Prehospital anesthesia in postcardiac arrest patients: a multicenter retrospective cohort study.

BACKGROUND: Currently, the data regarding the impact of prehospital postcardiac arrest anesthesia on target hemodynamic and ventilatory parameters of early postresuscitation care and recommendations on its implementation are rare. The present study examines the incidence and impact of prehospital postcardiac arrest anesthesia on hemodynamic and ventilatory target parameters of postresuscitation care. METHODS: In this multicentre observational study between 2019 and 2021 unconscious adult patients after out-of-hospital-cardiac arrest with the presence of a return-of-spontaneous circulation until hospital admission were included. Primary endpoint was the application of postarrest anesthesia. Secondary endpoints included the medication group used, predisposing factors to its implementation, and its influence on achieving target parameters of postresuscitation care (systolic blood pressure: ≥ 100 mmHg, etCO2:35-45 mmHg, SpO2: 94-98%) at hospital handover. RESULTS: During the study period 2,335 out-of-hospital resuscitations out of 391,305 prehospital emergency operations (incidence: 0.58%; 95% CI 0.54-0.63) were observed with a return of spontaneous circulation to hospital admission in 706 patients (30.7%; 95% CI 28.8-32.6; female: 34.3%; age:68.3 ± 14.2 years). Postcardiac arrest anesthesia was performed in 482 patients (68.3%; 95% CI 64.7-71.7) with application of hypnotics in 93.4% (n = 451), analgesics in 53.7% (n = 259) and relaxants in 45.6% (n = 220). Factors influencing postcardiac arrest sedation were emergency care by an anesthetist (odds ratio: 2.10; 95% CI 1.34-3.30; P < 0.001) and treatment-free interval ≤ 5 min (odds ratio: 1.59; 95% CI 1.01-2.49; P = 0.04). Although there was no evidence of the impact of performing postcardiac arrest anesthesia on achieving a systolic blood pressure ≥ 100 mmHg at the end of operation (odds ratio: 1.14; 95% CI 0.78-1.68; P = 0.48), patients with postcardiac arrest anesthesia were significantly more likely to achieve the recommended ventilation (odds ratio: 1.59; 95% CI 1.06-2.40; P = 0.02) and oxygenation (odds ratio:1.56; 95% CI 1.04-2.35; P = 0.03) targets. Comparing the substance groups, the use of hypnotics significantly more often enabled the target values for etCO2 to be reached alone (odds ratio:2.79; 95% CI 1.04-7.50; P = 0.04) as well as in combination with a systolic blood pressure ≥ 100 mmHg (odds ratio:4.42; 95% CI 1.03-19.01; P = 0.04). CONCLUSIONS: Postcardiac arrest anesthesia in out-of-hospital cardiac arrest is associated with early achievement of respiratory target parameters in prehospital postresuscitation care without evidence of more frequent hemodynamic complications.

Effects of COVID-19 on a mature citizen first responder system in the German district of Gütersloh: an observational study.

BACKGROUND: The aim of this study was to examine the impact of COVID-19 on the response rate of community-first-responders (CFR) and other out-of-hospital-cardiac-arrest (OHCA) outcomes using the smartphone-first-responder-system (SFRS) "Mobile Retter." METHODS: All adult non-traumatic OHCA in the district of Gütersloh between 01.01.2018-31.12.2021 were included. Periods of interest were 1) prior to the first COVID-19-lockdown; to 2) both lockdowns; and 3) the time in between, as well as after the COVID-19-lockdowns (pre-COVID-19, COVID-19-lockdown and COVID-19-pandemic respectively). The primary outcome was the CFR response rate defined as proportion of CFR alerts that were accepted by a CFR and in which at least one CFR arrived on scene of the emergency out of all CFR alerts. Secondary outcomes included the rate of CFR alerts, defined as proportion of OHCA to which CFR were summoned by the emergency medical dispatcher, as well as the rate of return-of-spontaneous-circulation (ROSC) and rate of survival until hospital discharge. We also examined the incidence COVID-19-infection of CFR in context of the SFRS. RESULTS: A total of 1064 OHCA-patients (mean age: 71.4±14.5 years; female: 33.8%) were included in the study (Pre-COVID-19: 539; COVID-19-lockdown: 109; COVID-19-pandemic: 416). The response rate was 64.0% (pre-COVID-19: 58.7%; COVID-19-lockdown: 63.5%; COVID-19-pandemic: 71.8%, P=0.002 vs. pre-COVID-19). The alert rate was 52.7% (pre-COVID-19: 56.2%; COVID-19-lockdown: 47.7%, P=0.04 vs. Pre-COVID-19; COVID-19-Pandemic: 49.5%, P=0.02 vs. pre-COVID-19). The ROSC-rate was 40.4% (pre-COVID-19: 41.0%; COVID-19-lockdown: 33.9%; COVID-19-pandemic: 41.4%) and hospital discharge rate 31.2% (Pre-COVID-19: 33.0%; COVID-19-lockdown: 36.8%; COVID-19-pandemic: 28.7%). The use of CFR was associated with favorable effects in terms of hospital admission (odds ratio [OR]: 0.654 (CI95: 0.444-0.963), P=0.03), hospital discharge (OR: 2.343 (CI95: 1.002-5.475), P=0.04). None of the CFR became infected with COVID-19. CONCLUSIONS: "Mobile-Retter" was associated with high response rates, improved outcome in OHCA patients and no COVID-19-infections of CFR during the COVID-19-pandemic and -lockdowns.

