Angiopoietin-2 is associated with capillary leak and predicts complications after cardiac surgery.

BACKGROUND: Patients undergoing cardiac surgery are prone to numerous complications. Increased vascular permeability may be associated with morbidity and mortality due to hemodynamic instability, fluid overload, and edema formation. We hypothesized that markers of endothelial injury and inflammation are associated with capillary leak, ultimately increasing the risk of postoperative complications. METHODS: In this prospective, observational, multidisciplinary cohort study at our tertiary academic medical center, we recruited 405 cardiac surgery patients. Patients were assessed daily using body impedance electrical analysis, ultrasound, sublingual intravital microscopy, and analysis of serum biomarkers. Multivariable models, as well as machine learning, were used to study the association of angiopoietin-2 with extracellular water as well as common complications after cardiac surgery. RESULTS: The majority of patients underwent coronary artery bypass grafting, valvular, or aortic surgeries. Across the groups, extracellular water increased postoperatively (20 ± 6 preoperatively to 29 ± 7L on postoperative day 2; P < 0.001). Concomitantly, the levels of the biomarker angiopoietin-2 rose, showing a strong correlation based on the time points of measurements (r = 0.959, P = 0.041). Inflammatory (IL-6, IL-8, CRP) and endothelial biomarkers (VE-Cadherin, syndecan-1, ICAM-1) suggestive of capillary leak were increased. After controlling for common risk factors of edema formation, we found that an increase of 1 ng/mL in angiopoietin-2 was associated with a 0.24L increase in extracellular water (P < 0.001). Angiopoietin-2 showed increased odds for the development of acute kidney injury (OR 1.095 [95% CI 1.032, 1.169]; P = 0.004) and was furthermore associated with delayed extubation, longer time in the ICU, and a higher chance of prolonged dependence on vasoactive medication. Machine learning predicted postoperative complications when capillary leak was added to standard risk factors. CONCLUSIONS: Capillary leak and subsequent edema formation are relevant problems after cardiac surgery. Levels of angiopoietin-2 in combination with extracellular water show promising potential to predict postoperative complications after cardiac surgery. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry (DRKS No. 00017057), Date of registration 05/04/2019, www.drks.de.

Argon preconditioning protects neuronal cells with a Toll-like receptor-mediated effect.

The noble gas argon has the potential to protect neuronal cells from cell death. So far, this effect has been studied in treatment after acute damage. Preconditioning using argon has not yet been investigated. In this study, human neuroblastoma SH-SY5Y cells were treated with different concentrations of argon (25%, 50%, and 74%; 21% O2, 5% CO2, balance nitrogen) at different time intervals before inflicting damage with rotenone (20 µM, 4 hours). Apoptosis was determined by flow cytometry after annexin V and propidium iodide staining. Surface expressions of Toll-like receptors 2 and 4 were also examined. Cells were also processed for analysis by western blot and qPCR to determine the expression of apoptotic and inflammatory proteins, such as extracellular-signal regulated kinase (ERK1/2), nuclear transcription factor-κB (NF-κB), protein kinase B (Akt), caspase-3, Bax, Bcl-2, interleukin-8, and heat shock proteins. Immunohistochemical staining was performed for TLR2 and 4 and interleukin-8. Cells were also pretreated with OxPAPC, an antagonist of TLR2 and 4 to elucidate the molecular mechanism. Results showed that argon preconditioning before rotenone application caused a dose-dependent but not a time-dependent reduction in the number of apoptotic cells. Preconditioning with 74% argon for 2 hours was used for further experiments showing the most promising results. Argon decreased the surface expression of TLR2 and 4, whereas OxPAPC treatment partially abolished the protective effect of argon. Argon increased phosphorylation of ERK1/2 but decreased NF-κB and Akt. Preconditioning inhibited mitochondrial apoptosis and the heat shock response. Argon also suppressed the expression of the pro-inflammatory cytokine interleukin-8. Immunohistochemistry confirmed the alteration of TLRs and interleukin-8. OxPAPC reversed the argon effect on ERK1/2, Bax, Bcl-2, caspase-3, and interleukin-8 expression, but not on NF-κB and the heat shock proteins. Taken together, argon preconditioning protects against apoptosis of neuronal cells and mediates its action via Toll-like receptors. Argon may represent a promising therapeutic alternative in various clinical settings, such as the treatment of stroke.

Inhalative as well as Intravenous Administration of H2S Provides Neuroprotection after Ischemia and Reperfusion Injury in the Rats' Retina.

