Heterocomplexes between the atypical chemokine MIF and the CXC-motif chemokine CXCL4L1 regulate inflammation and thrombus formation.

To fulfil its orchestration of immune cell trafficking, a network of chemokines and receptors developed that capitalizes on specificity, redundancy, and functional selectivity. The discovery of heteromeric interactions in the chemokine interactome has expanded the complexity within this network. Moreover, some inflammatory mediators, not structurally linked to classical chemokines, bind to chemokine receptors and behave as atypical chemokines (ACKs). We identified macrophage migration inhibitory factor (MIF) as an ACK that binds to chemokine receptors CXCR2 and CXCR4 to promote atherogenic leukocyte recruitment. Here, we hypothesized that chemokine-chemokine interactions extend to ACKs and that MIF forms heterocomplexes with classical chemokines. We tested this hypothesis by using an unbiased chemokine protein array. Platelet chemokine CXCL4L1 (but not its variant CXCL4 or the CXCR2/CXCR4 ligands CXCL8 or CXCL12) was identified as a candidate interactor. MIF/CXCL4L1 complexation was verified by co-immunoprecipitation, surface plasmon-resonance analysis, and microscale thermophoresis, also establishing high-affinity binding. We next determined whether heterocomplex formation modulates inflammatory/atherogenic activities of MIF. Complex formation was observed to inhibit MIF-elicited T-cell chemotaxis as assessed by transwell migration assay and in a 3D-matrix-based live cell-imaging set-up. Heterocomplexation also blocked MIF-triggered migration of microglia in cortical cultures in situ, as well as MIF-mediated monocyte adhesion on aortic endothelial cell monolayers under flow stress conditions. Of note, CXCL4L1 blocked binding of Alexa-MIF to a soluble surrogate of CXCR4 and co-incubation with CXCL4L1 attenuated MIF responses in HEK293-CXCR4 transfectants, indicating that complex formation interferes with MIF/CXCR4 pathways. Because MIF and CXCL4L1 are platelet-derived products, we finally tested their role in platelet activation. Multi-photon microscopy, FLIM-FRET, and proximity-ligation assay visualized heterocomplexes in platelet aggregates and in clinical human thrombus sections obtained from peripheral artery disease (PAD) in patients undergoing thrombectomy. Moreover, heterocomplexes inhibited MIF-stimulated thrombus formation under flow and skewed the lamellipodia phenotype of adhering platelets. Our study establishes a novel molecular interaction that adds to the complexity of the chemokine interactome and chemokine/receptor-network. MIF/CXCL4L1, or more generally, ACK/CXC-motif chemokine heterocomplexes may be target structures that can be exploited to modulate inflammation and thrombosis.

Lung Ultrasound as a Promising Diagnostic Tool for Primary Graft Dysfunction after Lung Transplantation.

PURPOSE: The aim of the study was to evaluate whether the quantification of B-lines via lung ultrasound after lung transplantation is feasible and correlates with the diagnosis of primary graft dysfunction. METHODS: Following lung transplantation, patients underwent daily lung ultrasound on postoperative days 1-3. B-lines were quantified by an ultrasound score based on the number of single and confluent B-lines per intercostal space, using a four-region protocol. The ultrasound score was correlated with the diagnosis of primary graft dysfunction. Furthermore, correlation analyses and receiver operating characteristics analyses taking into account ultrasound score, chest radiographs, and PaO2/FiO2 ratio were performed. RESULTS: A total of 32 patients (91 ultrasound measurements) were included, whereby 10 were diagnosed with primary graft dysfunction. The median B-line score was 5 [IQR: 4, 8]. There was a significant correlation between B-line score and the diagnosis of primary graft dysfunction (r = 0.59, p < 0.001). A significant correlation could also be seen between chest X-rays and primary graft dysfunction (r = 0.34, p = 0.008), but the B-line score showed superiority over chest X-rays with respect to diagnosing primary graft dysfunction in the receiver operating characteristics curves with an area under the curve value of 0.921 versus 0.708. There was a significant negative correlation between B-line score and PaO2/FiO2 ratio (r = -0.41, p < 0.001), but not between chest X-rays and PaO2/FiO2 ratio (r = -0.14, p = 0.279). CONCLUSION: The appearance of B-lines correlated well with primary graft dysfunction and outperformed chest radiographs.