Midazolam for Post-Arrest Sedation in Pre-Hospital Emergency Care­a Multicenter Propensity Score Analysis.

BACKGROUND: An out-of-hospital cardiac arrest (OHCA) with return of spontaneous circulation (ROSC) may need to be treated with airway management, emergency ventilation, invasive interventions, and post-arrest sedation. We investigated the influence of the use of midazolam for post-arrest sedation on achieving post-resuscitation care targets and the associated risk of hemodynamic complications. METHODS: All emergency rescue missions of the Dresden, Gütersloh, and Lippe medical rescue services in the years 2019-2021 were reviewed to identify adult patients who had OHCA, unconsciousness, and sustained ROSC with spontaneous circulation until arrival at the hospital; the findings were supplemented with data from the German Resuscitation Registry. Patients who received midazolam (alone or in combination with other anesthetic agents) for post-arrest sedation were compared with those who did not. The endpoints were the regaining of a systolic blood pressure ≥ 100 mmHg, end-tidal pCO2 35-45 mmHg, and oxygen saturation (SpO2) 94-98%. A propensity score analysis was used to adjust for age, sex, and variables potentially affecting hemodynamic status or the targets for oxygenation and ventilation. RESULTS: There were 2335 cases of OHCA among 391 305 emergency rescue missions. 571 patients had ROSC before arrival in the hospital (24.5%; female, 33.6%; age, 68 ± 14 years). Of the 395 among them (69.2%) who were treated with post-arrest sedation, 249 (63.0%) received midazolam. Patients who received midazolam reached the guideline-recommended targets for oxygenation, ventilation, and blood pressure more frequently than those who were not sedated: the respective odds ratios and 95% confidence intervals were 2.00 [1.20; 3.34], 1.57 [0.99; 2.48], and 1.41 [0.89; 2.21]. CONCLUSION: The pre-hospital administration of midazolam leads to more frequent pre-hospital attainment of the oxygenation and ventilation targets in post-resuscitation care, without any evidence of an elevated risk of hemodynamic complications.

Interleukin-18 and High-Mobility-Group-Protein B1 are Early and Sensitive Indicators for Cell Damage During Normothermic Machine Perfusion after Prolonged Cold Ischemic Storage of Porcine Liver Grafts.

In the era of organ machine perfusion, experimental models to optimize reconditioning of (marginal) liver grafts are needed. Although the relevance of cytokine signatures in liver transplantation has been analyzed previously, the significance of molecular monitoring during normothermic machine perfusion (NMP) remains elusive. Therefore, we developed a porcine model of cold ischemic liver graft injury after prolonged static cold storage (SCS) and subsequent NMP: Livers obtained from ten minipigs underwent NMP for 6 h directly after procurement (control group) or after 20 h of SCS. Grafts after prolonged SCS showed significantly elevated AST, ALT, GLDH and GGT perfusate concentrations, and reduced lactate clearance. Bile analyses revealed reduced bile production, reduced bicarbonate and elevated glucose concentrations after prolonged SCS. Cytokine analyses of graft perfusate simultaneously demonstrated an increase of pro-inflammatory cytokines such as Interleukin-1α, Interleukin-2, and particularly Interleukin-18. The latter was the only significantly elevated cytokine compared to controls, peaking as early as 2 h after reperfusion (11,012 ng/ml vs. 1,493 ng/ml; p = 0.029). Also, concentrations of High-Mobility-Group-Protein B1 were significantly elevated after 2 h of reperfusion (706.00 ng/ml vs. 148.20 ng/ml; p < 0.001) and showed positive correlations with AST (r 2 = 0.846) and GLDH (r 2 = 0.918) levels. Molecular analyses during reconditioning of liver grafts provide insights into the degree of inflammation and cell damage and could thereby facilitate future interventions during NMP reducing acute and chronic graft injury.

