Search

Purpose To evaluate the performance of the new SOFA-based sepsis definition in trauma patients. Materials and methods A single-centre, retrospective, observational study. Primary outcome was 30-day mortality including a censoring analysis for early deaths. The primary outcome was evaluated with logistic regression, receiver operating characteristics (ROC) curves and Kaplan-Meier survival analyses. Results 722 severely injured patients were included between 2007 and 2016. 315 patients fulfilled the sepsis-2 criteria and 148 fulfilled the sepsis-3 criteria during the first ten days in the ICU. The odds ratios for 30-day mortality were 0.7 (CI 0.4–1.2) for sepsis-2 and 1.5 (CI 0.8–2.6) for sepsis-3. When censoring patients dying at day 1, sepsis-3 became associated with 30-day mortality whereas sepsis-2 did not. This finding was persistent and enhanced through continuing day-by-day censoring of early deaths. The same pattern was seen for the ROC curves analyses, censoring of early deaths resulted in significant discriminatory properties for sepsis-3 but not for sepsis-2. Conclusions The sepsis-3 definition identifies much fewer patients and is more strongly associated with adverse outcomes than the sepsis-2 definition. The sepsis-3 definition seems to be useful in the post trauma setting.

Background Thioredoxin (TRX), an endogenous anti-oxidant protein induced in inflammatory conditions, has been shown to increase in plasma and to be associated with outcome in septic patients. This biomarker has never been studied in a trauma setting. We hypothesized that TRX would be increased after trauma and associated with post-injury sepsis. Methods Single-centre prospective observational study conducted at the intensive care unit (ICU) at the Karolinska University Hospital, Stockholm, Sweden, a level-1 trauma centre. Eighty-three severely injured trauma patients, 18 years or older, with an ICU stay of three days or more were included. Plasma samples were obtained on day 1 and 3 after informed consent. Clinical, physiological and outcome data were retrieved from the trauma and ICU research registries. Plasma samples were also obtained from 15 healthy subjects. In addition, a standardized porcine trauma model was conducted where a femur fracture followed by a controlled hemorrhage period were inflicted in four pigs. Results In pigs, however not significant, there was a continuing increase in plasma-TRX after femur fracture and sequential hemorrhage despite near normalisation of cardiac index and lactate levels. In patients, median injury severity score was 29 and 48 patients developed sepsis during their ICU stay. A three-fold increase in initial TRX was seen in trauma patients when compared to healthy volunteers. Thioredoxin was significantly higher in patients in shock on admission, those subject to massive transfusion and in the most severely injured patients. No difference was seen between survivors and non-survivors. Plasma-TRX on day 1 was significantly increased in patients who later developed post-injury sepsis. In a logistic regression analysis including TRX, C-reactive protein, injury severity, massive transfusion, and admission blood pressure, TRX was the only variable independently associated with post-injury sepsis. Conclusions This study demonstrates that TRX is released into plasma in response to severe trauma and independently associated with post-injury sepsis. The use of TRX as a biomarker in trauma patients needs further evaluation in larger studies. Level of evidence Retrospective cohort study, level III.

The re-establishment of adequate blood flow in a vessel with a reduced lumen due to an atherosclerotic plaque by percutaneous vascular intervention is a well established procedure. However, the long-term outcome of such interventions is negatively influenced by the development of intimal hyperplasia/restenosis. Although extensively researched, this still represents a significant clinical problem. Retinoids, i.e. natural and synthetic derivates of vitamin A, represent a potential therapeutic compound, since they have been shown to influence the vast majority of processes that ultimately lead to reocclusion of the injured vessel. Retinoids exert their effects at the transcriptional level through their nuclear receptors. Targeting multiple processes, i.e. proliferation, migration, extracellular matrix composition and cell differentiation, as well as coagulation/fibrinolysis, should increase their future role in the prevention of restenosis. The purpose of this review is to summarize the diverse effects of retinoids on pathobiological and biological processes activated at sites of vascular injury with particular emphasis on intimal hyperplasia/restenosis after endovascular interventions.