BACKGROUND: Neuronal ischemia-reperfusion injury (IRI), such as it can occur in glaucoma or strokes, is associated with neuronal cell death and irreversible loss of function of the affected tissue. Hydrogen sulfide (H2S) is considered a potentially neuroprotective substance, but the most effective route of application and the underlying mechanism remain to be determined. METHODS: Ischemia-reperfusion injury was induced in rats by a temporary increase in intraocular pressure (1 h). H2S was then applied by inhalation (80 ppm at 0, 1.5, and 3 h after reperfusion) or by intravenous administration of the slow-releasing H2S donor GYY 4137. After 24 h, the retinas were harvested for Western blotting, qPCR, and immunohistochemical staining. Retinal ganglion cell survival was evaluated 7 days after ischemia. RESULTS: Both inhalative and intravenously delivered H2S reduced retinal ganglion cell death with a better result from inhalative application. H2S inhalation for 1.5 h, as well as GYY 4137 treatment, increased p38 phosphorylation. Both forms of application enhanced the extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and inhalation showed a significant increase at all three time points. H2S treatment also reduced apoptotic and inflammatory markers, such as caspase-3, intracellular adhesion molecule 1 (ICAM-1), vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS). The protective effect of H2S was partly abolished by the ERK1/2 inhibitor PD98059. Inhalative H2S also reduced the heat shock response including heme oxygenase (HO-1) and heat shock protein 70 (HSP-70) and the expression of radical scavengers such as superoxide dismutases (SOD1, SOD2) and catalase. CONCLUSION: Hydrogen sulfide acts, at least in part, via the mitogen-activated protein kinase (MAPK) ERK1/2 to reduce apoptosis and inflammation. Both inhalative H2S and intravenous GYY 4137 administrations can improve neuronal cell survival.

Diagnosing capillary leak in critically ill patients: development of an innovative scoring instrument for non-invasive detection.

BACKGROUND: The concomitant occurrence of the symptoms intravascular hypovolemia, peripheral edema and hemodynamic instability is typically named Capillary Leak Syndrome (CLS) and often occurs in surgical critical ill patients. However, neither a unitary definition nor standardized diagnostic criteria exist so far. We aimed to investigate common characteristics of this phenomenon with a subsequent scoring system, determining whether CLS contributes to mortality. METHODS: We conducted this single-center, observational, multidisciplinary, prospective trial in two separately run surgical ICUs of a tertiary academic medical center. 200 surgical patients admitted to the ICU and 30 healthy volunteers were included. Patients were clinically diagnosed as CLS or No-CLS group (each N = 100) according to the grade of edema, intravascular hypovolemia, hemodynamic instability, and positive fluid balance by two independent attending physicians with > 10 years of experience in ICU. We performed daily measurements with non-invasive body impedance electrical analysis, ultrasound and analysis of serum biomarkers to generate objective diagnostic criteria. Receiver operating characteristics were used, while we developed machine learning models to increase diagnostic specifications for our scoring model. RESULTS: The 30-day mortility was increased among CLS patients (12 vs. 1%, P = 0.002), while showing higher SOFA-scores. Extracellular water was increased in patients with CLS with higher echogenicity of subcutaneous tissue [29(24-31) vs. 19(16-21), P < 0.001]. Biomarkers showed characteristic alterations, especially with an increased angiopoietin-2 concentration in CLS [9.9(6.2-17.3) vs. 3.7(2.6-5.6)ng/mL, P < 0.001]. We developed a score using seven parameters (echogenicity, SOFA-score, angiopoietin-2, syndecan-1, ICAM-1, lactate and interleukin-6). A Random Forest prediction model boosted its diagnostic characteristics (AUC 0.963, P < 0.001), while a two-parameter decision tree model showed good specifications (AUC 0.865). CONCLUSIONS: Diagnosis of CLS in critically ill patients is feasible by objective, non-invasive parameters using the CLS-Score. A simplified two-parameter diagnostic approach can enhance clinical utility. CLS contributes to mortality and should, therefore, classified as an independent entity. TRIAL REGISTRATION: German Clinical Trials Registry (DRKS No. 00012713), Date of registration 10/05/2017, www.drks.de.

Hydrogen Sulfide Reduces Ischemia and Reperfusion Injury in Neuronal Cells in a Dose- and Time-Dependent Manner.

BACKGROUND: The ischemia-reperfusion injury (IRI) of neuronal tissue, such as the brain and retina, leads to possible cell death and loss of function. Current treatment options are limited, but preliminary observations suggest a protective effect of hydrogen sulfide (H2S). However, the dosage, timing, and mechanism of inhaled H2S treatment after IRI requires further exploration. METHODS: We investigated possible neuroprotective effects of inhaled H2S by inducing retinal ischemia-reperfusion injury in rats for the duration of 1 h (120 mmHg), followed by the administration of hydrogen sulfide (H2S) for 1 h at different time points (0, 1.5, and 3 h after the initiation of reperfusion) and at different H2S concentrations (120, 80, and 40 ppm). We quantified the H2S effect by conducting retinal ganglion cell counts in fluorogold-labeled animals 7 days after IRI. The retinal tissue was harvested after 24 h for molecular analysis, including qPCR and Western blotting. Apoptotic and inflammatory mediators, transcription factors, and markers for oxidative stress were investigated. Histological analyses of the retina and the detection of inflammatory cytokines in serum assays were also performed. RESULTS: The effects of inhaled H2S were most evident at a concentration of 80 ppm administered 1.5 h after IRI. H2S treatment increased the expression of anti-apoptotic Bcl-2, decreased pro-apoptotic Bax expression, reduced the release of the inflammatory cytokines IL-1ß and TNF-α, attenuated NF-κB p65, and enhanced Akt phosphorylation. H2S also downregulated NOX4 and cystathionine ß-synthase. Histological analyses illustrated a reduction in TNF-α in retinal ganglion cells and lower serum levels of TNF-α in H2S-treated animals after IRI. CONCLUSION: After neuronal IRI, H2S mediates neuroprotection in a time- and dose-dependent manner. The H2S treatment modulated transcription factor NF-κB activation and reduced retinal inflammation.