Functional Testing for Tranexamic Acid Duration of Action Using Modified Viscoelastometry.

INTRODUCTION: Tranexamic acid (TXA) is the standard medication to prevent or treat hyperfibrinolysis. However, prolonged inhibition of lysis (so-called "fibrinolytic shutdown") correlates with increased mortality. A new viscoelastometric test enables bedside quantification of the antifibrinolytic activity of TXA using tissue plasminogen activator (TPA). MATERIALS AND METHODS: Twenty-five cardiac surgery patients were included in this prospective observational study. In vivo, the viscoelastometric TPA test was used to determine lysis time (LT) and maximum lysis (ML) over 96 h after TXA bolus. Additionally, plasma concentrations of TXA and plasminogen activator inhibitor 1 (PAI-1) were measured. Moreover, dose effect curves from the blood of healthy volunteers were performed in vitro. Data are presented as median (25-75th percentile). RESULTS: In vivo TXA plasma concentration correlated with LT (r = 0.55; p < 0.0001) and ML (r = 0.62; p < 0.0001) at all time points. Lysis was inhibited up to 96 h (LTTPA-test: baseline: 398 s [229-421 s] vs. at 96 h: 886 s [626-2,175 s]; p = 0.0013). After 24 h, some patients (n = 8) had normalized lysis, but others (n = 17) had strong lysis inhibition (ML <30%; p < 0.001). The high- and low-lysis groups differed regarding kidney function (cystatin C: 1.64 [1.42-2.02] vs. 1.28 [1.01-1.52] mg/L; p = 0.002) in a post hoc analysis. Of note, TXA plasma concentration after 24 h was significantly higher in patients with impaired renal function (9.70 [2.89-13.45] vs.1.41 [1.30-2.34] µg/mL; p < 0.0001). In vitro, TXA concentrations of 10 µg/mL effectively inhibited fibrinolysis in all blood samples. CONCLUSIONS: Determination of antifibrinolytic activity using the TPA test is feasible, and individual fibrinolytic capacity, e.g., in critically ill patients, can potentially be measured. This is of interest since TXA-induced lysis inhibition varies depending on kidney function.

Natriuretic Peptides as a Prognostic Marker for Delirium in Cardiac Surgery-A Pilot Study.

Background and Objectives: Delirium is a common and major complication subsequent to cardiac surgery. Despite scientific efforts, there are no parameters which reliably predict postoperative delirium. In delirium pathology, natriuretic peptides (NPs) interfere with the blood-brain barrier and thus promote delirium. Therefore, we aimed to assess whether NPs may predict postoperative delirium and long-term outcomes. Materials and Methods: To evaluate the predictive value of NPs for delirium we retrospectively analyzed data from a prospective, randomized study for serum levels of atrial natriuretic peptide (ANP) and the precursor of C-type natriuretic peptide (NT-proCNP) in patients undergoing coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass (off-pump coronary bypass grafting; OPCAB). Delirium was assessed by a validated chart-based method. Long-term outcomes were assessed 10 years after surgery by a telephone interview. Results: The overall incidence of delirium in the total cohort was 48% regardless of the surgical approach (CABG vs. OPCAB). Serum ANP levels >64.6 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 100% (75.3-100) and specificity of 42.9% (17.7-71.1). Serum NT-proCNP levels >1.7 pg/mL predicted delirium with a sensitivity (95% confidence interval) of 92.3% (64.0-99.8) and specificity of 42.9% (17.7-71.1). Both NPs could not predict postoperative survival or long-term cognitive decline. Conclusions: We found a positive correlation between delirium and preoperative plasma levels of ANP and NT-proCNP. A well-powered and prospective study might identify NPs as biomarkers indicating the risk of delirium and postoperative cognitive decline in patients at risk for postoperative delirium.

