incremental cost-effectiveness ratio of $50 467.44 per QALY compared with standard care. The preference for thawed plasma was robust across all 1- and 2-way sensitivity analyses. When considering only patients injured by a blunt mechanism, the incremental cost-effectiveness ratio decreased to $37 735.19 per QALY. Thawed plasma was preferred in 8140 of 10 000 iterations (81.4%) on probabilistic sensitivity analysis. A detailed analysis of incremental costs between strategies revealed most were attributable to the in-hospital and postdischarge lifetime care of critically ill patients surviving severe trauma. Conclusions and Relevance: In this study, prehospital thawed plasma transfusion during air medical transport for trauma patients in hemorrhagic shock was lifesaving and cost-effective compared with standard care and should become commonplace.


Assuntos
Resgate Aéreo , Transfusão de Componentes Sanguíneos/economia , Análise Custo-Benefício , Plasma , Choque Hemorrágico/terapia , Árvores de Decisões , Humanos , Cadeias de Markov , Anos de Vida Ajustados por Qualidade de Vida
7.
Ann Surg ; 274(3): 419-426, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132695

RESUMO

OBJECTIVE: We sought to characterize the timing of administration of prehospital tranexamic acid (TXA) and associated outcome benefits. BACKGROUND: TXA has been shown to be safe in the prehospital setting post-injury. METHODS: We performed a secondary analysis of a recent prehospital randomized TXA clinical trial in injured patients. Those who received prehospital TXA within 1 hour (EARLY) from time of injury were compared to those who received prehospital TXA beyond 1 hour (DELAYED). We included patients with a shock index of >0.9. Primary outcome was 30-day mortality. Kaplan-Meier and Cox Hazard regression were utilized to characterize mortality relationships. RESULTS: EARLY and DELAYED patients had similar demographics, injury characteristics, and shock severity but DELAYED patients had greater prehospital resuscitation requirements and longer prehospital times. Stratified Kaplan-Meier analysis demonstrated significant separation for EARLY patients (N = 238, log-rank chi-square test, 4.99; P = 0.03) with no separation for DELAYED patients (N = 238, log-rank chi-square test, 0.04; P = 0.83). Stratified Cox Hazard regression verified, after controlling for confounders, that EARLY TXA was associated with a 65% lower independent hazard for 30-day mortality [hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.19-0.65, P = 0.001] with no independent survival benefit found in DELAYED patients (HR 1.00, 95% CI 0.63-1.60, P = 0.999). EARLY TXA patients had lower incidence of multiple organ failure and 6-hour and 24-hour transfusion requirements compared to placebo. CONCLUSIONS: Administration of prehospital TXA within 1 hour from injury in patients at risk of hemorrhage is associated with 30-day survival benefit, lower incidence of multiple organ failure, and lower transfusion requirements.


Assuntos
Antifibrinolíticos/administração & dosagem , Serviços Médicos de Emergência , Hemorragia/prevenção & controle , Ácido Tranexâmico/administração & dosagem , Adulto , Transfusão de Sangue/estatística & dados numéricos , Método Duplo-Cego , Feminino , Hemorragia/mortalidade , Humanos , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/mortalidade , Choque Hemorrágico/tratamento farmacológico , Análise de Sobrevida , Fatores de Tempo
8.
Surgery ; 170(3): 707-712, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33789813

RESUMO

Surgeon-scientists provide critical perspectives to academic medicine, both as lead scientists and as collaborators. Successfully applying for and obtaining funding is critical to sustain a research program; however, significant challenges exist. It is imperative to be aware of and consider all funding sources available to surgeons during the evolution of one's career. Additionally, a deep understanding of intramural and extramural nonfinancial resources, such as mentorship relationships, grant writing, and career development courses, and research infrastructure are required. In this article, we present a set of recommendations and guidelines for surgeon-scientists to leverage funding resources with active planning longitudinally during their careers to sustain their research programs and provide their unique perspectives on surgical disease to the scientific community.