Argon reduces microglial activation and inflammatory cytokine expression in retinal ischemia/reperfusion injury.

We previously found that argon exerts its neuroprotective effect in part by inhibition of the toll-like receptors (TLR) 2 and 4. The downstream transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) are also affected by argon and may play a role in neuroprotection. It also has been demonstrated that argon treatment could mitigate brain damage, reduce excessive microglial activation, and subsequently attenuate brain inflammation. Despite intensive research, the further exact mechanism remains unclear. In this study, human neuroblastoma cells were damaged in vitro with rotenone over a period of 4 hours (to mimic cerebral ischemia and reperfusion damage), followed by a 2-hour post-conditioning with argon (75%). In a separate in vivo experiment, retinal ischemia/reperfusion injury was induced in rats by increasing intraocular pressure for 1 hour. Upon reperfusion, argon was administered by inhalation for 2 hours. Argon reduced the binding of the transcription factors signal transducer and activator of transcription 3, nuclear factor kappa B, activator protein 1, and nuclear factor erythroid 2-related factor 2, which are involved in regulation of neuronal damage. Flow cytometry analysis showed that argon downregulated the Fas ligand. Some transcription factors were regulated by toll-like receptors; therefore, their effects could be eliminated, at least in part, by the TLR2 and TLR4 inhibitor oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC). Argon treatment reduced microglial activation after retinal ischemia/reperfusion injury. Subsequent quantitative polymerase chain reaction analysis revealed a reduction in the pro-inflammatory cytokines interleukin (IL-1α), IL-1ß, IL-6, tumor necrosis factor α, and inducible nitric oxide synthase. Our results suggest that argon reduced the extent of inflammation in retinal neurons after ischemia/reperfusion injury by suppression of transcription factors crucial for microglial activation. Argon has no known side effects or narcotic properties; therefore, therapeutic use of this noble gas appears ideal for treatment of patients with neuronal damage in retinal ischemia/reperfusion injury. The animal experiments were approved by the Commission for Animal Care of the University of Freiburg (approval No. 35-9185.81/G14-122) on October 19, 2012.

Incidence of gastric insufflation at high compared with low laryngeal mask cuff pressure: A randomised controlled cross-over trial.

BACKGROUND: The success of ventilation with a laryngeal mask depends crucially on the seal between the mask and the periglottic tissue. Increasing the laryngeal mask's cuff volume is known to reduce oral air leakage but may lead to gastric insufflation. OBJECTIVE: We hypothesised that a lower cuff pressure would result in less gastric insufflation. We sought to compare gastric insufflation with laryngeal mask cuff pressures of 20 cmH2O (CP20) and 60 cmH2O (CP60) during increasing peak airway pressures in a randomised controlled double-blind cross-over study. We also evaluated the incidence of gastric insufflation at the recommended peak airway pressure of 20 cmH2O or less and during both intermittent positive airway pressure and continuous positive airway pressure. METHODS: After obtaining ethics approval and written informed consent, 184 patients ventilated via laryngeal mask received a stepwise increase in peak airway pressure from 15 to 30 cmH2O with CP20 and CP60 in turn. Gastric insufflation was determined via real-time ultrasound and measurement of the cross-sectional area of the gastric antrum. The primary endpoint was the incidence of gastric insufflation at the different laryngeal mask cuff pressures. RESULTS: Data from 164 patients were analysed. Gastric insufflation occurred less frequently at CP20 compared with CP60 (P < 0.0001). Gastric insufflation was detected in 35% of cases with CP20 and in 48% with CP60 at a peak airway pressure of 20 cmH2O or less. Gastric insufflation occurred more often during continuous than during intermittent positive airway pressures (P < 0.01). CONCLUSION: A laryngeal mask cuff pressure of 20 cmH2O may reduce the risk of gastric insufflation during mechanical ventilation. Surprisingly, peak airway pressure of 20 cmH2O or less may already induce significant gastric insufflation. Continuous positive airway pressure should be avoided due to an increased risk of gastric insufflation. CLINICAL TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (DRKS00010583) https://www.drks.de.