Altered renal functions in patients with occlusion of an accessory renal artery after endovascular stenting of an infrarenal aneurysm.

OBJECTIVE: Coverage of an accessory renal artery (ARA) during endovascular aneurysm repair (EVAR) may result in renal infarction (RI) or decline in renal function. Until now, it remains vague which patients are at risk to develop these complications. We therefore analyzed the effect of ARA sealing by EVAR with respect to the occurrence of RI and renal function. METHODS: A retrospective analysis of the medical records and computed tomographic scans of patients who underwent EVAR within a period of 5 years was performed. Particular attention was paid to the presence or absence of accessory renal arteries and renal function before EVAR. Thirty-four patients with ARA were matched 1:3 to 102 patients without ARA. The results after EVAR were analyzed in patients with and without ARA. In patients with ARA, we further examined the results after EVAR in patients with an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min and eGFR < 60 mL/min before EVAR. RESULTS: Before EVAR, the median eGFR was 74 mL/min (25th/75th percentiles, 57/89) in patients with ARA and 72 mL/min (25th/75th percentiles, 63/87) in patients without ARA. Alterations in eGFR were significantly pronounced in patients with ARA when compared with patients without ARA 1 week after EVAR (ARA, -10.7 ± 16.9 mL/min vs without ARA, 1.2 ± 13.3 mL/min; P = .002) and after 6 months (ARA, -10.8 ± 17.4 mL/min vs without ARA, 1.2 ± 13.3 mL/min; P = .001). RI only occurred in patients with ARA. Within the group of patients with ARA, patients with normal renal function (NF) showed a more pronounced decline in eGFR preoperatively when compared with patients with impaired renal function (IF) 1 week after EVAR (NF, -14.3 ± 18.0 mL/min vs IF, -1.3 ± 10.8 mL/min; P = .02) and after 6 months (NF, -15.8 ± 17.9 mL/min vs IF, 0.1 ± 15.2 mL/min; P = .007). CONCLUSIONS: The decrease in renal function was more pronounced in patients with ARA after EVAR when compared with patients without ARA undergoing EVAR. In patients with ARA, the observed decline in renal function was significantly distinct in patients presenting NF preoperatively. Consequently, the risk of IF after EVAR seems to be increased in patients with ARA and normal preoperative renal function.

Predicting the Necessity for Extracorporeal Circulation During Lung Transplantation: A Feasibility Study.

OBJECTIVE: The factors leading to the implementation of unplanned extracorporeal circulation during lung transplantation are poorly defined. Consequently, the authors aimed to identify patients at risk for unplanned extracorporeal circulation during lung transplantation. DESIGN: Retrospective data analysis. SETTING: Single-center university hospital. PARTICIPANTS: A development data set of 170 consecutive patients and an independent validation cohort of 52 patients undergoing lung transplantation. INTERVENTIONS: The authors investigated a cohort of 170 consecutive patients undergoing single or sequential bilateral lung transplantation without a priori indication for extracorporeal circulation and evaluated the predictive capability of distinct preoperative and intraoperative variables by using automated model building techniques at three clinically relevant time points (preoperatively, after endotracheal intubation, and after establishing single-lung ventilation). MEASUREMENTS AND MAIN RESULTS: Preoperative mean pulmonary arterial pressure was the strongest predictor for unplanned extracorporeal circulation. A logistic regression model based on preoperative mean pulmonary arterial pressure and lung allocation score achieved an area under the receiver operating characteristic curve of 0.85. Consequently, the authors developed a novel 3-point scoring system based on preoperative mean pulmonary arterial pressure and lung allocation score, which identified patients at risk for unplanned extracorporeal circulation and validated this score in an independent cohort of 52 patients undergoing lung transplantation. CONCLUSIONS: The authors showed that patients at risk for unplanned extracorporeal circulation during lung transplantation could be identified by their novel 3-point score.

