RESUMO
BACKGROUND: Major surgery triggers trauma-like stress responses linked to age, surgery duration, and blood loss, resembling polytrauma. This similarity suggests elective surgery as a surrogate model for studying polytrauma immune responses. We investigated stress responses across age groups and compared them with those of polytrauma patients. STUDY DESIGN: Patients undergoing major spinal reconstruction surgery were divided into older (age >65 years, n = 5) and young (age 18 to 39 years, n = 6) groups. A comparison group consisted of matched trauma patients (n = 8). Blood samples were collected before, during, and after surgery. Bone marrow mononuclear cells and peripheral blood mononuclear cells were analyzed using cellular indexing of transcriptomes and epitopes sequencing or single-cell RNA sequencing. Plasma was subjected to dual-platform proteomic analysis (SomaLogic and O-link). RESULTS: Response to polytrauma was highest within 4 hours. By comparison, the response to surgery was highest at 24 hours. Both insults triggered significant changes in cluster of differentiation 14 monocytes, with increased inflammation and lower major histocompatibility complex-class 2 expression. Older patient's cluster of differentiation 14 monocytes displayed higher inflammation and less major histocompatibility complex-class 2 suppression; a trend was also seen in bone marrow mononuclear cells. Although natural killer cells were markedly activated after polytrauma, they were suppressed after surgery, especially in older patients. In plasma, innate immunity proteins dominated at 24 hours, shifting to adaptive immunity proteins by 6 weeks with heightened inflammation in older patients. Senescence-associated secretory phenotype proteins were higher in older patients at baseline and further elevated during and after surgery. CONCLUSIONS: Although both major surgery and polytrauma initiate immune and stress responses, substantial differences exist in timing and cellular profiles, suggesting major elective surgery is not a suitable surrogate for the polytrauma response. Nonetheless, distinct responses in young vs older patients highlight the utility of elective spinal in studying patient-specific factors affecting outcomes after major elective surgery.
Assuntos
Traumatismo Múltiplo , Cirurgia Plástica , Humanos , Idoso , Adolescente , Adulto Jovem , Adulto , Transcriptoma , Leucócitos Mononucleares , Proteômica , Envelhecimento , Traumatismo Múltiplo/cirurgia , Perfilação da Expressão Gênica , Imunidade , InflamaçãoRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Metformina , Sepse , Adulto , Estado Terminal , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hospitalização , Humanos , Metformina/uso terapêutico , Estudos Retrospectivos , Sepse/complicações , Sepse/tratamento farmacológicoRESUMO
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 TempoRESUMO
BACKGROUND: Trauma is the leading cause of death and disability for individuals under age 55. Many severely injured trauma patients experience complicated clinical courses despite appropriate initial therapy. We sought to identify novel circulating metabolomic signatures associated with clinical outcomes following trauma. STUDY DESIGN: Untargeted metabolomics and circulating plasma immune mediator analysis was performed on plasma collected during 3 post-injury time periods (<6 hours [h], 6 h-24h, day 2-day 5) in critically ill trauma patients enrolled between April 2004 and May 2013 at UPMC Presbyterian Hospital in Pittsburgh, PA. Inclusion criteria were age ≥ 18 years, blunt mechanism, ICU admission, and expected survival ≥ 24 h. Exclusion criteria were isolated head injury, spinal cord injury, and pregnancy. Exploratory endpoints included length of stay (overall and ICU), ventilator requirements, nosocomial infection, and Marshall organ dysfunction (MOD) score. The top 50 metabolites were isolated using repeated measures ANOVA and multivariate empirical Bayesian analysis for further study. RESULTS: Eighty-six patients were included for analysis. Sphingolipids were enriched significantly (chi-square, p < 10-6) among the top 50 metabolites. Clustering of sphingolipid patterns identified 3 patient subclasses: nonresponders (no time-dependent change in sphingolipids, n = 41), sphingosine/sphinganine-enhanced (n = 24), and glycosphingolipid-enhanced (n = 21). Compared with the sphingolipid-enhanced subclasses, nonresponders had longer mean length of stay, more ventilator days, higher MOD scores, and higher circulating levels of proinflammatory immune mediators IL-6, IL-8, IL-10, MCP1/CCL2, IP10/CXCL10, and MIG/CXCL9 (all p < 0.05), despite similar Injury Severity Scores (p = 0.12). CONCLUSIONS: Metabolomic analysis identified broad alterations in circulating plasma sphingolipids after blunt trauma. Circulating sphingolipid signatures and their association with both clinical outcomes and circulating inflammatory mediators suggest a possible link between sphingolipid metabolism and the immune response to trauma.