Assuntos
Pesquisa Biomédica/economia , Organização do Financiamento/organização & administração , Cirurgia Geral/organização & administração , Mentores , Pesquisadores/economia , Cirurgiões/economia , Humanos , Cirurgiões/tendências , Estados Unidos
9.
Trauma Surg Acute Care Open ; 6(1): e000648, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33634214

RESUMO

BACKGROUND: Prehospital plasma administration during air medical transport reduces the endotheliopathy of trauma, circulating pro-inflammatory cytokines, and 30-day mortality among traumatically injured patients at risk of hemorrhagic shock. No clinical data currently exists evaluating the age of thawed plasma and its association with clinical outcomes and biomarker expression post-injury. METHODS: We performed a secondary analysis from the prehospital plasma administration randomized controlled trial, PAMPer. We dichotomized the age of thawed plasma creating three groups: standard-care, YOUNG (day 0-1) plasma, and OLD (day 2-5) plasma. We generated HRs and 95% CIs for mortality. Among all patients randomized to plasma, we compared predicted biomarker values at hospital admission (T0) and 24 hours later (T24) controlling for key difference between groups with a multivariable linear regression. Analyses were repeated in a severely injured subgroup. RESULTS: Two hundred and seventy-one patients were randomized to standard-care and 230 to plasma (40% YOUNG, 60% OLD). There were no clinically or statistically significant differences in demographics, injury, admission vital signs, or laboratory values including thromboelastography between YOUNG and OLD. Compared with standard-care, YOUNG (HR 0.66 (95% CI 0.41 to 1.07), p=0.09) and OLD (HR 0.64 (95% CI 0.42 to 0.96), p=0.03) plasma demonstrated reduced 30-day mortality. Among those randomized to plasma, plasma age did not affect mortality (HR 1.04 (95% CI 0.60 to 1.82), p=0.90) and/or adjusted serum markers by plasma age at T0 or T24 (p>0.05). However, among the severely injured subgroup, OLD plasma was significantly associated with increased adjusted inflammatory and decreased adjusted endothelial biomarkers at T0. DISCUSSION: Age of thawed plasma does not result in clinical outcome or biomarker expression differences in the overall PAMPer study cohort. There were biomarker expression differences in those patients with severe injury. Definitive investigation is needed to determine if the age of thawed plasma is associated with biomarker expression and outcome differences following traumatic injury. LEVEL OF EVIDENCE: II.

10.
J Perioper Pract ; 31(3): 80-88, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32301383

RESUMO

BACKGROUND: Perioperative stroke-related mortality in the non-cardiovascular, non-neurological surgery population is an uncommon, yet devastating outcome. A combination of emboli and hypoperfusion may cause large vessel occlusions leading to perioperative strokes and mortality. Identifying independent risk factors for perioperative stroke-related mortality may enhance risk-stratification algorithms and preventative therapies. OBJECTIVES: This study utilised cause-of-death data to determine independent risk scores for common surgical comorbidities that may lead to perioperative stroke-related mortality, including atrial fibrillation and asymptomatic carotid stenosis. METHODS: This retrospective, IRB-exempt, case-control study evaluated non-cardiovascular, non-neurological surgical patients in a claims-based database. ICD-10-CM and ICD-9-CM codes identified cause of death and comorbidity incidences, respectively. A multivariate regression analysis then established adjusted independent risk scores of each comorbidity in relation to perioperative stroke-related mortality. RESULTS: Patients with atrial fibrillation were more likely (1.7 aOR, 95% CI (1.1, 2.8) p = 0.02) to die from perioperative stroke-related mortality than from other causes. No association was found with asymptomatic carotid stenosis. Further, in-hospital strokes (25.9 aOR, 95% CI (16.0, 41.8) p < 0.001) or diabetes (1.8 aOR, 95% CI (1.1, 2.9) p = 0.02) may increase perioperative stroke-related mortality risk. CONCLUSIONS: Atrial fibrillation, diabetes and in-hospital strokes may be independent risk factors for perioperative stroke-related mortality in the non-cardiovascular, non-neurological surgery population.