A Comparison of Web-Based with Traditional Classroom-Based Training of Lung Ultrasound for the Exclusion of Pneumothorax.

BACKGROUND: Lung ultrasound (LUS) is a well-established method that can exclude pneumothorax by demonstration of pleural sliding and the associated ultrasound artifacts. The positive diagnosis of pneumothorax is more difficult to obtain and relies on detection of the edge of a pneumothorax, called the "lung point." Yet, anesthesiologists are not widely taught these techniques, even though their patients are susceptible to pneumothorax either through trauma or as a result of central line placement or regional anesthesia techniques performed near the thorax. In anticipation of an increased training demand for LUS, efficient and scalable teaching methods should be developed. In this study, we compared the improvement in LUS skills after either Web-based or classroom-based training. We hypothesized that Web-based training would not be inferior to "traditional" classroom-based training beyond a noninferiority limit of 10% and that both would be superior to no training. Furthermore, we hypothesized that this short training session would lead to LUS skills that are similar to those of ultrasound-trained emergency medicine (EM) physicians. METHODS: After a pretest, anesthesiologists from 4 academic teaching hospitals were randomized to Web-based (group Web), classroom-based (group class), or no training (group control) and then completed a posttest. Groups Web and class returned for a retention test 4 weeks later. All 3 tests were similar, testing both practical and theoretical knowledge. EM physicians (group EM) performed the pretest only. Teaching for group class consisted of a standardized PowerPoint lecture conforming to the Consensus Conference on LUS followed by hands-on training. Group Web received a narrated video of the same PowerPoint presentation, followed by an online demonstration of LUS that also instructs the viewer to perform an LUS on himself using a clinically available ultrasound machine and submit smartphone snapshots of the resulting images as part of a portfolio system. Group Web received no other hands-on training. RESULTS: Groups Web, class, control, and EM contained 59, 59, 20, and 42 subjects. After training, overall test results of groups Web and class improved by a mean of 42.9% (±18.1% SD) and 39.2% (±19.2% SD), whereas the score of group control did not improve significantly. The test improvement of group Web was not inferior to group class. The posttest scores of groups Web and class were not significantly different from group EM. In comparison with the posttests, the retention test scores did not change significantly in either group. CONCLUSIONS: When training anesthesiologists to perform LUS for the exclusion of pneumothorax, we found that Web-based training was not inferior to traditional classroom-based training and was effective, leading to test scores that were similar to a group of clinicians experienced in LUS.

Application of interleukin-22 mediates protection in experimental acetaminophen-induced acute liver injury.

Acetaminophen (APAP, paracetamol)-induced hepatotoxicity, although treatable by timely application of N-acetylcysteine, can be fatal. Because it is among the common causes of acute liver failure in intensive care units and in light of its gradually increasing incidence, the need for novel therapeutic strategies aimed at severe intoxication is apparent. Recently, it has been shown that IL-22, a STAT3-activating cytokine, has the capability to mediate liver protection. Herein, the protective potential of IL-22 in murine APAP-induced hepatotoxicity was assessed. Intravenous administration of prophylactic IL-22 significantly reduced serum alanine aminotransferase levels and histopathologic damage in APAP-induced liver injury, a process that coincided with increased hepatocyte proliferation in vivo. Concomitant gene expression analysis revealed hepatic induction of genes prototypically up-regulated by the IL-22/STAT3 axis, among others suppressor of cytokine signaling-3, lipocalin-2, and α1-antichymotrypsin. Notably, in a translational setting of therapeutic treatment 2 hours after APAP, IL-22 supported protection in the context of suboptimal N-acetylcysteine dosing. IL-22 likewise connected to augmented hepatocyte proliferation in this experimental setting. As detected by analysis of inflammatory cytokine production, systemically applied IL-22 did not display acute immunomodulation/stimulation in otherwise untreated or endotoxemic mice. Those latter observations clearly confirm acute tolerability of systemically applied IL-22. Observations presented altogether suggest that therapeutic IL-22 administration is a conceivable tissue-protective regimen aimed at hard-to-treat patients with severe APAP-induced hepatotoxicity.