Assuntos
Metaboloma , Esfingolipídeos/sangue , Ferimentos não Penetrantes/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Cuidados Críticos/métodos , Cuidados Críticos/estatística & dados numéricos , Estado Terminal , Feminino , Humanos , Escala de Gravidade do Ferimento , Tempo de Internação/estatística & dados numéricos , Estudos Longitudinais , Masculino , Metabolômica , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Prognóstico , Estudos Prospectivos , Ferimentos não Penetrantes/diagnóstico , Ferimentos não Penetrantes/imunologia , Ferimentos não Penetrantes/terapia , Adulto JovemRESUMO
OBJECTIVES: The physiology of nearly all mammalian organisms are entrained by light and exhibit circadian rhythm. The data derived from animal studies show that light influences immunity, and these neurophysiologic pathways are maximally entrained by the blue spectrum. Here, we hypothesize that bright blue light reduces acute kidney injury by comparison with either bright red or standard, white fluorescent light in mice subjected to sepsis. To further translational relevance, we performed a pilot clinical trial of blue light therapy in human subjects with appendicitis. DESIGN: Laboratory animal research, pilot human feasibility trial. SETTING: University basic science laboratory and tertiary care hospital. SUBJECTS: Male C57BL/6J mice, adult (> 17 yr) patients with acute appendicitis. INTERVENTIONS: Mice underwent cecal ligation and puncture and were randomly assigned to a 24-hour photoperiod of bright blue, bright red, or ambient white fluorescent light. Subjects with appendicitis were randomized to receive postoperatively standard care or standard care plus high-illuminance blue light. MEASUREMENTS AND MAIN RESULTS: Exposure to bright blue light enhanced bacterial clearance from the peritoneum, reduced bacteremia and systemic inflammation, and attenuated the degree of acute kidney injury. The mechanism involved an elevation in cholinergic tone that augmented tissue expression of the nuclear orphan receptor REV-ERBα and occurred independent of alterations in melatonin or corticosterone concentrations. Clinically, exposure to blue light after appendectomy was feasible and reduced serum interleukin-6 and interleukin-10 concentrations. CONCLUSIONS: Modifying the spectrum of light may offer therapeutic utility in sepsis.
Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Apendicite/terapia , Fototerapia/métodos , Sepse/complicações , Adulto , Animais , Citocinas/biossíntese , Feminino , Humanos , Hidrocortisona/sangue , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas Microbiológicas , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Distribuição AleatóriaRESUMO
OBJECTIVE: To evaluate the association of trauma center volume change over time with mortality. BACKGROUND: Regionalization of trauma systems assumes a volume-outcome relationship for severe injury. Whereas this has been shown for cross-sectional volume, it is unclear whether volume changes over time translate into predictable outcome changes. METHODS: Retrospective cohort study of severely injured (injury severity score >15) patients from the National Trauma Databank 2000 to 2012. A center-level standardized mortality ratio (SMR) was constructed (ratio of observed to expected deaths). Expected mortality was obtained from multilevel logistic regression model, adjusting for demographics, mechanism, vital signs, and injury severity. Center-level percent volume change was assessed across early (2000-2006) and late (2007-2012) periods. Longitudinal panel modeling evaluated association between annual SMR change and volume change over preceding years. RESULTS: There were 839,809 patients included from 287 centers. Each 1% increase in volume was associated with 73% increased odds of improving SMR over time [odds ratio (OR) 1.73; 95% confidence interval (CI) 1.03-2.91; P = 0.03]. Each 1% decrease in volume was associated with 2-fold increase in odds of worsening SMR over time (OR 2.14; 95% CI 1.07-4.26, P = 0.03). Significant improvement in the SMR emerged after 3 or more preceding years of increasing volume (SMR change -0.008; 95% CI -0.015, -0.002; P = 0.01). This benefit occurred only in centers that were level I or II verified. CONCLUSIONS: Increasing volume was associated with improving outcomes, whereas decreasing volume was associated with worsening outcomes. High-level trauma center infrastructure seems to facilitate the volume-outcome relationship. The trauma center designation process should consider volume changes in the overall system.