Supportive Hepatocyte Transplantation after Partial Hepatectomy Enhances Liver Regeneration in a Preclinical Pig Model.

BACKGROUND: Hepatocyte transplantation (HTx) is regarded as a potential treatment modality for various liver diseases including acute liver failure. We developed a preclinical pig model to evaluate if HTx could safely support recovery from liver function impairment after partial hepatectomy. METHODS: Pigs underwent partial hepatectomy with reduction of the liver volume by 50% to induce a transient but significant impairment of liver function. Thereafter, 2 protocols for HTx were evaluated and compared to a control group receiving liver resection only (group 1, n = 5). Portal pressure-controlled HTx was performed either immediately after surgery (group 2, n = 6) or 3 days postoperatively (group 3, n = 5). In all cases, liver regeneration was monitored by conventional laboratory tests and the novel noninvasive maximum liver function capacity (LiMAx) test with a follow-up of 4 weeks. RESULTS: Partial hepatectomy significantly impaired liver function according to conventional liver function tests as well as LiMAx in all groups. A mean of 4.10 ± 1.1 × 108 and 3.82 ± 0.7 × 108 hepatocytes were transplanted in groups 2 and 3, respectively. All animals remained stable with respect to vital parameters during and after HTx. The animals in group 2 showed enhanced liver regeneration as observed by mean postoperative LiMAx values (621.5 vs. 331.3 µg/kg/h on postoperative day 7; p < 0.001) whereas HTx in group 3 led to a significant increase in mean liver-specific coagulation factor VII (112.2 vs. 54.0% on postoperative day 7; p = 0.003) compared to controls (group 1), respectively. In both experimental groups, thrombotic material was observed in the portal veins and pulmonary arteries on histology, despite the absence of clinical symptoms. CONCLUSION: HTx can be performed safely and effectively immediately after a partial (50%) hepatectomy as well as 3 days postoperatively, with comparable results regarding the enhancement of liver function and regeneration.

Influence of alcohol consumption on blood coagulation in rotational thromboelastometry (ROTEM): an in-vivo study.

BACKGROUND: Twenty-five to 85% of trauma patients are under the influence of alcohol in addition to experiencing injury-related coagulation impairment. Viscoelastic point-of-care tests (thrombelastography [TEG], rotational thromboelastometry [ROTEM]) are popular tools for rapid hemostasis assessment and therapeutic decision-making in this and other settings. While alcohol affects these tests in-vitro, their specific effects in-vivo are unclear. Therefore, we evaluated the effects of alcohol ingestion on ROTEM parameters. METHODS: Twenty volunteers provided informed consent to drinking red wine, whisk(e)y, or vodka to a target blood alcohol concentration of 1 ‰ within one hour, calculated with the Widmark formula. Blood samples were collected before drinking, at a breath alcohol concentration of 0.5 ‰, and at 1.0 ‰, but no later than one hour. After each blood collection, ExTEM and FibTEM tests were performed directly "at the bedside." RESULTS: All participants had a blood alcohol concentration (BAC) of 0.00 ‰ at the beginning. The mean BACs at the second and third collection were 0.48 and 0.76 ‰, respectively. There were no significant differences in the ExTEM parameters. FibTEM measurements showed a significant difference at the A10 value (13.0 vs. 14.0 mm, P = 0.014) and a trend at the maximum amplitude (maximum clot firmness [MCF] 13.7 vs. 16.2 mm, P = 0.075). We saw no significant differences in fibrinolysis parameters and no hyperfibrinolysis in our ROTEM measurements. CONCLUSIONS: Ethanol ingestion can impair early fibrin polymerization. These results might be of special relevance in trauma and support routine application of ROTEM/TEG in such cases.

Porcine model for the study of liver regeneration enhanced by non-invasive 13C-methacetin breath test (LiMAx test) and permanent portal venous access.