IL-36γ/IL-1F9, an innate T-bet target in myeloid cells.

By concerted action in dendritic (DC) and T cells, T-box expressed in T cells (T-bet, Tbx21) is pivotal for initiation and perpetuation of Th1 immunity. Identification of novel T-bet-regulated genes is crucial for further understanding the biology of this transcription factor. By combining siRNA technology with genome-wide mRNA expression analysis, we sought to identify new T-bet-regulated genes in predendritic KG1 cells activated by IL-18. One gene robustly dependent on T-bet was IL-36γ, a recently described novel IL-1 family member. Promoter analysis revealed a T-bet binding site that, along with a κB site, enables efficient IL-36γ induction. Using knock-out animals, IL-36γ reliance on T-bet was extended to murine DC. IL-36γ expression by human myeloid cells was confirmed using monocyte-derived DC and M1 macrophages. The latter model was employed to substantiate dependence of IL-36γ on endogenous T-bet in human primary cells. Ectopic expression of T-bet likewise mediated IL-36γ production in HaCaT keratinocytes that otherwise lack this transcription factor. Additional experiments furthermore revealed that mature IL-36γ has the capability to establish an inflammatory gene expression profile in human primary keratinocytes that displays enhanced mRNA levels for TNFα, CCL20, S100A7, inducible NOS, and IL-36γ itself. Data presented herein shed further light on involvement of T-bet in innate immunity and suggest that IL-36γ, besides IFNγ, may contribute to functions of this transcription factor in immunopathology.

Lipid peroxidation in multidrug-resistant Gram-negative sepsis: translating science to the septic patient?

Multidrug-resistant Gram-negative induced sepsis poses an increasing threat to the vulnerable intensive care patient. The study by Toufekoula and colleagues reports the serum and tissue concentration of malondialdehyde (MDA), the toxic end product of lipid peroxidation, during the course of experimental and human Gram-negative sepsis. The complementary results from this dual experimental and clinical approach argue for highly compartmentalized lipid peroxidation during sepsis. Establishing a correlation between MDA concentration and survival provides valuable insights into the pathophysiology of Gram-negative sepsis. Yet, further studies are needed to understand and establish MDA as a biomarker during sepsis aggravated by organ failure.

Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury.

High-pressure ventilation induces barotrauma and pulmonary inflammation, thus leading to ventilator-induced lung injury (VILI). IL-22 has both immunoregulatory and tissue-protective properties. Functional IL-22 receptor expression is restricted to nonleukocytic cells, such as alveolar epithelial cells. When applied via inhalation, IL-22 reaches the pulmonary system directly and in high concentrations, and may protect alveolar epithelial cells against cellular stress and biotrauma associated with VILI. In A549 lung epithelial cells, IL-22 was able to induce rapid signal transducer and activator of transcription (STAT)-3 phosphorylation/activation, and hereon mediated stable suppressor of cytokine signaling (SOCS) 3 expression detectable even 24 hours after onset of stimulation. In a rat model of VILI, the prophylactic inhalation of IL-22 before induction of VILI (peak airway pressure = 45 cm H(2)O) protected the lung against pulmonary disintegration and edema. IL-22 reduced VILI-associated biotrauma (i.e., pulmonary concentrations of macrophage inflammatory protein-2, IL-6, and matrix metalloproteinase 9) and mediated pulmonary STAT3/SOCS3 activation. In addition, despite a short observation period of 4 hours, inhaled IL-22 resulted in an improved survival of the rats. These data support the hypothesis that IL-22, likely via activation of STAT3 and downstream genes (e.g., SOCS3), is able to protect against cell stretch and pulmonary baro-/biotrauma by enhancing epithelial cell resistibility.