Assuntos
Acidente Vascular Cerebral , Estudos de Casos e Controles , Comorbidade , Mortalidade Hospitalar , Humanos , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia
11.
Surgery ; 169(2): 257-263, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33077199

RESUMO

BACKGROUND: The current coronavirus disease 2019 pandemic has had an unprecedented impact on all physicians and has resulted in dramatic changes to clinical and research operations. No study has yet looked at the impact of coronavirus disease 2019 on the surgical research community. In this study, we sought to understand the impact of the pandemic and its associated restrictions on academic surgeons. METHODS: We surveyed members of the Association for Academic Surgery and the Society of University Surgeons. Survey questions included demographics, current challenges to basic and clinical research activities, attitudes toward remote work and productivity maintenance, and the solutions implemented to maintain productivity. RESULTS: Of 301 respondents, 70% cited a negative impact on research productivity due to mandatory building shutdowns, minimized personnel as a result of social distancing, and suspensions of animal work and clinical trials, with senior faculty and division chiefs and chairs more likely to report a negative impact (P = .001). Only 11% of respondents are documenting their financial losses, and only 19% indicated they received appropriate guidance regarding why and how to monitor the financial impact of the pandemic. Researchers have attempted to maintain research productivity through a focus on remote work, including manuscript writing, grant writing, and data analysis. Some participants have found silver linings, including more time to dedicate to research and family as a result of fewer clinical duties. CONCLUSION: Productivity strategies developed during the pandemic, including writing, remote work and meetings, and structured scheduling, are lessons that will allow the surgical research community to be resilient in the face of future disruptions.


Assuntos
Pesquisa Biomédica , COVID-19/epidemiologia , Pandemias , Atitude do Pessoal de Saúde , Eficiência Organizacional , Docentes de Medicina , Humanos , Cirurgiões , Inquéritos e Questionários , Estados Unidos/epidemiologia
13.
Antioxid Redox Signal ; 35(17): 1407-1425, 2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33587005

RESUMO

Aims: We sought to investigate the relationship between macrohemodynamic resuscitation and microcirculatory parameters with the response of microcirculatory flow, tissue-specific parameters of metabolic stress and injury. We hypothesized that early resuscitation based on macrohemodynamic parameters does not prevent the development of organ dysfunction in a porcine model of endotoxemic shock, and that sublingual microcirculatory parameters are associated with markers of tissue metabolic stress and injury. Results: Both resuscitation groups had significant increases in creatinine and neutrophil gelatinase-associated lipocalin as compared with baseline. Neither the macrovascular response to endotoxemia or resuscitation, nor group allocation predicted the development of acute kidney injury (AKI). Only a microvascular flow index (MFI) <2.5 was associated with the development of renal tubular injury and AKI, and with increased renal, liver, peritoneal, and sublingual lactate/pyruvate (L/P) ratio and lactate. Among systemic parameters, only partial pressure of carbon dioxide (PCO2) gap >6 and P(a-v)CO2/C(v-a)O2 >1.8 were associated with increased organ L/P ratio and AKI. Innovation and Conclusion: Our findings demonstrate that targeting macrohemodynamics to guide resuscitation during endotoxemic shock failed to predict tissue metabolic stress and the response of the microvasculature to resuscitation, and was unsuccessful in preventing tubular injury and AKI. Mechanistically, our data suggest that loss of hemodynamic coherence and decoupling of microvascular flow from tissue metabolic demand during endotoxemia may explain the lack of association between macrohemodynamics and perfusion goals. Finally, we demonstrate that MFI, PCO2 gap, and P(v-a)CO2/C(a-v)O2 ratio outperformed macrohemodynamic parameters at predicting the development of renal metabolic stress and tubular injury, and therefore, that these indices merit further validation as promising resuscitation targets. Antioxid. Redox Signal. 35, 1407-1425.


