Critical care hepatology: definitions, incidence, prognosis and role of liver failure in critically ill patients.

Organ dysfunction or overt failure is a commonplace event in the critically ill affecting up to 70% of patients during their stay in the ICU. The outcome depends on the resolution of impaired organ function, while a domino-like deterioration of organs other than the primarily affected ones paves the way for increased mortality. "Acute Liver Failure" was defined in the 1970s as a rare and potentially reversible severe liver injury in the absence of prior liver disease with hepatic encephalopathy occurring within 8 weeks. Dysfunction of the liver in general reflects a critical event in "Multiple Organ Dysfunction Syndrome" due to immunologic, regulatory and metabolic functions of liver parenchymal and non-parenchymal cells. Dysregulation of the inflammatory response, persistent microcirculatory (hypoxic) impairment or drug-induced liver injury are leading problems that result in "secondary liver failure," i.e., acquired liver injury without underlying liver disease or deterioration of preexisting (chronic) liver disease ("Acute-on-Chronic Liver Failure"). Conventional laboratory markers, such as transaminases or bilirubin, are limited to provide insight into the complex facets of metabolic and immunologic liver dysfunction. Furthermore, inhomogeneous definitions of these entities lead to widely ranging estimates of incidence. In the present work, we review the different definitions to improve the understanding of liver dysfunction as a perpetrator (and therapeutic target) of multiple organ dysfunction syndrome in critical care.

Extracorporeal carbon dioxide removal with the Advanced Organ Support system in critically ill COVID-19 patients.

Disturbed oxygenation is foremost the leading clinical presentation in COVID-19 patients. However, a small proportion also develop carbon dioxide removal problems. The Advanced Organ Support (ADVOS) therapy (ADVITOS GmbH, Munich, Germany) uses a less invasive approach by combining extracorporeal CO2 -removal and multiple organ support for the liver and the kidneys in a single hemodialysis device. The aim of our study is to evaluate the ADVOS system as treatment option in-COVID-19 patients with multi-organ failure and carbon dioxide removal problems. COVID-19 patients suffering from severe respiratory insufficiency, receiving at least two treatments with the ADVOS multi system (ADVITOS GmbH, Munich, Germany), were eligible for study inclusion. Briefly, these included patients with acute kidney injury (AKI) according to KDIGO guidelines, and moderate or severe ARDS according to the Berlin definition, who were on invasive mechanical ventilation for more than 72 hours. In total, nine COVID-19 patients (137 ADVOS treatment sessions with a median of 10 treatments per patient) with moderate to severe ARDS and carbon dioxide removal problems were analyzed. During the ADVOS treatments, a rapid correction of acid-base balance and a continuous CO2 removal could be observed. We observed a median continuous CO2 removal of 49.2 mL/min (IQR: 26.9-72.3 mL/min) with some treatments achieving up to 160 mL/min. The CO2 removal significantly correlated with blood flow (Pearson 0.421; P < .001), PaCO2 (0.341, P < .001) and HCO 3 - levels (0.568, P < .001) at the start of the treatment. The continuous treatment led to a significant reduction in PaCO2 from baseline to the last ADVOS treatment. In conclusion, it was feasible to remove CO2 using the ADVOS system in our cohort of COVID-19 patients with acute respiratory distress syndrome and multiorgan failure. This efficient removal of CO2 was achieved at blood flows up to 300 mL/min using a conventional hemodialysis catheter and without a membrane lung or a gas phase.

Registry on extracorporeal multiple organ support with the advanced organ support (ADVOS) system: 2-year interim analysis.