INTRODUCTION: Despite advances in perioperative management and surgical technique, postoperative liver failure remains a feared complication after hepatic resection. Various supportive treatment options are under current discussion, but lack of structured evaluation. We therefore established a porcine model of major liver resection to study regeneration after partial hepatectomy in a reliable and well-defined pre-clinical setting. METHODS: Major hepatectomy was performed on seven minipigs with the intention to set up a non-lethal but relevant transient impairment of liver function. For steady postoperative vascular access (e.g. for blood withdrawal, measurement of venous pressure), permanent catheters were implanted into the internal jugular and portal veins, respectively. Animals were followed up for 30 days; clinical and laboratory results were recorded in detail. Monitoring was enhanced by non-invasive determination of the maximum liver function capacity (LiMAx test). RESULTS AND CONCLUSIONS: The established porcine model appeared suitable for evaluation of postoperative liver regeneration. Clinical characteristics and progression of liver function impairment as well as subsequent recovery were comparable to courses known from surgery in humans. Laboratory parameters (e.g. liver enzymes, bilirubin, INR, coagulation factor II) showed relevant derangements during postoperative days (POD) 0 to 3 followed by normalization until POD 7. Application of the LiMAx test was feasible in minipigs, again showing values comparable to humans and kinetics in line with obtained laboratory parameters. The exteriorized portal vein catheters enabled intra- and postoperative monitoring of portal venous pressures as well as easy access for blood withdrawal without relevant risk of postoperative complications.

Investigation of the influence of xenoreactive antibodies on activation of complement and coagulation in an ex vivo perfusion animal study using porcine kidneys.

During pig-to-primate xenotransplantation or perfusion of porcine organs with human blood, a xenogeneic coagulopathy with consecutive development of thrombotic microangiopathy (TMA) can be observed. The aim of this study was to elucidate the influence of the reduction of xenoreactive natural antibodies on the coagulopathy using an ex vivo perfusion system. Thirteen perfusion experiments using landrace wild-type porcine kidneys were performed in three different experimental groups: autologous, xenogeneic, and immunoadsorption. During and after perfusion, blood and tissue samples were collected to assess markers of coagulation, complement, inflammation, and endothelial activation. Immunoadsorption prior to perfusion did not prolong perfusion time (174 min ±28) compared to xenogeneic (182 min ±22) experiments, whereas autologous perfusion was possible for maximum of 240 min in all experiments. Activation of coagulation was similar comparing perfusions after immunoadsorption (D-Dimer 24 186 µg/l ±5813; TAT 566 µg/l ±34) to xenogeneic (D-Dimer 22 175 µg/l ±7826, TAT 600 µg/l ±0) experiments. But antibody-mediated complement activation was reduced in the immunoadsorption group. TNF-alpha and markers of endothelial cell activation were lower in the immunoadsorption group compared to the xenogeneic experiments. In this ex vivo perfusion model, we observed that marked removal of xenogeneic antibodies can reduce complement activation via the classical pathway as well as endothelial cell activation and inflammation. Immunoadsorption cannot prevent the activation of the terminal complement cascade and coagulation.

Use of Rotational Thromboelastometry in Liver Transplantation Is Associated With Reduced Transfusion Requirements.

OBJECTIVES: Increased transfusion requirements in liver transplantation have been reported to be associated with worsened outcomes, more frequent reinterventions, and higher expenses. Anesthesiologists might counteract this through improved coagulation management. We evaluated the effects of rotational thromboelastometry on transfusion and coagulation product requirements and on outcome measurements. MATERIALS AND METHODS: Patients who were 14 years or older and who were undergoing liver transplant at Hannover Medical School between January 2005 and December 2009 were included in this retrospective analysis. Demographic, clinical, and laboratory data, use of rotational thromboelastometry, intraoperative need for blood or coagulation products and antifibrinolytic substances, and clinical course were recorded. Correlations were examined using appropriate statistical tests. RESULTS: Our study included 413 patients. Use of rotational thromboelastometry was associated with less frequent intraoperative administration of red blood cell concentrates, fresh frozen plasma, platelet concentrates, prothrombin complex concentrates, and antithrombin concentrates (all P < .05). In addition, univariate and multivariate tests showed that rotational thromboelastometry was correlated with decreased need for red blood cell concentrates and fresh frozen plasma (all P < .05). Intraoperative administration rates of antifibrinolytic substances and fibrinogen concentrate were significantly increased in patients who received rotational thromboelastometry monitoring (both P < .05). However, use of rotational thromboelastometry was not associated with massive transfusion rates (> 10 units vs less), clinical outcome, or length of stay in the intensive care unit (all P > .05). CONCLUSIONS: Use of rotational thromboelastometry during liver transplant may reduce the need for intraoperative transfusion and coagulation products. Relevant effects of rotational thromboelastometry on patient outcomes or lengths of stay in the intensive care unit could not be ascertained. However, readjustment of therapeutic thresholds may improve the clinical impact.

Preoperative Recipient Parameters Allow Early Estimation of Postoperative Outcome and Intraoperative Transfusion Requirements in Liver Transplantation.