Assuntos
Endotoxemia , Animais , Hemodinâmica/fisiologia , Microcirculação/fisiologia , Perfusão , Ressuscitação , Estresse Fisiológico , Suínos
14.
Cell Rep Med ; 2(12): 100478, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-35028617

RESUMO

Trauma is a leading cause of death and morbidity worldwide. Here, we present the analysis of a longitudinal multi-omic dataset comprising clinical, cytokine, endotheliopathy biomarker, lipidome, metabolome, and proteome data from severely injured humans. A "systemic storm" pattern with release of 1,061 markers, together with a pattern suggestive of the "massive consumption" of 892 constitutive circulating markers, is identified in the acute phase post-trauma. Data integration reveals two human injury response endotypes, which align with clinical trajectory. Prehospital thawed plasma rescues only endotype 2 patients with traumatic brain injury (30-day mortality: 30.3 versus 75.0%; p = 0.0015). Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) was identified as the most predictive circulating biomarker to identify endotype 2-traumatic brain injury (TBI) patients. These response patterns refine the paradigm for human injury, while the datasets provide a resource for the study of critical illness, trauma, and human stress responses.


Assuntos
Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/terapia , Genômica , Análise por Conglomerados , Estudos de Coortes , Humanos , Metaboloma , Plasma , Proteoma/metabolismo , Fatores de Tempo , Resultado do Tratamento
15.
JAMA Netw Open ; 3(10): e2016869, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33057642

RESUMO

Importance: Prehospital plasma administration improves survival in injured patients at risk for hemorrhagic shock and transported by air ambulance. Traumatic brain injury (TBI) is a leading cause of death following trauma, but few early interventions improve outcomes. Objective: To assess the association between prehospital plasma and survival in patients with TBI. Design, Setting, and Participants: The Prehospital Air Medical Plasma (PAMPer) trial was a pragmatic, multicenter, phase 3, cluster randomized clinical trial involving injured patients who were at risk for hemorrhagic shock during air medical transport to a trauma center. The trial was conducted at 6 US sites with 9 level-I trauma centers (comprising 27 helicopter emergency services bases). The original trial analyzed 501 patients, including 230 patients who were randomized to receive plasma and 271 randomized to standard care resuscitation. This secondary analysis of a predefined subgroup included patients with TBI. Data analysis was performed from October 2019 to February 2020. Interventions: Patients were randomized to receive standard care fluid resuscitation or 2 units of thawed plasma. Main Outcomes and Measures: The primary outcome was mortality at 30 days. Patients with TBI were prespecified as a subgroup for secondary analysis and for measurement of markers of brain injury. The 30-day survival benefit of prehospital plasma in subgroups with and without TBI as diagnosed by computed tomography was characterized using Kaplan-Meier survival analysis and Cox proportional hazard regression. Results: In total, 166 patients had TBI (median [interquartile range] age, 43.00 [25.00-59.75] years; 125 men [75.3%]). When compared with the 92 patients who received standard care, the 74 patients with TBI who received prehospital plasma had improved 30-day survival even after adjustment for multiple confounders and assessment of the degree of brain injury with clinical variables and biomarkers (hazard ratio [HR], 0.55; 95% CI, 0.33-0.94; P = .03). Receipt of prehospital plasma was associated with improved survival among patients with TBI with a prehospital Glasgow Coma Scale score of less than 8 (HR, 0.56; 95% CI, 0.35-0.91) and those with polytrauma (HR, 0.50; 95% CI, 0.28-0.89). Patients with TBI transported from the scene of injury had improved survival following prehospital plasma administration (HR, 0.45; 95% CI, 0.26-0.80; P = .005), whereas patients who were transferred from an outside hospital showed no difference in survival for the plasma intervention (HR, 1.00; 95% CI, 0.33-3.00; P = .99). Conclusions and Relevance: These findings are exploratory, but they suggest that receipt of prehospital plasma is associated with improved survival in patients with computed tomography-positive TBI. The prehospital setting may be a critical period to intervene in the care of patients with TBI. Future studies are needed to confirm the clinical benefits of early plasma resuscitation following TBI and concomitant polytrauma. Trial Registration: ClinicalTrials.gov Identifier: NCT01818427.


