[Show abstract][Hide abstract] ABSTRACT: Cardiac surgery encompasses various stimuli that trigger pro-inflammatory mediators, reactive oxygen species and mobilization of leucocytes. The aim of this study was to evaluate the effect of xenon on the inflammatory response during cardiac surgery.
This randomized trial enrolled 30 patients who underwent elective on-pump coronary-artery bypass grafting in balanced anaesthesia of either xenon or sevoflurane. For this secondary analysis, blood samples were drawn prior to the operation, intra-operatively and on the first post-operative day to measure the pro- and anti-inflammatory cytokines interleukin-6 (IL-6), interleukin-8/C-X-C motif ligand 8 (IL-8/CXCL8), and interleukin-10 (IL-10). Chemokines such as C-X-C motif ligand 12/ stromal cell-derived factor-1α (CXCL12/SDF-1α) and macrophage migration inhibitory factor (MIF) were measured to characterize xenon’s perioperative inflammatory profile and its impact on migration of peripheral blood mononuclear cells (PBMC).
Xenon enhanced the postoperative increase of IL-6 compared to sevoflurane (Xenon: 90.7 versus sevoflurane: 33.7 pg/ml; p = 0.035) and attenuated the increase of IL-10 (Xenon: 127.9 versus sevoflurane: 548.3 pg/ml; p = 0.028). Both groups demonstrated a comparable intraoperative increase of oxidative stress (intra-OP: p = 0.29; post-OP: p = 0.65). While both groups showed an intraoperative increase of the cardioprotective mediators MIF and CXCL12/SDF-1α, only MIF levels decreased in the xenon group on the first postoperative day (50.0 ng/ml compared to 23.3 ng/ml; p = 0.012), whereas it remained elevated after sevoflurane anaesthesia (58.3 ng/ml to 53.6 ng/ml). Effects of patients’ serum on chemotactic migration of peripheral mononuclear blood cells taken from healthy volunteers indicated a tendency towards enhanced migration after sevoflurane anaesthesia (p = 0.07).
Compared to sevoflurane, balanced xenon anaesthesia triggers pro-inflammatory effects and suppresses the anti-inflammatory response in cardiac surgery patients even though the clinical significance remains unknown.
This clinical trial was approved by the European Medicines Agency (EudraCT-number: 2010-023942-63) and at ClinicalTrials.gov (NCT01285271; first received: January 24, 2011).
Preview · Article · Dec 2015 · Critical care (London, England)
[Show abstract][Hide abstract] ABSTRACT: Background In this observational study near infrared spectroscopy (NIRS) was evaluated as a non-invasive monitor of impaired tissue oxygenation (StO2) after cardiac surgery. StO2, cardiac output, mixed venous oxygen saturation and mean arterial pressure were compared with lactate clearance as established measure for sufficient tissue perfusion and oxygen metabolism. Methods Forty patients after cardiac surgery (24 aortocoronary bypass grafting, 5 heart valve, 3 ascending aorta and 8 combined procedures) were monitored until postoperative day 1 with NIRS of the thenar muscle (InSpectra™ StO2-monitor, Hutchinson Technology), a pulmonary-artery catheter and intermittent blood gas analyses for the assessment of lactate clearance. Results StO2 was reduced 4 h after surgery (75 ± 6 %), but recovered at day 1 (84 ± 5 %), while lactate concentration remained increased. Using uni- and multivariate regression analysis, minimum StO2 (r = 0.46, p <0.01) and cardiac index (r = 0.40, p <0.05) correlated with lactate clearance at day 1, while minimum mixed venous saturation and mean arterial pressure did not. In a receiver-operating characteristics (ROC) analysis, minimum StO2 (with a threshold of 75 %) predicted a lactate clearance <10 % at day 1 with an area under the ROC-curve of 0.83, a sensitivity of 78 % and a specificity of 88 %. In the subgroup with StO2 <75 %, troponin and creatine kinase MB were significantly increased at day 1. Conclusions StO2 below 75 % in the first hours after surgery was a better early indicator of persistent impaired lactate clearance at day 1 than cardiac index, mixed venous oxygen saturation or mean arterial pressure.