Effects of short-term infusion of lipid emulsions on pro-inflammatory cytokines and lymphocyte apoptosis in septic and non-septic rats.

Long-term administration of PUFA is known to modulate immune functions and apoptotic pathways depending on the respective amount of n-6 and n-3 fatty acids (FA). Data on short-term effects on apoptotic pathways are rare. Apoptosis of splenic lymphocytes is the hallmark of detrimental sepsis. Therefore, we aimed to compare the immediate effects of parenterally administered n-6-enriched soyabean oil (SO)- and n-3-enriched fish oil (FO)-based lipid emulsions after laparotomy (LAP; sham procedure) and after induction of acute, severe sepsis by caecal ligation and incision. After 390 min of observation time, plasma was analysed for IL-1ß, IL-6 and NEFA. Apoptosis in splenic lymphocytes was quantified by Annexin-V expression. After LAP, infusion of both FO and SO did not change cytokine concentrations. Sepsis increased both cytokines. FO but not SO further augmented the rise. After LAP, SO increased NEFA, and both lipid emulsions reduced free arachidonic acid (AA). Sepsis resulted in a dramatic decrease in NEFA and AA. The drop in NEFA and AA was prevented by both SO and FO. In addition, FO resulted in an increased concentration of n-3 FA under both conditions. Infusion of both lipid emulsions induced apoptosis in splenic lymphocytes after LAP. Sepsis-induced apoptosis was not further enhanced by FO or SO. The present study shows that short-term administration of FO as opposed to SO caused pro-inflammatory effects during sepsis. Moreover, short-term administration of both SO and FO suffices to induce apoptosis in splenic lymphocytes. Finally, SO and FO do not further enhance sepsis-induced splenic apoptosis.

Cecal ligation and incision: an acute onset model of severe sepsis in rats.

BACKGROUND: Sepsis is a leading cause of death among critically ill patients. Up to now, severe sepsis with acute onset in animals has been induced mainly through injection of single bacteria species or endotoxin and not through a surgical procedure, which might adequately mirror the situation in septic patients. We therefore aimed to establish a surgical model of severe sepsis in rodents fulfilling international sepsis criteria. MATERIALS AND METHODS: Twenty-eight anesthetized/ventilated Sprague Dawley rats underwent laparotomy and cecal mobilization. The cecum was either replaced into the abdomen (SHAM, n = 14) or the cecum and the mesenteric blood vessels were ligated, and the cecum was opened through a 1.5 cm blade incision (cecal ligation and incision, CLI, n = 14). RESULTS: Within 390 min, mortality was 0% (SHAM) and 50% (CLI), respectively. Compared with SHAM, CLI resulted in a 43% reduction of mean arterial blood pressure and in severe metabolic acidosis as measured by arterial base excess and pH. CLI led to a 15-fold increase in mononuclear cell population and to a 5-fold accumulation of nitrite in peritoneal lavage. Abdominal swabs from the Douglas cavity in CLI-animals showed gram-positive and gram-negative bacterial growth on agar compared with sterile swabs from SHAM-animals. In CLI-animals, plasma IL-1beta level was increased to 435 pg/mL (SHAM: 10 pg/mL) and plasma IL-6 level to 19718 pg/mL (SHAM: 832 pg/mL). CONCLUSIONS: CLI causes bacterial peritonitis with subsequent systemic inflammation and organ dysfunction. Thus, CLI mimics clinical sepsis and provides a surgical short term model of severe sepsis in rodents.