Assuntos
Centros de Traumatologia/estatística & dados numéricos , Ferimentos e Lesões/mortalidade , Adulto , Estudos Transversais , Feminino , Mortalidade Hospitalar , Humanos , Escala de Gravidade do Ferimento , Masculino , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Centros de Traumatologia/normas , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Older adult trauma patients are at increased risk of poor outcome, both immediately after injury and beyond hospital discharge. Identifying patients early in the hospital stay who are at increased risk of death after discharge can be challenging. METHODS: Retrospective analysis was performed using our trauma registry linked with the social security death index from 2010 to 2014. Age was categorized as 18 to 64 and 65 years or older. We calculated mortality rates by age category then selected elderly patients with mechanism of injury being a fall for further analysis. Computed Tomography Abbreviated Assessment of Sarcopenia for Trauma (CAAST) was obtained by measuring psoas muscle cross-sectional area adjusted for height and weight. Kaplan-Meier survival analysis was performed, and proportional hazards regression modeling was used to determine independent risk factors for in-hospital and out-of-hospital mortality. RESULTS: A total of 23,622 patients were analyzed (16,748, aged 18-64 years; and 6,874, aged 65 or older). In-hospital mortality was 1.96% for ages 18 to 64 and 7.19% for age 65 or older (p < 0.001); postdischarge 6-month mortality was 1.1% for ages 18 to 64 and 12.86% for age 65 or older (p < 0.001). Predictors of in-hospital and postdischarge mortality for ages 18 to 64 and in-hospital mortality for ages 65 or older group included injury characteristics such as ISS, admission vitals, and head injury. Predictors of postdischarge mortality for age 65or older included skilled nursing before admission, disposition, and mechanism of injury being a fall. A total of 57.5% (n = 256) of older patients who sustained a fall met criteria for sarcopenia. Sarcopenia was the strongest predictor of out-of-hospital mortality in this cohort with a hazard ratio of 4.77 (95% confidence interval, 2.71-8.40; p < 0.001). CONCLUSION: Out of hospital does not assure out of danger for the elderly. Sarcopenia is a strong predictor of 6-month postdischarge mortality for older adults. The CAAST measurement is an efficient and inexpensive measure that can allow clinicians to target older trauma patients at risk of poor outcome for early intervention and/or palliative care services. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level III.