[Show abstract][Hide abstract] ABSTRACT: Heparanase is an endo-β-glucuronidase that cleaves heparan sulfate side chains from their proteoglycans. Thereby, heparanase liberates highly potent circulating heparan sulfate-fragments (HS-fragments) and triggers the fatal and excessive inflammatory response in sepsis. As a potential anti-inflammatory agent for sepsis therapy, peptide 19-2.5 belongs to the class of synthetic anti-lipopolysaccharide peptides; however, its activity is not restricted to Gram-negative bacterial infection. We hypothesized that peptide 19-2.5 interacts with heparanase and/or HS, thereby reducing the levels of circulating HS-fragments in murine and human sepsis. Our data indicate that the treatment of septic mice with peptide 19-2.5 compared to untreated control animals lowers levels of plasma heparanase and circulating HS-fragments and reduces heparanase activity. Additionally, mRNA levels of heparanase in heart, liver, lung, kidney and spleen are downregulated in septic mice treated with peptide 19-2.5 compared to untreated control animals. In humans, plasma heparanase level and activity are elevated in septic shock. The ex vivo addition of peptide 19-2.5 to plasma of septic shock patients decreases heparanase activity but not heparanase level. Isothermal titration calorimetry revealed a strong exothermic reaction between peptide 19-2.5 and heparanase and HS-fragments. However, a saturation character has been identified only in the peptide 19-2.5 and HS interaction. In conclusion, the findings of our current study indicate that peptide 19-2.5 interacts with heparanase, which is elevated in murine and human sepsis and consecutively attenuates the generation of circulating HS-fragments in systemic inflammation. Thus, peptide 19-2.5 seems to be a potential anti-inflammatory agent in sepsis.
[Show abstract][Hide abstract] ABSTRACT: To secure the functionality of activated macrophages in the innate immune response, efficient life span control is required. Recognition of bacterial lipopolysaccharides (LPS) by toll-like receptor 4 (TLR4) induces downstream signaling pathways, which merge to induce the expression of cytokine genes and anti-apoptotic genes. MicroRNAs (miRNAs) have emerged as important inflammatory response modulators, but information about their functional impact on apoptosis is scarce. To identify miRNAs differentially expressed in response to LPS, cDNA libraries from untreated and LPS-activated murine macrophages were analyzed by deep sequencing and regulated miRNA expression was verified by Northern blotting and qPCR. Employing TargetScan™ we identified CASPASE-3 (CASP-3) mRNA that encodes a key player in apoptosis as potential target of LPS-induced miR-155. LPS-dependent primary macrophage activation revealed TLR4-mediated enhancement of miR-155 expression and CASP-3 mRNA reduction. Endogenous CASP-3 and cleaved CASP-3 protein declined in LPS-activated macrophages. Accumulation of miR-155 and CASP-3 mRNA in miRNA-induced silencing complexes (miRISC) was demonstrated by ARGONAUTE 2 (AGO2) immunoprecipitation. Importantly, specific antagomir transfection effectively reduced mature miR-155 and resulted in significantly elevated CASP-3 mRNA levels in activated macrophages. In vitro translation assays demonstrated that the target site in the CASP-3 mRNA 3'UTR mediates miR-155-dependent Luciferase reporter mRNA destabilization. Strikingly, Annexin V staining of macrophages transfected with antagomir-155 and stimulated with LPS prior to staurosporine (SSP) treatment implied that LPS-induced miR-155 prevents apoptosis through CASP-3 mRNA down-regulation. In conclusion, we report that miR-155-mediated CASP-3 mRNA destabilization in LPS-activated RAW 264.7 macrophages suppresses apoptosis, as a prerequisite to maintain their crucial function in inflammation.