Carbon Monoxide Exerts Functional Neuroprotection After Cardiac Arrest Using Extracorporeal Resuscitation in Pigs.

OBJECTIVES: Neurologic damage following cardiac arrest remains a major burden for modern resuscitation medicine. Cardiopulmonary resuscitation with extracorporeal circulatory support holds the potential to reduce morbidity and mortality. Furthermore, the endogenous gasotransmitter carbon monoxide attracts attention in reducing cerebral injury. We hypothesize that extracorporeal resuscitation with additional carbon monoxide application reduces neurologic damage. DESIGN: Randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Landrace-hybrid pigs. INTERVENTIONS: In a porcine model, carbon monoxide was added using a novel extracorporeal releasing system after resuscitation from cardiac arrest. MEASUREMENTS AND MAIN RESULTS: As markers of cerebral function, neuromonitoring modalities (somatosensory-evoked potentials, cerebral oximetry, and transcranial Doppler ultrasound) were used. Histopathologic damage and molecular markers (caspase-3 activity and heme oxygenase-1 expression) were analyzed. Cerebral oximetry showed fast rise in regional oxygen saturation after carbon monoxide treatment at 0.5 hours compared with extracorporeal resuscitation alone (regional cerebral oxygen saturation, 73% ± 3% vs 52% ± 8%; p < 0.05). Median nerve somatosensory-evoked potentials showed improved activity upon carbon monoxide treatment, whereas post-cardiac arrest cerebral perfusion differences were diminished. Histopathologic damage scores were reduced compared with customary resuscitation strategies (hippocampus: sham, 0.4 ± 0.2; cardiopulmonary resuscitation, 1.7 ± 0.4; extracorporeal cardiopulmonary resuscitation, 2.3 ± 0.2; extracorporeal cardiopulmonary resuscitation with carbon monoxide application [CO-E-CPR], 0.9 ± 0.3; p < 0.05). Furthermore, ionized calcium-binding adaptor molecule 1 staining revealed reduced damage patterns upon carbon monoxide treatment. Caspase-3 activity (cardiopulmonary resuscitation, 426 ± 169 pg/mL; extracorporeal cardiopulmonary resuscitation, 240 ± 61 pg/mL; CO-E-CPR, 89 ± 26 pg/mL; p < 0.05) and heme oxygenase-1 (sham, 1 ± 0.1; cardiopulmonary resuscitation, 2.5 ± 0.4; extracorporeal cardiopulmonary resuscitation, 2.4 ± 0.2; CO-E-CPR, 1.4 ± 0.2; p < 0.05) expression were reduced after carbon monoxide exposure. CONCLUSIONS: Carbon monoxide application during extracorporeal resuscitation reduces injury patterns in neuromonitoring and decreases histopathologic cerebral damage by reducing apoptosis. This may lay the basis for further clinical translation of this highly salutary substance.

Carbon monoxide improves haemodynamics during extracorporeal resuscitation in pigs.

AIMS: Heart disease of different aetiology remains the leading cause of cardiac arrest (CA). Despite efforts to improve the quality of cardiopulmonary resuscitation (CPR), subsequent myocardial and systemic damage after CA still present a major long-term burden. Low-dose carbon monoxide (CO) is known to exert protective effects in cardiovascular pathophysiology but clinical applications are challenged by unfavourable delivery modes. We tested the hypothesis that extracorporeal resuscitation (E-CPR) in combination with controlled fast onset CO delivery results in improved cardiac physiology and haemodynamics. Damage-associated molecular pattern (DAMP) signalling may be part of the molecular mechanism. METHODS AND RESULTS: In an established porcine model, E-CPR was performed. While E-CPR leads to similar results as compared to a conventional CPR strategy, CO delivery in combination with E-CPR demonstrated significant cardioprotection. Cardiac performance analysis using echocardiography and thermodilution techniques showed a CO-dependent improved cardiac function compared to severe myocardial dysfunction in CPR and E-CPR (left ventricular ejection fraction: Sham 49 ± 5; CPR 26 ± 2; E-CPR 25 ± 2; CO-E-CPR 31 ± 4; P < 0.05). While sublingual microcirculation was significantly compromised in CPR and E-CPR, CO delivery demonstrated a significant improvement in microvascular function (microvascular flow index: Sham 2.9 ± 0.1; CPR 2.2 ± 0.1; E-CPR 1.8 ± 0.1; CO-E-CPR 2.7 ± 0.1; P < 0.01). Histological and serological myocardial damage markers were significantly reduced (hsTroponin-T Sham 0.01 ± 0.001; CPR 1.9 ± 0.2; E-CPR 3.5 ± 1.2; CO-E-CPR 0.5 ± 0.2 ng/mL; P < 0.05). DAMP signalling was decreased ipse facto leading to influence of cardioprotective heat shock and cyclooxygenase response. CONCLUSIONS: CO treatment restores myocardial function and improves systemic macro- and microhaemodynamics in E-CPR through a reduction in DAMPs.