Assuntos
Sistema de Registros , Medição de Risco/métodos , Sarcopenia/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Ferimentos e Lesões/complicações , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Incidência , Escala de Gravidade do Ferimento , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Sarcopenia/epidemiologia , Sarcopenia/etiologia , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados Unidos/epidemiologia , Ferimentos e Lesões/diagnóstico por imagem , Adulto JovemRESUMO
OBJECTIVE: Intimal hyperplasia (IH) contributes to the failure of vascular interventions. While many investigational therapies inhibit the development of IH in animal models, few of these potential therapies can reverse established lesions. Inhaled carbon monoxide (CO) dramatically inhibits IH in both rats and pigs when given perioperatively. It also prevented the development of pulmonary arterial hypertension in rodents. Interestingly, CO could reverse pulmonary artery structural changes and right heart hemodynamic changes when administered after the establishment of pulmonary hypertension. Thus, we hypothesize that inhaled CO may mediate the regression of established neointimal lesions. METHODS: Rats underwent carotid artery balloon angioplasty injury. Carotid arteries were collected at 2 and 4 weeks after injury for morphometric analysis of the neointima. Another group was treated with inhaled CO (250 parts per million) for 1 hour daily from week 2 until week 4. Additional rats were sacrificed 3 days after initiating CO treatment, and the carotid arteries were examined for apoptosis by terminal deoxynucleotidyl transferase dUTP nick end-labeling, proliferation by Ki67 staining, and autophagy by microtubule-associated protein light chain 3 I/II staining. RESULTS: At 2 weeks following injury, sizable neointimal lesions had developed (intimal/media = 0.92 ± 0.22). By 4 weeks, lesion size remained stable (0.80 ± 0.09). Delayed inhaled CO treatment greatly reduced neointimal lesion size vs the 2- and 4-week control mice (0.38 ± 0.05; P < .05). Arteries from the CO-treated rats exhibited significantly reduced apoptosis compared with control vessels (3.18% ± 1.94% vs 16.26% ± 5.91%; P = .036). Proliferation was also dramatically reduced in the CO-treated animals (2.98 ± 1.55 vs 10.37 ± 2.80; P = .036). No difference in autophagy between control and CO-treated rats was detected. CONCLUSIONS: Delayed administration of inhaled CO reduced established neointimal lesion size. This effect was mediated by the antiproliferative effect of CO on medial and intimal smooth muscle cells without increases in arterial wall apoptosis or autophagy. Future studies will examine additional time points to determine if there is temporal variation in the rates of apoptosis and autophagy.
Assuntos
Monóxido de Carbono/administração & dosagem , Lesões das Artérias Carótidas/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Neointima , Administração por Inalação , Angioplastia com Balão , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/patologia , Artéria Carótida Externa/efeitos dos fármacos , Artéria Carótida Externa/patologia , Modelos Animais de Doenças , Esquema de Medicação , Hiperplasia , Masculino , Músculo Liso Vascular/patologia , Ratos Sprague-Dawley , Fatores de TempoRESUMO
OBJECTIVE(S): Clinical research characterizing the mechanisms responsible for sex-based outcome differences postinjury remain conflicting. We sought to characterize an X chromosome-linked IRAK-1 (IL-1 receptor-associated kinase) polymorphism as an alternative mechanism responsible for sex differences postinjury. IRAK-1 is key intermediate in the toll-like receptor (TLR) pathway thought to drive inflammation postinjury. METHODS: A prospective cohort study was performed over a 24-month period. Bluntly injured patients requiring intensive care unit admission were enrolled, whereas patients with isolated brain and spinal cord injuries were excluded. Outcomes of interest included multiple organ failure (MOF, Marshall MOD score > 5) and mortality. Logistic regression was utilized to determine the independent risk of poor outcome associated with the IRAK-1 variant after controlling for important differences. RESULTS: In an enrolled cohort of 321 patients, the IRAK-1 variant was common (12.5%). Patients with and without the variant were similar in age, injury severity, and 24hr blood transfusion. After controlling for important confounders, the IRAK1 variant was independently associated with more than eightfold (OR = 8.4, P = 0.005, 95% CI: 1.9-37.1) and 11-fold (OR = 11.8, P = 0.037, 95% CI: 1.1-121) greater risk of MOF and mortality, respectively. These differences were most prominent in men, whereas women heterozygous for the variant demonstrated worse outcome in a dose-dependent fashion. CONCLUSIONS: The IRAK1 polymorphism is a strong independent predictor of MOF and mortality postinjury and represents a common variant with prognostic potential. These data demonstrate the importance of TLR signaling postinjury and supports that a genetic mechanism may drive sex outcome differences postinjury.