[Show abstract][Hide abstract] ABSTRACT: The heart is one of the most frequently affected organs in sepsis. Recent studies focused on lipopolysaccharide induced mitochondrial dysfunction, however myocardial dysfunction is not restricted to Gram-negative bacterial sepsis. The purpose of this study was to investigate circulating heparan sulfate (HS) as an endogenous danger associated molecule causing cardiac mitochondrial dysfunction in sepsis. We used an in vitro model with native sera (SsP) and sera eliminated from HS (HS-free), both of septic shock patients, to stimulate murine cardiomyocytes. As determined by extracellular flux analyzing, SsP increased basal mitochondrial respiration, but reduced maximum mitochondrial respiration, compared to unstimulated cells (p < 0.0001 and p < 0.0001, respectively). Cells stimulated with HS-free serum revealed unaltered basal and maximum mitochondrial respiration, compared to unstimulated cells (p = 0.1174 and p = 0.8992, respectively). Cellular ATP-level were decreased in SsP-stimulated cells but unaltered in cells stimulated with HS-free serum compared to unstimulated cells (p < 0.0001 and p = 0.1593, respectively). Live-cell imaging revealed an increased production of mitochondrial reactive oxygen species in cells stimulated with SsP compared to cells stimulated with HS-free serum (p < 0.0001). Expression of peroxisome proliferator-activated receptors (PPARα and PPARγ) and their co-activators PGC-1α, which regulate mitochondrial function were studied using PCR. Cells stimulated with SsP showed downregulated PPARs and PGC-1α mRNA-levels compared to HS-free serum (p = 0.0082, p = 0.0128 and p = 0.0185 respectively). Blocking Toll-like receptor 4 revealed an inhibition of HS-dependent downregulation of PPARs and PGC-1α (all p < 0.0001). In conclusion, circulating HS in serum of septic shock patients cause cardiac mitochondrial dysfunction, suggesting HS may be targets of therapeutics in septic cardiomyopathy.
No preview · Article · Nov 2015 · Shock (Augusta, Ga.)
[Show abstract][Hide abstract] ABSTRACT: The demographic challenge of the ageing society is associated with increasing comorbidity. On the other hand, there will be an ageing workforce in medicine, resulting in an imbalance between the demand and supply of medical care in the near future. In rural areas in particular, this imbalance is already present today. Based on three best practice projects carried out by our telemedical center in Aachen, including emergency medicine, intensive care medicine, and the rehabilitation planning of geriatric trauma care, some experience and the potential of the intersectoral provision of care, supported by telemedicine, are demonstrated. Telemedicine is the provision of medical services over a geographical distance by using tele-communication and data transfer. It has been proven to ensure a constant quality of health care. Telemedical support enables shared expertise independent of time and space, and allows efficient allocation of resources. A review of international experience supports this notion.
[Show abstract][Hide abstract] ABSTRACT: In view of demographic changes over the past few decades, the average age of trauma patients is progressively increasing. We therefore aimed to summarize the specific characteristics of geriatric trauma and to identify potential fields for further research to improve the care of elderly trauma patients.
Review of the literature.
Due to the diverse risk factors (e.g., pre-existing conditions, limited physiological reserve), geriatric patients are prone to developing severe complications, even after less severe trauma. Yet, age is not considered as the only predictor of worse outcomes, and it should not be considered the only criterion for limiting care in those patients. It is crucial that age-specific treatment guidelines are developed to optimize the outcomes for senior trauma patients. Based on the current literature, these guidelines should emphasize the importance of field triage directly to a trauma center, along with the activation of the trauma team. Furthermore, early intensive monitoring, aggressive resuscitation, and time of surgical intervention are of upmost importance to reduce mortality.
The impact of several factors [age, premedical conditions (PMC), decreased physiological reserves, and impaired immune function] on the post-traumatic course of elderly trauma patients needs to be clarified in future experimental and clinical studies for the early identification of geriatric high-risk patients and for the development of age-adapted therapeutic strategies.
Full-text · Article · Aug 2015 · European Journal of Trauma and Emergency Surgery