Assuntos
Lesões Encefálicas Traumáticas/mortalidade , Lesões Encefálicas Traumáticas/terapia , Reanimação Cardiopulmonar/métodos , Serviços Médicos de Emergência/métodos , Hidratação/métodos , Plasma , Choque Hemorrágico/prevenção & controle , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Estados Unidos
16.
BMC Emerg Med ; 20(1): 76, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004018

RESUMO

OBJECTIVES: With increased focus on early resuscitation methods following injury to improve patient outcomes, studies are employing exception from informed consent (EFIC) enrollment. Few studies have assessed patients' opinions following participation in an EFIC study, and none have been conducted within the realm of traumatic hemorrhage. We surveyed those patients and surrogates previously enrolled in the Prehospital Air Medical Plasma (PAMPer) Trial to clarify their opinions related to consent and emergency research. METHODS: Telephone calls were made between January-June 2019 to all patients who were enrolled under EFIC in the PAMPer study at the Pittsburgh site (169 of the 501 total patients enrolled, May 2014-Oct 2017) and their surrogates. Questions gauging approval of EFIC enrollment were asked before discussion of PAMPer trial outcomes, after disclosure of positive outcomes, and after a hypothetical negative trial outcome was proposed. RESULTS: Of the total 647 telephone calls made, ninety-three interviews, reflecting 70 of 169 patient enrollments, were conducted. This included 13 in which only the patient was interviewed, 23 in which the patient and a surrogate were interviewed, and 34 in which only a surrogate was interviewed. Nearly half (48.4%) of respondents did not recall their personal or family member enrollment in the study. No patients or surrogates recalled hearing about the study through community consultation or being aware of opt out procedures. Patients and surrogates were glad they were enrolled (90.3%), agreed with EFIC use for their personal enrollment (88.17%), and agreed with the general use of EFIC for the PAMPer study (81.7%). Disclosure of the true positive PAMPer study outcome resulted in a significant increase in opinions regarding personal enrollment, EFIC for personal enrollment, and EFIC for general enrollment (all p < 0.001). Disclosure of a hypothetical neutral or negative study outcome resulted in significant decreases in opinions regarding EFIC for personal enrollment (p = 0.003) and EFIC for general enrollment (p < 0.001). CONCLUSIONS: Clinical trial participants with traumatic hemorrhagic shock enrolled with EFIC, and surrogates of such participants, are generally accepting of EFIC. The results of the trial in which EFIC was utilized significantly affected patient and surrogate agreement with personal and general EFIC enrollment.


Assuntos
Resgate Aéreo , Serviços Médicos de Emergência/ética , Hemorragia/terapia , Consentimento Livre e Esclarecido/ética , Plasma , Ressuscitação/métodos , Adulto , Feminino , Hemorragia/mortalidade , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Pennsylvania
17.
JAMA Surg ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33016996