Sevoflurane and isoflurane decrease TNF-alpha-induced gene expression in human monocytic THP-1 cells: potential role of intracellular IkappaBalpha regulation.

The nuclear factor (NF)-kappaB/inhibitory (I)kappaBalpha pathway is one of the most important intracellular signal transduction pathways during inflammation which is induced by a variety of major early response cytokines. Recent studies suggest that volatile anesthetics interfere with inflammatory cytokine production through inhibition of intracellular signal transduction pathways. We, therefore, aimed to investigate the effects of the volatile anesthetics sevoflurane and isoflurane on NF-kappaB/IkappaBalpha-dependent intracellular signal transduction in human monocytic THP-1 cells induced by tumor necrosis factor-alpha (TNF-alpha) and production of interleukin-8 (IL-8) and downstream heme oxygenase-1 (HO-1). THP-1 cells, a human monocytic cell line, were used in an in vitro model which enables the exposure to volatile anesthetics. Using this model, THP-1 cells were subjected to sevoflurane or isoflurane exposure (1 MAC each) and were stimulated with TNF-alpha (50 or 100 ng/ml). Compared to untreated cells, expression of intracellular HO-1-protein and release of IL-8 into cell culture supernatants and corresponding mRNA expression were attenuated in THP-1 cells exposed to sevoflurane and isoflurane, respectively. Moreover, translocation of NF-kappaB and degradation of IkappaBalpha were markedly reduced by both anesthetics. Notably, under unstimulated conditions, exposure to sevoflurane induced a sustained upregulation of the IkappaBalpha content in THP-1 cells. We demonstrated inhibition of TNF-alpha-induced gene expression and release of IL-8 and HO-1 in human monocytic THP-1 cells exposed to both volatile anesthetics. This was associated with an upregulated intracellular IkappaBalpha content followed by decreased NF-kappaB translocation. This was more sustained during exposure to sevoflurane and may provide an additional intracellular mechanism for the anti-inflammatory effects associated with sevoflurane administration.

Haemadsorption improves intraoperative haemodynamics and metabolic changes during aortic surgery with hypothermic circulatory arrest.

OBJECTIVES: Aortic surgery involving hypothermic circulatory arrest (HCA) results in a systemic inflammatory response that may negatively influence outcome. An extracorporeal haemadsorption (HA) device (CytoSorb®) that removes inflammatory triggers may improve haemodynamic and metabolic reactions due to excessive inflammation and, ultimately, outcome. METHODS: As a single-centre experience, the data of 336 patients who had undergone aortic surgery with HCA between 2013 and 2017 were retrospectively analysed. Patients with HA were matched to patients receiving standard therapy without HA (Control) by propensity score matching and compared subsequently. RESULTS: During aortic surgery with HCA, HA significantly reduced the requirement of norepinephrine (HA: 0.102 µg/kg/min; Control: 0.113; P = 0.043). Severe disturbances of acid-base balance as reflected by a pH lower than 7.19 (HA: 7.1%; Control: 11.6%; P = 0.139), maximum lactate concentrations (HA: 3.75 mmol/l; Control: 4.23 P = 0.078) and the need for tris-hydroxymethylaminomethane buffer (HA: 6.5%; Control: 13.7%; P = 0.045) were less frequent with HA. Compared to standard therapy, HA decreased the need for transfusion of packed red blood cells (1 unit; P = 0.021) and fresh frozen plasma (3 units; P = 0.001), but increased the requirement of prothrombin complex concentrate (800 IE, P = 0.0036). HA did not affect inflammatory laboratory markers on the first postoperative day. Differences in operative mortality (HA: 4.8%; Control: 8.8%) and the length of hospital stay (HA: 13.5 days; Control: 14) were not statistically significant. CONCLUSIONS: HA significantly reduces the need for vasopressors, the amount of transfusion and improves acid-base balance in aortic surgery with HCA. Multicentre prospective trials are required to confirm these results.