Extracorporeal resuscitation with carbon monoxide improves renal function by targeting inflammatory pathways in cardiac arrest in pigs.

Deleterious consequences like acute kidney injury frequently occur upon successful resuscitation from cardiac arrest. Extracorporeal life support is increasingly used to overcome high cardiac arrest mortality. Carbon monoxide (CO) is an endogenous gasotransmitter, capable of reducing renal injury. In our study, we hypothesized that addition of CO to extracorporeal resuscitation hampers severity of renal injury in a porcine model of cardiac arrest. Hypoxic cardiac arrest was induced in pigs. Animals were resuscitated using a conventional [cardiopulmonary resuscitation (CPR)], an extracorporeal (E-CPR), or a CO-assisted extracorporeal (CO-E-CPR) protocol. CO was applied using a membrane-controlled releasing system. Markers of renal injury were measured, and histopathological analyses were carried out. We investigated renal pathways involving inflammation as well as apoptotic cell death. No differences in serum neutrophil gelatinase-associated lipocalin (NGAL) were detected after CO treatment compared with Sham animals (Sham 71 ± 7 and CO-E-CPR 95 ± 6 ng/mL), while NGAL was increased in CPR and E-CPR groups (CPR 135 ± 11 and E-CPR 124 ± 5 ng/mL; P < 0.05). Evidence for histopathological damage was abrogated after CO application. CO increased renal heat shock protein 70 expression and reduced inducible cyclooxygenase 2 (CPR: 60 ± 8; E-CPR 56 ± 8; CO-E-CPR 31 ± 3 µg/mL; P < 0.05). Caspase 3 activity was decreased (CPR 1,469 ± 276; E-CPR 1,670 ± 225; CO-E-CPR 755 ± 83 pg/mL; P < 0.05). Furthermore, we found a reduction in renal inflammatory signaling upon CO treatment. Our data demonstrate improved renal function by extracorporeal CO treatment in a porcine model of cardiac arrest. CO reduced proinflammatory and proapoptotic signaling, characterizing beneficial aspects of a novel treatment option to overcome high mortality.

Epidural analgesia and avoidance of blood transfusion are associated with reduced mortality in patients with postoperative pulmonary complications following thoracotomic esophagectomy: a retrospective cohort study of 335 patients.

BACKGROUND: Postoperative pulmonary complications (PPCs) represent the most frequent complications after esophagectomy. The aim of this study was to identify modifiable risk factors for PPCs and 90-days mortality related to PPCs after esophagectomy in esophageal cancer patients. METHODS: This is a single center retrospective cohort study of 335 patients suffering from esophageal cancer who underwent esophagectomy between 1996 and 2014 at a university hospital center. Statistical processing was conducted using univariate and multivariate stepwise logistic regression analysis of patient-specific and procedural risk factors for PPCs and mortality. RESULTS: The incidence of PPCs was 52% (175/335) and the 90-days mortality rate of patients with PPCs was 8% (26/335) in this study cohort. The univariate and multivariate analysis revealed the following independent risk factors for PPCs and its associated mortality. ASA score ≥ 3 was the only independent patient-specific risk factor for the incidence of PPCs and 90-days mortality of patients with an odds ratio for PPCs being 1.7 (1.1-2.6 95% CI) and an odds ratio of 2.6 (1.1-6.2 95% CI) for 90-days mortality. The multivariate approach depicted two independent procedural risk factors including transfusion of packed red blood cells (PRBCs) odds ratio of 1.9 (1.2-3 95% CI) for PPCs and an odds ratio of 5.0 (2.0-12.6 95% CI) for 90-days mortality; absence of thoracic epidural anesthesia (TEA) revealed the highest odds ratio 2.0 (1.01-3.8 95% CI) for PPCs and an odds ratio of 3.9 (1.6-9.7 95% CI) for 90-days mortality. CONCLUSION: In esophageal cancer patients undergoing esophagectomy via thoracotomy, epidural analgesia and the avoidance of intraoperative blood transfusion are significantly associated with a reduced 90-days mortality related to PPCs.

Modifiable Risk Factors for Delayed Graft Function After Deceased Donor Kidney Transplantation.