RESUMO

IMPORTANCE: In-hospital administration of tranexamic acid after injury improves outcomes in patients at risk for hemorrhage. Data demonstrating the benefit and safety of the pragmatic use of tranexamic acid in the prehospital phase of care are lacking for these patients. OBJECTIVE: To assess the effectiveness and safety of tranexamic acid administered before hospitalization compared with placebo in injured patients at risk for hemorrhage. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, phase 3, multicenter, double-blind, placebo-controlled, superiority randomized clinical trial included injured patients with prehospital hypotension (systolic blood pressure ≤90 mm Hg) or tachycardia (heart rate ≥110/min) before arrival at 1 of 4 US level 1 trauma centers, within an estimated 2 hours of injury, from May 1, 2015, through October 31, 2019. INTERVENTIONS: Patients received 1 g of tranexamic acid before hospitalization (447 patients) or placebo (456 patients) infused for 10 minutes in 100 mL of saline. The randomization scheme used prehospital and in-hospital phase assignments, and patients administered tranexamic acid were allocated to abbreviated, standard, and repeat bolus dosing regimens on trauma center arrival. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day all-cause mortality. RESULTS: In all, 927 patients (mean [SD] age, 42 [18] years; 686 [74.0%] male) were eligible for prehospital enrollment (460 randomized to tranexamic acid intervention; 467 to placebo intervention). After exclusions, the intention-to-treat study cohort comprised 903 patients: 447 in the tranexamic acid arm and 456 in the placebo arm. Mortality at 30 days was 8.1% in patients receiving tranexamic acid compared with 9.9% in patients receiving placebo (difference, -1.8%; 95% CI, -5.6% to 1.9%; P = .17). Results of Cox proportional hazards regression analysis, accounting for site, verified that randomization to tranexamic acid was not associated with a significant reduction in 30-day mortality (hazard ratio, 0.81; 95% CI, 0.59-1.11, P = .18). Prespecified dosing regimens and post-hoc subgroup analyses found that prehospital tranexamic acid were associated with significantly lower 30-day mortality. When comparing tranexamic acid effect stratified by time to treatment and qualifying shock severity in a post hoc comparison, 30-day mortality was lower when tranexamic acid was administered within 1 hour of injury (4.6% vs 7.6%; difference, -3.0%; 95% CI, -5.7% to -0.3%; P < .002). Patients with severe shock (systolic blood pressure ≤70 mm Hg) who received tranexamic acid demonstrated lower 30-day mortality compared with placebo (18.5% vs 35.5%; difference, -17%; 95% CI, -25.8% to -8.1%; P < .003). CONCLUSIONS AND RELEVANCE: In injured patients at risk for hemorrhage, tranexamic acid administered before hospitalization did not result in significantly lower 30-day mortality. The prehospital administration of tranexamic acid after injury did not result in a higher incidence of thrombotic complications or adverse events. Tranexamic acid given to injured patients at risk for hemorrhage in the prehospital setting is safe and associated with survival benefit in specific subgroups of patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02086500.

18.
Cell Calcium ; 92: 102286, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32932146

RESUMO

Sepsis and shock states impose mitochondrial stress, and in response, adaptive mechanisms such as fission, fusion and mitophagy are induced to eliminate damaged portions of or entire dysfunctional mitochondria. The mechanisms underlying these events are being elucidated; yet a direct link between loss of mitochondrial membrane potential ΔΨm and the initiation of fission, fusion and mitophagy remains to be well characterized. The direct association between the magnitude of the ΔΨm and the capacity for mitochondria to buffer Ca2+ renders Ca2+ uniquely suited as the signal engaging these mechanisms in circumstances of mitochondrial stress that lower the ΔΨm. Herein, we show that the calcium/calmodulin-dependent protein kinase (CaMK) IV mediates an adaptive slowing in oxidative respiration that minimizes oxidative stress in the kidneys of mice subjected to either cecal ligation and puncture (CLP) sepsis or endotoxemia. CaMKIV shifts the balance towards mitochondrial fission and away from fusion by 1) directly phosphorylating an activating Serine616 on the fission protein DRP1 and 2) reducing the expression of the fusion proteins Mfn1/2 and OPA-1. CaMKIV, through its function as a direct PINK1 kinase and regulator of Parkin expression, also enables mitophagy. These data support that CaMKIV serves as a keystone linking mitochondrial stress with the adaptive mechanisms of mitochondrial fission, fusion and mitophagy that mitigate oxidative stress in the kidneys of mice responding to sepsis.


Assuntos
Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Dinâmica Mitocondrial , Sepse/patologia , Animais , Ceco/patologia , Células HEK293 , Humanos , Córtex Renal/patologia , Córtex Renal/ultraestrutura , Ligadura , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Mitofagia , Estresse Oxidativo , Proteínas Quinases/metabolismo , Punções , Ubiquitina-Proteína Ligases/metabolismo
20.
JAMA Surg ; 155(9): 895-896, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32520345
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