Inhaled levosimendan reduces mortality and release of proinflammatory mediators in a rat model of experimental ventilator-induced lung injury.

OBJECTIVES: Mechanical ventilation during critical care can cause structural and functional disturbances in the lung with subsequent release of proinflammatory mediators, termed ventilator-induced lung injury (VILI). VILI progressively provokes decreased efficiency of gas exchange with subsequent hypoxic pulmonary vasoconstriction leading to cardiopulmonary alterations, such as pulmonary hypertension and right heart failure. We therefore aimed to evaluate whether inhalation therapy with levosimendan, a calcium-sensitizer with pulmonary vasodilating properties, could attenuate VILI and improve short-term survival in a rat experimental model. DESIGN: Experimental animal model. SETTING: University hospital. SUBJECTS: Forty male Sprague-Dawley rats. INTERVENTIONS: Rats were randomly treated as follows (n = 8, each group): 1) inhalation of the solvent only before induction of VILI, no further intervention; 2) inhalation of 240 microg of levosimendan before VILI induction; 3) inhalation of 24 microg of levosimendan before VILI induction; 4) intravenous administration of 24 microg/kg levosimendan before VILI induction; 5) control group with surgical preparation only. All groups were observed for 4 hrs. MEASUREMENTS AND MAIN RESULTS: After 4 hrs following induction of VILI, levels of interleukin-1beta and macrophage inflammatory protein-2 in plasma and bronchoalveolar lavage fluid were analyzed by enzyme-linked immunosorbent assay. Nitric oxide release from alveolar macrophages was measured by Griess assay. Content of matrix metalloproteinase-2 and matrix metalloproteinase-9 in bronchoalveolar lavage fluid was analyzed by gelatin zymography. Inhalation of 240 microg of levosimendan significantly improved survival after 4 hrs and mean arterial blood pressure compared with VILI only. Additionally, inhalation of 240 microg and infusion of 24 microg/kg levosimendan significantly reduced the release of interleukin-1beta, the nitric oxide release from alveolar macrophages, macrophage inflammatory protein-2 in plasma, and the macrophage inflammatory protein-2 and matrix metalloproteinase-9 content in bronchoalveolar lavage fluid compared with VILI only. CONCLUSIONS: Our study demonstrates that prophylactic inhalation of 240 microg of levosimendan improves survival and reduces release of inflammatory mediators in our experimental model of VILI. This might affect the clinical prophylaxis and treatment of VILI.

Short-term exposure to high-pressure ventilation leads to pulmonary biotrauma and systemic inflammation in the rat.

Though often lifesaving, mechanical ventilation itself bears the risk of lung damage [ventilator-induced lung injury (VILI)]. The underlying molecular mechanisms have not been fully elucidated, but stress-induced mediators seem to play an important role in biotrauma related to VILI. Our purpose was to evaluate an animal model of VILI that allows the observation of pathophysiologic changes along with parameters of biotrauma. For VILI induction, rats (n=16) were ventilated with a peak airway pressure (pmax) of 45 cm H2O and end-expiratory pressure (PEEP) of 0 for 20 min, followed by an observation time of 4 h. In the control group (n=8) the animals were ventilated with a pmax of 20 cm H2O and PEEP of 4. High-pressure ventilation resulted in an increase in paCO2 and a decrease in paO2 and mean arterial pressure. Only 4 animals out of 16 survived 4 h and VILI lungs showed severe macroscopic and microscopic damage, oedema and neutrophil influx. High-pressure ventilation increased the cytokine levels of macrophage inflammatory protein-2 and IL-1beta in bronchoalveolar lavage and plasma. VILI also induced pulmonary heat shock protein-70 expression and the activity of matrix metalloproteinases. The animal model used enabled us to observe the effect of high-pressure ventilation on mortality, lung damage/function and biotrauma. Thus, by combining barotrauma with biotrauma, this animal model may be suitable for studying therapeutical approaches to VILI.