CONTEXT: Liver transplantation is a complex intervention, and early anticipation of personnel and logistic requirements is of great importance. Early identification of high-risk patients could prove useful. We therefore evaluated prognostic values of recipient parameters commonly available in the early preoperative stage regarding postoperative 30- and 90-day outcomes and intraoperative transfusion requirements in liver transplantation. DESIGN, SETTING, AND PARTICIPANTS: All adult patients undergoing first liver transplantation at Hannover Medical School between January 2005 and December 2010 were included in this retrospective study. Demographic, clinical, and laboratory data as well as clinical courses were recorded. Prognostic values regarding 30- and 90-day outcomes were evaluated by uni- and multivariate statistical tests. Identified risk parameters were used to calculate risk scores. RESULTS: There were 426 patients (40.4% female) included with a mean age of 48.6 (11.9) years. Absolute 30-day mortality rate was 9.9%, and absolute 90-day mortality rate was 13.4%. Preoperative leukocyte count >5200/µL, platelet count <91 000/µL, and creatinine values ≥77 µmol/L were relevant risk factors for both observation periods ( P < .05, respectively). A score based on these factors significantly differentiated between groups of varying postoperative outcomes and intraoperative transfusion requirements ( P < .05, respectively). CONCLUSION: A score based on preoperative creatinine, leukocyte, and platelet values allowed early estimation of postoperative 30- and 90-day outcomes and intraoperative transfusion requirements in liver transplantation. Results might help to improve timely logistic and personal strategies.

Outcome of acute respiratory distress syndrome in university and non-university hospitals in Germany.

BACKGROUND: This study investigates differences in treatment and outcome of ventilated patients with acute respiratory distress syndrome (ARDS) between university and non-university hospitals in Germany. METHODS: This subanalysis of a prospective, observational cohort study was performed to identify independent risk factors for mortality by examining: baseline factors, ventilator settings (e.g., driving pressure), complications, and care settings-for example, case volume of ventilated patients, size/type of intensive care unit (ICU), and type of hospital (university/non-university hospital). To control for potentially confounding factors at ARDS onset and to verify differences in mortality, ARDS patients in university vs non-university hospitals were compared using additional multivariable analysis. RESULTS: Of the 7540 patients admitted to 95 ICUs from 18 university and 62 non-university hospitals in May 2004, 1028 received mechanical ventilation and 198 developed ARDS. Although the characteristics of ARDS patients were very similar, hospital mortality was considerably lower in university compared with non-university hospitals (39.3% vs 57.5%; p = 0.012). Treatment in non-university hospitals was independently associated with increased mortality (OR (95% CI): 2.89 (1.31-6.38); p = 0.008). This was confirmed by additional independent comparisons between the two patient groups when controlling for confounding factors at ARDS onset. Higher driving pressures (OR 1.10; 1 cmH2O increments) were also independently associated with higher mortality. Compared with non-university hospitals, higher positive end-expiratory pressure (PEEP) (mean ± SD: 11.7 ± 4.7 vs 9.7 ± 3.7 cmH2O; p = 0.005) and lower driving pressures (15.1 ± 4.4 vs 17.0 ± 5.0 cmH2O; p = 0.02) were applied during therapeutic ventilation in university hospitals, and ventilation lasted twice as long (median (IQR): 16 (9-29) vs 8 (3-16) days; p < 0.001). CONCLUSIONS: Mortality risk of ARDS patients was considerably higher in non-university compared with university hospitals. Differences in ventilatory care between hospitals might explain this finding and may at least partially imply regionalization of care and the export of ventilatory strategies to non-university hospitals.

Effect of Clopidogrel on Thrombus Formation in an Ex Vivo Parallel Plate Flow Chamber Model Cannot Be Reversed by Addition of Platelet Concentrates or vWF Concentrate.

BACKGROUND: Hemorrhage is the most important complication of antithrombotic therapy with P2Y12 receptor blockers. The administration of platelet concentrates (PCs) and von Willebrand factor (vWF) concentrates are common procedures to normalize impaired primary hemostasis in bleeding patients. We tested whether this strategy reverses the effect of clopidogrel using a parallel plate flow chamber model. METHODS: Whole blood from patients, who received a loading dose of clopidogrel with 600 mg and an ongoing dual antiplatelet therapy with 75 mg/d clopidogrel and 100 mg/d acetyl salicylic acid, compared with blood from healthy volunteers was examined in a collagen-coated parallel plate flow chamber. Blood was perfused by suction at a shear rate of 300/s, which is equivalent to 14 dynes/cm to resemble shear stress in conduit arteries. Platelet-covered area, individual thrombus size, and the average thrombus size were assessed morphometrically. The equivalent of 2 or 5 units of PC and/or 2 U/mL of vWF concentrate were used in an attempt to restore coagulation capacity in blood samples of clopidogrel-treated patients. RESULTS: In this model, clopidogrel reduced the increase of thrombus size. The equivalent of 2 U of PC or 2 U/mL of vWF alone did not show any significant changes in thrombus size. 5 U of PC increased thrombus size in clopidogrel-treated patients (P < .05). Thrombus size in clopidogrel blood was increased by combined PC and vWF treatment (by 50%, P < .05), but this increase did not reach control levels (P < .05). CONCLUSIONS: This flow chamber model is suitable for detection of the antiplatelet effect of clopidogrel. Ex vivo addition of PC or vWF does not overcome the effects of clopidogrel in this model, but the combination of both shows a mild and significant improvement in thrombus size.