PURPOSE: Delayed graft function is a major complication after kidney transplantation affecting patients' long-term outcome. The aim of this study was to identify modifiable risk factors for delayed graft function after deceased donor kidney transplantation. METHODS: This is a single-center retrospective cohort study of a university transplantation center. Univariate and multivariate step-wise logistic regression analysis of patient-specific and procedural risk factors were conducted. RESULTS: We analyzed 380 deceased donor kidney transplantation patients between October 30, 2008 and December 30, 2017. The incidence of delayed graft function was 15% (58/380). Among the patient-specific risk factors recipient diabetes (2.8 [1.4-5.9] odds ratio [OR] [95% confidence interval [CI]]), American Society of Anesthesiologist score of 4 (2.7 [1.2-6.5] OR [95% CI]), cold ischemic time >13 hours (2.8 [1.5-5.3] OR [95% CI]) and donor age >55 years (1.9 [1.01-3.6] OR [95% CI]) revealed significance. The significant intraoperative, procedural risk factors included the use of colloids (3.9 [1.4-11.3] OR [95% CI]), albumin (3.0 [1.2-7.5] OR [95% CI]), crystalloids >3000 mL (3.1 [1.2-7.5] OR [95% CI]) and mean arterial pressure <80 mm Hg at the time of reperfusion (2.4 [1.2-4.8] OR [95% CI]). CONCLUSION: Patients undergoing deceased donor kidney transplantation with a mean arterial pressure >80 mm Hg at the time of transplant reperfusion without requiring excessive fluid therapy in terms of colloids, albumin or crystalloids >3000 mL are less likely to develop delayed graft function.

Lower rate of delayed graft function is observed when epidural analgesia for living donor nephrectomy is administered.

BACKGROUND: The beneficial effects of epidural analgesia (EDA) in terms of pain control and postoperative convalescence are widely known and led to a frequent use for patients who underwent living donor kidney nephrectomy. The objective of this study was to determine whether general anesthesia (GA) plus EDA compared to GA only, administered for living donor nephrectomy has effects on postoperative graft function in recipients. METHODS: In this monocentric, retrospective cohort analysis we analyzed the closed files of all consecutive donor- recipient pairs who underwent living donor kidney transplantations from 2008 to 2017. The outcome variable was delayed graft function (DGF), defined as at least one hemodialysis within seven days postoperatively, once hyperacute rejection, vascular or urinary tract complications were ruled out. Statistical analyses of continuous variables were calculated using the two-tail Student's t test and Fisher exact test for categorical variables with a significance level of p < 0.05, respectively. RESULTS: The study enclosed 291 consecutive living donor kidney transplantations. 99 kidney donors received epidural analgesia whereas 192 had no epidural analgesia. The groups showed balanced pretransplantational characteristics and comparable donors´ and recipients' risk factors. 9 out of all 291 recipients needed renal replacement therapy (RRT) during the first 7 days due to delayed graft function; none of these donors received EDA. The observed rate of DGF in recipients whose kidney donors received epidural analgesia was significantly lower (0% vs. 4.6%; p = 0.031). CONCLUSIONS: In our cohort we observed a significantly lower rate of DGF when epidural analgesia for donor nephrectomy was administered. Due to restrictions of the study design this observation needs further confirmation by prospective studies.

Phosphodiesterase-4 inhibition reduces ECLS-induced vascular permeability and improves microcirculation in a rodent model of extracorporeal resuscitation.

Extracorporeal circulation can be accompanied by increased vascular permeability leading to pathological fluid balance and organ dysfunction. The second messenger cAMP is involved in capillary permeability and maintains endothelial integrity. The aim of the present study was to evaluate the effect of phosphodiesterase-4 (PDE4) inhibition with rolipram on extracorporeal circulation-induced capillary leakage, microcirculatory dysfunction, and organ injury in rodents. Rats were randomly allocated to the following groups: sham ( n = 5), venoarterial extracorporeal circulation [extracorporeal life support (ECLS), n = 7], ECLS + rolipram ( n = 7), extracorporeal resuscitation (ECPR; n = 7), and ECPR + rolipram ( n = 7). In the groups that underwent ECPR, ECLS-based cardiopulmonary resuscitation (ECPR) was performed after the induction of hypoxic cardiac arrest. Upon return of spontaneous circulation, rolipram was administered intravenously. The mesenteric microcirculation was studied using intravital microscopy, and organ specimens were harvested upon completion of the study. ECLS and ECPR induced a proinflammatory response (cytokines IL-1ß, IL-6, and TNF-α). Although PDE4 expression was upregulated in vascular tissue, PDE4 inhibition abrogated impaired microcirculation and capillary leak (albumin extravasation of the sham group: 1 ± 0.03-fold, ECLS group: 1.2 ± 0.05-fold, ECLS + rolipram group: 0.99 ± 0.04-fold, ECPR group: 1.6 ± 0.04-fold, and ECPR + rolipram group: 1.06 ± 0.02-fold from the sham group, P < 0.05). PDE4 inhibition led to stabilization of vascular cAMP levels but did not affect cytokine levels. Capillary leak was reduced, as demonstrated by the decrease of the systemic biomarkers soluble vascular-endothelial cadherin and activated complement 3. Histological analysis revealed reduced injury to the lungs and kidneys after PDE4 inhibition, with a significant decrease in systemic renal damage markers. Our findings demonstrate that extracorporeal circulation causes an inflammatory reaction associated with decreased vascular cAMP levels, increased vascular permeability, and impaired microcirculation. PDE4 inhibition proved to be capable of reducing these side effects in ECLS and ECPR, leading to reduced microcirculatory, renal, and pulmonary injury. NEW & NOTEWORTHY Various complications are common after extracorporeal circulation. Among these, endothelial injury may cause impaired microcirculation and capillary leak. Here, we report that phosphodiesterase-4 inhibition targeting endothelial cAMP is capable of reducing microvascular complications in a rodent model of extracorporeal resuscitation. Microcirculation and vascular permeability are influenced without targeting extracorporeal circulation-induced inflammation. Thus, pulmonary and renal organ protection may be conferred.