ABSTRACT: The objective of this registry is to collect data on real-life treatment conditions for patients for whom multiple organ dialysis with Advanced Organ Support (ADVOS) albumin hemodialysis is indicated.This registry was performed under routine conditions and without any study-specific intervention, diagnostic procedures, or assessments. Data on clinical laboratory tests, health status, liver function, vital signs, and examinations were collected (DRKS-ID: DRKS00017068). Mortality rates 28 and 90 days after the first ADVOS treatment, adverse events and ADVOS treatment parameters, including treatment abortions, were documented.This analysis was performed 2 years after the first patient was included on January 18, 2017. As of February 20, 2019, 4 clinical sites in Germany participated and enrolled 118 patients with a median age of 60 (IQR: 45, 69) of whom 70 were male (59.3%). Patients had a median SOFA Score of 14 (IQR: 11, 16) and a predicted mortality of 80%. The median number of failing organs was 3 (IQR: 2, 4).Four hundred twenty nine ADVOS treatments sessions were performed with a median duration of 17 hours (IQR: 6, 23). A 5.8% of the ADVOS sessions (25 of 429) were aborted due to device related errors, while 14.5% (62 of 429) were stopped for other reasons. Seventy nine adverse events were documented, 13 of them device related (all clotting, and all recovered without sequels).A significant reduction in serum creatinine (1.5 vs 1.2 mg/dl), blood urea nitrogen (24 vs 17 mg/dl) and bilirubin (6.9 vs 6.5 mg/dl) was observed following the first ADVOS treatment session. Blood pH, bicarbonate (HCO3-) and base excess returned to the physiological range, while partial pressure of carbon dioxide (pCO2) remained unchanged. At the time of the analysis, 28- and 90-day mortality were 60% and 65%, respectively, compared to an expected ICU-mortality rate of 80%. SOFA score was an independent predictor for outcome in a multivariable logistic regression analysis.The reported data show a high quality and completion of all participating centers. Data interpretation must be cautious due to the small number of patients, and the nature of the registry, without a control group. However, the data presented here show an improvement of expected mortality rates. Minor clotting events similar to other dialysis therapies occurred during the treatments.

Respiratory and metabolic acidosis correction with the ADVanced Organ Support system.

BACKGROUND: The lung, the kidney, and the liver are major regulators of acid-base balance. Acidosis due to the dysfunction of one or more organs can increase mortality, especially in critically ill patients. Supporting compensation by increasing ventilation or infusing bicarbonate is often ineffective. Therefore, direct removal of acid may represent a novel therapeutic approach. This can be achieved with the ADVanced Organ Support (ADVOS) system, an enhanced renal support therapy based on albumin dialysis. Here, we demonstrate proof of concept for this technology. METHODS: An ex vivo model of either hypercapnic (i.e., continuous CO2 supply) or lactic acidosis (i.e., lactic acid infusion) using porcine blood was subjected to hemodialysis with ADVOS. A variety of operational parameters including blood and dialysate flows, different dialysate pH settings, and acid and base concentrate compositions were tested. Comparisons with standard continuous veno-venous hemofiltration (CVVH) using high bicarbonate substitution fluid and continuous veno-venous hemodialysis (CVVHD) were also performed. RESULTS: Sixty-one milliliters per minute (2.7 mmol/min) of CO2 was removed using a blood flow of 400 ml/min and a dialysate pH of 10 without altering blood pCO2 and HCO3- (36 mmHg and 20 mmol/l, respectively). Up to 142 ml/min (6.3 mmol/min) of CO2 was eliminated if elevated pCO2 (117 mmHg) and HCO3- (63 mmol/l) were allowed. During continuous lactic acid infusion, an acid load of up to 3 mmol/min was compensated. When acidosis was triggered, ADVOS multi normalized pH and bicarbonate levels within 1 h, while neither CVVH nor CVVHD could. The major determinants to correct blood pH were blood flow, dialysate composition, and initial acid-base status. CONCLUSIONS: In conclusion, ADVOS was able to remove more than 50% of the amount of CO2 typically produced by an adult human. Blood pH was maintained stable within the physiological range through compensation of a metabolic acid load by albumin dialysate. These in vitro results will require confirmation in patients.

Evaluation of an ADVanced Organ Support (ADVOS) system in a two-hit porcine model of liver failure plus endotoxemia.