Application of the Liver Maximum Function Capacity Test in Acute Liver Failure: A Helpful Tool for Decision-Making in Liver Transplantation?

Background. Despite aggressive intensive medical management acute liver failure (ALF) may require high-urgency liver transplantation (LTx). Available prognostic scores do not apply for all patients; reliable tools to identify individuals in need of LTx are highly required. The liver maximum function capacity test (LiMAx) might represent an appropriate option. Referring to a case of ALF after Amanita phalloides-intoxication the potential of the LiMAx-test in this setting is discussed. Presentation of Case. LiMAx was performed in a 27-year-old patient prior to and after high-urgency LTx. In accordance with clinical appearance of hepatic encephalopathy, coagulopathy, and acute kidney failure, the LiMAx-test constituted a fulminant course of ALF with hardly any detectable metabolic activity. Following LTx with a marginal donor organ (95% hepatosteatosis), uptake of liver function was demonstrated by postoperative increase of the LiMAx-value. The patient was discharged from hospital on postoperative day 26. Discussion. ALF often is associated with a critical state of the patient that requires almost immediate decision-making regarding further therapy. Application of a noninvasive liver function test might help to determine the prognosis of ALF and support decision-making for or against LTx as well as acceptance of a critical donor organ in case of a critically ill patient.

Effect of TNF-alpha blockade on coagulopathy and endothelial cell activation in xenoperfused porcine kidneys.

BACKGROUND: Following pig-to-primate kidney transplantation, endothelial cell activation and xenogenic activation of the recipient's coagulation eventually leading to organ dysfunction and microthrombosis can be observed. In this study, we examined the effect of a TNF-receptor fusion protein (TNF-RFP) on endothelial cell activation and coagulopathy utilizing an appropriate ex vivo perfusion system. METHODS: Using an ex vivo perfusion circuit based on C1-Inhibitor (C1-Inh) and low-dose heparin administration, we have analyzed consumptive coagulopathy following contact of human blood with porcine endothelium. Porcine kidneys were recovered following in situ cold perfusion with Histidine-tryptophan-ketoglutarate (HTK) organ preservation solution and were immediately connected to a perfusion circuit utilizing freshly drawn pooled porcine or human AB blood. The experiments were performed in three individual groups: autologous perfusion (n = 5), xenogenic perfusion without any further pharmacological intervention (n = 10), or with addition of TNF-RFP (n = 5). After perfusion, tissue samples were obtained for real-time PCR and immunohistological analyses. Endothelial cell activation was assessed by measuring the expression levels of E-selectin, ICAM-1, and VCAM-1. RESULTS: Kidney survival during organ perfusion with human blood, C1-Inh, and heparin, but without any further pharmacological intervention was 126 ± 78 min. Coagulopathy was observed with significantly elevated concentrations of D-dimer and thrombin-antithrombin complex (TAT), resulting in the formation of multiple microthrombi. Endothelial cell activation was pronounced, as shown by increased expression of E-selectin and VCAM-1. In contrast, pharmacological intervention with TNF-RFP prolonged organ survival to 240 ± 0 min (max. perfusion time; no difference to autologous control). Formation of microthrombi was slightly reduced, although not significantly, if compared to the xenogenic control. D-dimer and TAT were elevated at similar levels to the xenogenic control experiments. In contrast, endothelial cell activation, as shown by real-time PCR, was significantly reduced in the TNF-RFP group. CONCLUSION: We conclude that although coagulopathy was not affected, TNF-RFP is able to suppress inflammation occurring after xenoperfusion in this ex vivo perfusion model.

Recombinant human antithrombin prevents xenogenic activation of hemostasis in a model of pig-to-human kidney transplantation.