Somatosensory and transcranial motor evoked potential monitoring in a porcine model for experimental procedures.

Evoked potential monitoring has evolved as an essential tool not only for elaborate neurological diagnostics, but also for general clinical practice. Moreover, it is increasingly used to guide surgical procedures and prognosticate neurological outcome in the critical care unit, e.g. after cardiac arrest. Experimental animal models aim to simulate a human-like scenario to deduct relevant clinical information for patient treatment and to test novel therapeutic opportunities. Porcine models are particularly ideal due to a comparable cardiovascular system and size. However, certain anatomic disparities have to be taken into consideration when evoked potential monitoring is used in animal models. We describe a non-invasive and reproducible set-up useful for different modalities in porcine models. We further illustrate hints to overcome multi-faceted problems commonly occurring while using this sophisticated technique. Our descriptions can be used to answer a plethora of experimental questions, and help to further facilitate experimental therapeutic innovation.

Perioperative cytokine profile during lung surgery predicts patients at risk for postoperative complications-A prospective, clinical study.

BACKGROUND: Postoperative complications after lung surgery are frequent, having a detrimental effect on patients' further course. Complications may lead to an increased length of hospital stay and cause additional costs. Several risk factors have been identified but it is still difficult to predict contemporary which patients are at risk. We hypothesized that patients who show an increased inflammatory response at the time of wound closure and 24 hours after surgery are at risk of postoperative complications within 30 days after surgery. METHODS: Postoperative complications (pulmonary, cardiac, neurological and renal) of 96 patients scheduled for lung surgery at the Medical Center-University of Freiburg were analyzed in this prospective, clinical study. Blood samples for cytokine analysis (Interleukin (IL)-6, IL-8, IL-10, Tumor necrosis factor [TNF]-α, IL-1ß and IL12p70) were taken before surgery, at wound closure and 24 hours after surgery. Cytokine levels of patients with and without postoperative complications were analyzed by Receiver operating characteristic (ROC) curve analysis. To adjust the results according to existing covariates a multivariate logistic regression analysis was conducted. RESULTS: The complication and non-complication group differed significantly according to nicotine dependency, Angiotensin-receptor-II blocker medication, rate of thoracotomy and preoperative lung function. The intraoperative hemodynamic parameters and therapy did not differ between the groups. Twenty-nine patients (30%) developed postoperative complications within 30 days after surgery. Plasma concentrations of IL-6, IL-10 and IL-8 at the time of wound closure and 24 hours after surgery were higher in the complication group. Multivariate regression analysis on postoperative complications revealed an Odds ratio of 56 for patients with IL-6 and IL-8 levels above the 3rd quartile measured on the first postoperative day. CONCLUSIONS: Perioperative detection of increased plasma concentrations of inflammatory cytokines in lung surgery may be used in addition to other clinical predictors to identify patients at risk for postoperative complications. TRIAL REGISTRATION: German Clinical Trials Register 00006961.

Evaluation of hemodynamic goal-directed therapy to reduce the incidence of bone cement implantation syndrome in patients undergoing cemented hip arthroplasty - a randomized parallel-arm trial.

BACKGROUND: The bone cement implantation syndrome (BCIS) is a frequent and potentially disastrous intraoperative complication in patients undergoing cemented hip arthroplasty. Several risk factors have been identified, however randomized controlled trials to reduce the incidence of BCIS are still pending. We hypothesized that goal-directed hemodynamic therapy guided by esophageal Doppler monitoring (EDM) may reduce the incidence of BCIS in a randomized, controlled parallel-arm trial. METHODS: After approval of the local ethics committee, 90 patients scheduled for cemented hip arthroplasty at the Medical Center - University of Freiburg were randomly assigned to either standard hemodynamic management or goal-directed therapy (GDT) guided by an esophageal Doppler monitoring-based algorithm. The primary endpoint was the incidence of overall BCIS including grade 1-3 after cementation of the femoral stem. Secondary endpoints included cardiac function, length of hospital stay and postoperative complications. RESULTS: Ninety patients were finally analyzed. With regards to the primary endpoint, the overall incidence of BCIS showed no difference between the GDT and control group. Compared to the control group, patients of the GDT group showed a higher cardiac index before and after bone cement implantation (2.7 vs. 2.2 [l●min- 1●m- 2]; 2.8 vs. 2.4 [l●min- 1●m- 2]; P = 0.003, P = 0.042), whereas intraoperative amount of fluids and mean arterial pressure did not differ. CONCLUSIONS: The implementation of a specific hemodynamic goal-directed therapy did not reduce the overall incidence of BCIS in patients undergoing cemented hip arthroplasty. TRIAL REGISTRATION: This randomized clinical two-arm parallel study was approved by the local Ethics Committee, Freiburg, Germany [EK 160/15, PI: U. Goebel] and registered in the German Clinical Trials Register ( DRKS No. 00008778 , 16th of June, 2015).