BACKGROUND: Novel extracorporeal procedures are constantly being developed and evaluated for use in patients with sepsis. Preclinical evaluation of such procedures usually requires testing in large animal models. In the present work, the safety and efficacy of a recently developed ADVanced Organ Support (ADVOS) system in a newly developed large animal two-hit model of liver failure combined with endotoxemia were tested. METHODS: After establishing the model in more than 50 animals, a randomized study was performed. An inflammatory cholestatic liver injury was initially provoked in pigs. Three days after surgery, endotoxin was gradually administered during 7½ h. Animals were randomized to receive standard medical treatment either with (ADVOS group, n = 5) or without ADVOS (control group, n = 5). The ADVOS treatment was started 2½ h after endotoxemia and continued for 7 h. Survival, cardiovascular, respiratory, renal, liver, coagulation, and cerebral parameters were analyzed. RESULTS: Three days after surgery, cholestatic injury resulted in hyperbilirubinemia [5.0 mg/dl (IQR 4.3-5.9 mg/dl)], hyperammonemia [292 µg/dl (IQR 291-296 µg/dl)], leukocytosis [20.2 103/µl (IQR 17.7-21.8 103/µl)], and hyperfibrinogenemia [713 mg/dl (IQR 654-803 mg/dl)]. After endotoxemia, the ADVOS procedure stabilized cardiovascular, respiratory, and renal parameters and eliminated surrogate markers as bilirubin [2.3 (IQR 2.3-3.0) vs. 5.5 (IQR 4.6-5.6) mg/dl, p = 0.001] and creatinine [1.4 (IQR 1.1-1.7) vs. 2.3 (IQR 2.1-3.1) mg/dl, p = 0.01]. Mortality: All animals in the ADVOS group survived, while all animals in the control group expired during the 10-h observation period (p = 0.002). No adverse events related to the procedure were observed. CONCLUSIONS: The ADVOS procedure showed a promising safety and efficacy profile and improved survival in a sepsis-like animal model with dysfunction of multiple organs. An amelioration of major organ functions (heart and lung) combined with removal of markers for kidney and liver function was observed.

Evaluation of the immunological profile of antibody-functionalized metal-filled single-walled carbon nanocapsules for targeted radiotherapy.

This study investigates the immune responses induced by metal-filled single-walled carbon nanotubes (SWCNT) under in vitro, ex vivo and in vivo settings. Either empty amino-functionalized CNTs [SWCNT-NH2 (1)] or samarium chloride-filled amino-functionalized CNTs with [SmCl3@SWCNT-mAb (3)] or without [SmCl3@SWCNT-NH2 (2)] Cetuximab functionalization were tested. Conjugates were added to RAW 264.7 or PBMC cells in a range of 1 µg/ml to 100 µg/ml for 24 h. Cell viability and IL-6/TNFα production were determined by flow cytometry and ELISA. Additionally, the effect of SWCNTs on the number of T lymphocytes, B lymphocytes and monocytes within the PBMC subpopulations was evaluated by immunostaining and flow cytometry. The effect on monocyte number in living mice was assessed after tail vein injection (150 µg of each conjugate per mouse) at 1, 7 and 13 days post-injection. Overall, our study showed that all the conjugates had no significant effect on cell viability of RAW 264.7 but conjugates 1 and 3 led to a slight increase in IL-6/TNFα. All the conjugates resulted in significant reduction in monocyte/macrophage cell numbers within PBMCs in a dose-dependent manner. Interestingly, monocyte depletion was not observed in vivo, suggesting their suitability for future testing in the field of targeted radiotherapy in mice.

Endocytosis in gene therapy with non-viral vectors.

Gene therapy or the delivery of genetic material can be carried out not only with viral vectors, but with non-viral vectors too. Although the use of non-viral carriers is safer, this approach has generally been poorer in terms of transfection efficiency. In order to improve the transfection rates, it is important to exactly know the path that the nanoparticles go through. In this way, we can understand the reason why some of these vectors fail or are successful in their duties. This review aims to summarize the different stages and barriers that nanocarriers have to overcome during endocytosis so as to reach the cytoplasm, in the case of RNA, or the nucleus, in the case of DNA. In addition, different strategies that could be employed to improve the success of the carriers in each stage are suggested.

Design of antibody-functionalized carbon nanotubes filled with radioactivable metals towards a targeted anticancer therapy.

In the present work we have devised the synthesis of a novel promising carbon nanotube carrier for the targeted delivery of radioactivity, through a combination of endohedral and exohedral functionalization. Steam-purified single-walled carbon nanotubes (SWCNTs) have been initially filled with radioactive analogues (i.e. metal halides) and sealed by high temperature treatment, affording closed-ended CNTs with the filling material confined in the inner cavity. The external functionalization of these filled CNTs was then achieved by nitrene cycloaddition and followed by the derivatization with a monoclonal antibody (Cetuximab) targeting the epidermal growth factor receptor (EGFR), overexpressed by several cancer cells. The targeting efficiency of the so-obtained conjugate was evaluated by immunostaining with a secondary antibody and by incubation of the CNTs with EGFR positive cells (U87-EGFR+), followed by flow cytometry, confocal microscopy or elemental analyses. We demonstrated that our filled and functionalized CNTs can internalize more efficiently in EGFR positive cancer cells.