BACKGROUND: Xenogenic activation of hemostasis (XAH) represents a major hurdle for the transplantation of discordant animal organs into humans as it results in thrombotic microangiopathy (TMA). We have previously shown that recombinant human-activated protein C (rhAPC) mitigates XAH and TMA in an ex vivo model of pig-to-human kidney transplantation. However, the use of rhAPC may not be feasible in a perioperative setting due to possible bleeding complications. METHODS: Here, we explored the effects of another natural inhibitor of coagulation, human recombinant antithrombin (rhAT), in comparison with rhAPC. Unmodified porcine kidneys (n = 25) were perfused ex vivo with porcine blood, human blood, or human blood supplemented with rhAPC or rhAT. Surrogate parameters of organ survival, markers of XAH (D- Dimer, thrombin-antithrombin complex [TAT], fibrinogen, antithrombin activity, plasminogen), endothelial cell and platelet activation (E-selectin, P-selectin), platelet function tests and histological signs of TMA were evaluated. RESULTS: Perfusion was feasible for > 240 min in all experiments with autologous porcine blood, but limited to 126 ± 78 min with human blood due to increased vascular resistance. Addition of rhAT protected from TMA and allowed for perfusion times > 240 min. In addition, there were less signs of XAH with reduced release of P-selectin and overexpression of E-selectin, whereas the progressive loss of platelet function, observed during discordant perfusion, was prevented. The effect of rhAT was dose-dependent with maximum protection obtained at 3 IU/ml. CONCLUSION: In conclusion, in this ex vivo model of discordant xenotransplantation, rhAT reduced XAH and prevented TMA in doses that appear feasible for use in clinical or preclinical transplantation settings.

Desmopressin (DDAVP) improves recruitment of activated platelets to collagen but simultaneously increases platelet endothelial interactions in vitro.

Platelet dysfunction can cause clinically relevant bleeding. Treatment with DDAVP is advocated for this condition. DDAVP increases von Willebrand factor (VWF) on endothelial cells (ECs) and in plasma. VWF could facilitate platelet deposition on subendothelial collagen. VWF also facilitates platelet/EC interactions. Therefore DDAVP could precipitate thromboembolic events. We used a flow chamber model to study in vitro and ex vivo if DDAVP alters recruitment of platelets to EC and collagen. Resting or TRAP-activated platelets and EC were treated individually or simultaneously with 0.4 ng/ml DDAVP. Fluorophor-labeled platelets (10(6)/ml) were resuspended in reconstituted blood and superfused across EC and collagen in an in vitro flow chamber model at arterial shear (320 s(-1)). Adhesion of platelets to the respective surface was recorded fluorescence microscopically and platelet covered area was assessed. TRAP significantly induced adhesiveness of platelets for collagen and EC. DDAVP pretreatment of platelets did not affect adhesiveness of resting or TRAP-activated platelets for collagen or EC. Adhesiveness of resting but not TRAP-activated platelets was induced on DDAVP-treated EC. DDAVP-conditioned EC supernatant contained vWF and significantly increased platelet deposition on collagen. Platelets from patients with clinically suspected platelet dysfunction undergoing aortic valve replacement exhibited decreased platelet deposition on collagen surfaces. In summary, our data confirm that DDAVP can induce release of platelet adhesion promoting factors from EC, which is most likely vWF. DDAVP has no direct effect on platelets. Blood samples from DDAVP-treated patients do not exhibit significantly augmented platelet deposition on collagen ex vivo. This influence of released promoting factors might cause an increase of undesirable interactions of platelets with EC.

Respiratory risk score for the prediction of 3-month mortality and prolonged ventilation after liver transplantation.

Survival of critically ill patients is significantly affected by prolonged ventilation. The goal of this study was the development of a respiratory risk score (RRS) for the prediction of 3-month mortality and prolonged ventilation after liver transplantation (LT). Two hundred fifty-four consecutive LT patients from a single center were retrospectively randomized into a training group for model design and a validation group. A receiver operating characteristic (ROC) curve analysis was used to test sensitivity and specificity. The accuracy of the predictions was assessed with the Brier score, and the model calibration was assessed with the Hosmer-Lemeshow test. Cutoff values were determined with the best Youden index. The RRS was calculated in the first 24 hours as follows: (laboratory Model for End-Stage Liver Disease score > 30 = 2.36 points) + (fresh frozen plasma > 13.5 U = 2.70 points) + (partial pressure of arterial oxygen/fraction of inspired oxygen ratio < 200 mm Hg = 2.23 points) + (packed red blood cells > 10.5 U = 3.50 points) + (preoperative mechanical ventilation = 3.87 points) + (preoperative dialysis = 2.83 points) + (donor steatosis hepatis > 40% = 2.95 points). The RSS demonstrated high predictive accuracy, good model calibration, and c statistics > 0.7 in the training and validation groups. The RSS was able to predict 3-month mortality [cutoff = 6.64, area under the (ROC) curve (AUROC) = 0.794] and prolonged ventilation (cutoff = 3.69, AUROC = 0.798) with sensitivities of 69% and 81%, specificities of 83% and 73%, and overall model correctness of 76% and 77%, respectively. In conclusion, this study provides the first prognostic model for the prediction of 3-month mortality and prolonged ventilation after LT with high sensitivity and specificity and good model accuracy. The application of the RRS to an external cohort would be desirable for its further validation and introduction as a clinical tool for intensive care resource planning and prognostic decision making.