Vascular disease is multifactorial and smooth muscle cells (SMCs) play a key role. Retinoids have been shown to influence many disease-promoting processes including proliferation and differentiation in the vessel wall. Phenotypic heterogeneity of vascular SMCs is a well-known phenomenon and phenotypic modulation of SMCs precedes intimal hyperplasia. The SMCs that constitute the intimal hyperplasia demonstrate a distinct phenotype and differ in gene expression compared to medial SMCs. Cellular retinol-binding protein-1 (CRBP-I), involved in retinoid metabolism, is highly expressed in intimal SMCs, indicating altered retinoid metabolism in this subset of cells. The aim of this study was to evaluate the metabolism of all-trans ROH (atROH), the circulating prohormone to active retinoids, in vascular SMCs of different phenotypes. The results show an increased uptake of atROH in intimal SMCs compared to medial SMCs as well as increased expression of the retinoid-metabolizing enzymes retinol dehydrogenase-5 and retinal dehydrogenase-1 and, in conjunction with this gene expression, increased production of all-trans retinoic acid (atRA). Furthermore, the retinoic acid-catabolizing enzyme CYP26A1 is expressed at higher levels in medial SMCs compared to intimal SMCs. Thus, both retinoid activation and deactivation processes are in operation. To analyze if the difference in ROH metabolism was also correlated to differences in the biological response to retinol, the effects of ROH on proliferation of SMCs with this phenotypic heterogeneity were studied. We found that intimal SMCs showed a dose- and time-dependent growth inhibition when treated with atROH in contrast to medial SMCs, in which atROH had a mitogenic effect. This study shows, for the first time, that (1) vascular SMCs are able to synthesize biologically active atRA from the prohormone atROH, (2) intimal SMCs have a higher capacity to internalize atROH and metabolize atROH into atRA compared to medial SMCs and (3) atROH inhibits growth of intimal SMCs, but induces medial SMC growth.

Abstract —We have recently shown that all- trans retinoic acid (tRA) modulates arterial smooth muscle cell (SMC) morphologic features and biochemical composition in vitro. It has been proposed that different SMC phenotypes coexist in arteries, which may be retrieved in culture: hence, a differential action of tRA on distinct SMC subsets is conceivable. We have examined the effect of tRA on SMC proliferation, migration, plasminogen activator activity, and α-smooth muscle actin expression in 2 phenotypically different rat SMC populations, cultured respectively from the normal aortic media and from the intimal thickening (IT) after endothelial injury. tRA inhibited proliferation and increased migration and tissue-type plasminogen activator activity in both SMC populations, but decreased α-smooth muscle actin only in SMC cultured from the IT. The action of tRA is mediated by 2 families of nuclear receptors, RAR and RXR, each containing 3 isoforms, α, β, and γ. RAR and RAR-α agonists, but not RXR agonists, inhibited SMC proliferation in both cell populations and α-smooth muscle actin expression only in IT SMC. When administered intraperitoneally to balloon-injured rats, tRA and RAR-α agonists reduced the intimal hyperplasia in the carotid artery. Our results show that tRA and synthetic retinoids can affect the proliferation, migration, and differentiation of SMC in vitro. Furthermore, retinoids are able to reduce the IT induced by endothelial injury in vivo.

To investigate the effect of synthetic retinoids on septic shock induced by lipopolysaccharide (LPS) in rats.Randomised study.University hospital laboratory, Sweden.31 male Sprague Dawley rats randomised into four groups: controls, given vehicle alone (n = 6), LPS 6 mg/kg body weight alone (n = 12), and LPS 6 mg/kg but pretreated with the retinoic acid receptor-alpha (RAR-alpha) agonists CD336 (n = 6) and CD2081 (n = 7).Arterial blood pressure and heart rate measured hourly for four hours; mortality.LPS caused a pronounced fall in blood pressure within one hour of injection in all groups of rats. Of the 12 rats given LPS but not RAR-alpha agonists, 6 died before the end of the experiment. By contrast, all animal given either CD336 or CD2081 survived. The significantly improved survival was found despite no significant improvements in either mean arterial pressure or heart rate.Pretreatment with selective synthetic RAR-alpha agonists improves survival after LPS-induced septic shock in rats. These agents may have therapeutic potential in the treatment of septic shock in humans.

Trauma is one of the leading causes of mortality worldwide, resulting in a great global burden of disability and mortality [1, 2]. Approximately half of all trauma deaths occur during the first hours due to traumatic brain injury or massive bleeding. Later deaths are due to, for example, sepsis or multiple organ failure [3]. Independent risk factors for post-injury sepsis are still somewhat poorly defined. Injury Severity Score (ISS), male gender, age, low Glasgow Coma Scale (GCS) and massive blood transfusion have been suggested as risk factors [4]. Thioredoxin (TRX) is thought to have important anti-oxidant properties but it also functions as an endogenous anti-inflammatory mediator [5]. The link between high plasma levels of TRX and sepsis has been studied previously, although with conflicting evidence [5, 6]. TRX-levels in trauma patients and the possible correlation to secondary complications such as post-injury sepsis and acute respiratory distress syndrome (ARDS) have to our knowledge not been studied previously.