Improved lung recruitment and oxygenation during mandatory ventilation with a new expiratory ventilation assistance device: A controlled interventional trial in healthy pigs.

BACKGROUND: In contrast to conventional mandatory ventilation, a new ventilation mode, expiratory ventilation assistance (EVA), linearises the expiratory tracheal pressure decline. OBJECTIVE: We hypothesised that due to a recruiting effect, linearised expiration oxygenates better than volume controlled ventilation (VCV). We compared the EVA with VCV mode with regard to gas exchange, ventilation volumes and pressures and lung aeration in a model of peri-operative mandatory ventilation in healthy pigs. DESIGN: Controlled interventional trial. SETTING: Animal operating facility at a university medical centre. ANIMALS: A total of 16 German Landrace hybrid pigs. INTERVENTION: The lungs of anaesthetised pigs were ventilated with the EVA mode (n=9) or VCV (control, n=7) for 5 h with positive end-expiratory pressure of 5 cmH2O and tidal volume of 8 ml kg. The respiratory rate was adjusted for a target end-tidal CO2 of 4.7 to 6 kPa. MAIN OUTCOME MEASURES: Tracheal pressure, minute volume and arterial blood gases were recorded repeatedly. Computed thoracic tomography was performed to quantify the percentages of normally and poorly aerated lung tissue. RESULTS: Two animals in the EVA group were excluded due to unstable ventilation (n=1) or unstable FiO2 delivery (n=1). Mean tracheal pressure and PaO2 were higher in the EVA group compared with control (mean tracheal pressure: 11.6 ±â€Š0.4 versus 9.0 ±â€Š0.3 cmH2O, P < 0.001 and PaO2: 19.2 ±â€Š0.7 versus 17.5 ±â€Š0.4 kPa, P = 0.002) with comparable peak inspiratory tracheal pressure (18.3 ±â€Š0.9 versus 18.0 ±â€Š1.2 cmH2O, P > 0.99). Minute volume was lower in the EVA group compared with control (5.5 ±â€Š0.2 versus 7.0 ±â€Š1.0 l min, P = 0.02) with normoventilation in both groups (PaCO2 5.4 ±â€Š0.3 versus 5.5 ±â€Š0.3 kPa, P > 0.99). In the EVA group, the percentage of normally aerated lung tissue was higher (81.0 ±â€Š3.6 versus 75.8 ±â€Š3.0%, P = 0.017) and of poorly aerated lung tissue lower (9.5 ±â€Š3.3 versus 15.7 ±â€Š3.5%, P = 0.002) compared with control. CONCLUSION: EVA ventilation improves lung aeration via elevated mean tracheal pressure and consequently improves arterial oxygenation at unaltered positive end-expiratory pressure (PEEP) and peak inspiratory pressure (PIP). These findings suggest the EVA mode is a new approach for protective lung ventilation.

Overcoming safety challenges in CO therapy - Extracorporeal CO delivery under precise feedback control of systemic carboxyhemoglobin levels.

Carbon monoxide (CO) has demonstrated therapeutic potential in multiple inflammatory conditions including intensive care applications such as organ transplantation or sepsis. Approaches to translate these findings into future therapies, however, have been challenged by multiple hurdles including handling and toxicity issues associated with systemic CO delivery. Here, we describe a membrane-controlled Extracorporeal Carbon Monoxide Release System (ECCORS) for easy implementation into Extracorporeal Membrane Oxygenation (ECMO) setups, which are being used to treat cardiac and respiratory diseases in various intensive care applications. Functionalities of the ECCORS were investigated in a pig model of veno-arterial ECMO. By precisely controlling CO generation and delivery as a function of systemic carboxyhemoglobin levels, the system allows for an immediate onset of therapeutic CO-levels while preventing CO-toxicity. Systemic carboxyhemoglobin levels were profiled in real-time by monitoring exhaled CO levels as well as by pulse oximetry, enabling self-contained and automatic feedback control of CO generation within ECCORS. Machine learning based mathematical modeling was performed to increase the predictive power of this approach, laying foundation for high precision systemic CO delivery concepts of tomorrow.