Value of the preoperative SOFT-score, P-SOFT-score, SALT-score and labMELD-score for the prediction of short-term patient and graft survival of high-risk liver transplant recipients with a pre-transplant labMELD-score ≥30.

BACKGROUND: The SOFT-score, P-SOFT-score, SALT-score and labMELD-score have been applied for the prediction of survival of liver transplant recipients after transplantation. We analysed the value of these scores for the prediction of short-term survival in high-risk liver transplant recipients with a labMELD-score ≥30. MATERIAL/METHODS: Retrospective single-centre analysis including 88 consecutive liver transplants in adults between 01.01.2007 and 31.12.2010 with a pretransplant labMELD-score ≥30 and follow-up until the 31.12.2011. Combined and living-related liver transplants were excluded. ROC-curve analysis was used to calculate sensitivity, specificity and overall model correctness of prognostic models. RESULTS: The P-SOFT-score demonstrated a significant influence on 1-year patient survival (p=0.045, Mann-Whitney-U test). Multivariate Cox regression analysis showed a significant influence of the P-SOFT-score on patient (p=0.013; Exp(B)=1.050; 95%CI: 1.010-1.091) and on graft survival (p=0.023; Exp(B)=1.042; 95%CI: 1.006-1.080). ROC-curve analysis showed areas under the curve (AUROCs) <0.5 for the SOFT-score, P-SOFT-score, SALT-score and the labMELD-score ≥30 for the prediction of 3-month patient and graft survival as well as 1-year patient and graft survival. CONCLUSIONS: Our results imply that the SOFT-score, P-SOFT-score, SALT-score and labMELD-score ≥30 all have a sensitivity, specificity and overall model correctness that is unable to discriminate short-term survivors from non-survivors in a collective of high-risk liver transplant recipients sufficiently in order to guide clinical decision making in the current German transplant situation with decreasing numbers of deceased liver donors, decreasing donor organ quality and increasingly sick transplant candidates.

Value of the SOFA score as a predictive model for short-term survival in high-risk liver transplant recipients with a pre-transplant labMELD score ≥ 30.

INTRODUCTION: The Sequential Organ Failure Assessment (SOFA) score has been applied for the prediction of survival in critically ill patients. We analysed the value of the SOFA score for the prediction of short-term survival after liver transplantation in high-risk liver transplant recipients with a labMELD score ≥30. PATIENTS AND METHODS: We conducted a retrospective single-centre analysis including 88 consecutive liver transplants in adults between January 1, 2007 and December 31, 2010 with a pre-transplant labMELD score ≥30. The SOFA score was assessed preoperatively, directly after transplantation and on post-operative days (PODs) 1-10. Combined and living-related liver transplants were excluded. Receiver operating characteristic (ROC) curve analysis with the Hosmer-Lemeshow test and application of the Brier score were used to calculate sensitivity, specificity, overall model correctness and calibration. Cutoff values were selected with the best Youden index. RESULTS: ROC curve analysis showed areas under the curve (AUROCs) >0.8 for the SOFA score on PODs 1-10 for the prediction of hospital mortality, 30-day mortality and 3-month mortality with Hosmer-Lemeshow test results that confirmed good model calibration (p > 0.05). The Brier score demonstrated an accuracy of prediction (<0.25) of hospital mortality, 30-day mortality and 3-month mortality for the SOFA scores on PODs 4-9 indicating superior accuracy on PODs 7 and 8 with cutoff values for the SOFA score between 16.5 and 18.5. The pre-transplant SOFA score failed to reach AUROCs >0.7 (0.603-0.663) for the prediction of short-term survival. CONCLUSIONS: Our results confirm the usefulness of the SOFA score in high-risk liver recipients during the early post-operative course, especially on PODs 7-8 for the prediction of hospital mortality, 30-day mortality and 3-month mortality and may be useful to predict futile early acute retransplantation.