Elevation of neutrophil-derived factors in patients after multiple trauma.

Trauma represents one of the leading causes of death worldwide. Traumatic injuries elicit a dynamic inflammatory response with systemic release of inflammatory cytokines. Disbalance of this response can lead to systemic inflammatory response syndrome or compensatory anti-inflammatory response syndrome. As neutrophils play a major role in innate immune defence and are crucial in the injury-induced immunological response, we aimed to investigate systemic neutrophil-derived immunomodulators in trauma patients. Therefore, serum levels of neutrophil elastase (NE), myeloperoxidase (MPO) and citrullinated histone H3 (CitH3) were quantified in patients with injury severity scores above 15. Additionally, leukocyte, platelet, fibrinogen and CRP levels were assessed. Lastly, we analysed the association of neutrophil-derived factors with clinical severity scoring systems. Although the release of MPO, NE and CitH3 was not predictive of mortality, we found a remarkable increase in MPO and NE in trauma patients as compared with healthy controls. We also found significantly increased levels of MPO and NE on Days 1 and 5 after initial trauma in critically injured patients. Taken together, our data suggest a role for neutrophil activation in trauma. Targeting exacerbated neutrophil activation might represent a new therapeutic option for critically injured patients.

A randomized placebo-controlled phase II study of a Pseudomonas vaccine in ventilated ICU patients.

BACKGROUND: Currently, no vaccine against Pseudomonas is available. IC43 is a new, recombinant, protein (OprF/I)-based vaccine against the opportunistic pathogen, Pseudomonas aeruginosa, a major cause of serious hospital-acquired infections. IC43 has proven immunogenicity and tolerability in healthy volunteers, patients with burns, and patients with chronic lung diseases. In order to assess the immunogenicity and safety of IC43 in patients who are most at risk of acquiring Pseudomonas infections, it was evaluated in mechanically ventilated ICU patients. METHODS: We conducted a randomized, placebo-controlled, partially blinded study in mechanically ventilated ICU patients. The immunogenicity of IC43 at day 14 was determined as the primary endpoint, and safety, efficacy against P. aeruginosa infections, and all-cause mortality were evaluated as secondary endpoints. Vaccinations (100 µg or 200 µg IC43 with adjuvant, or 100 µg IC43 without adjuvant, or placebo) were given twice in a 7-day interval and patients were followed up for 90 days. RESULTS: Higher OprF/I IgG antibody titers were seen at day 14 for all IC43 groups versus placebo (P < 0.0001). Seroconversion (≥4-fold increase in OprF/I IgG titer from days 0 to 14) was highest with 100 µg IC43 without adjuvant (80.6%). There were no significant differences in P. aeruginosa infection rates, with a low rate of invasive infections (pneumonia or bacteremia) in the IC43 groups (11.2-14.0%). Serious adverse events (SAEs) considered possibly related to therapy were reported by 2 patients (1.9%) in the group of 100 µg IC43 with adjuvant. Both SAEs resolved and no deaths were related to study treatment. Local tolerability symptoms were mild and rare (<5% of patients), a low rate of treatment-related treatment-emergent adverse events (3.1-10.6%) was observed in the IC43 groups. CONCLUSION: This phase II study has shown that IC43 vaccination of ventilated ICU patients produced a significant immunogenic effect. P. aeruginosa infection rates did not differ significantly between groups. In the absence of any difference in immune response following administration of 100 µg IC43 without adjuvant compared with 200 µg IC43 with adjuvant, the 100 µg dose without adjuvant was considered for further testing of its possible benefit of improved outcomes. There were no safety or mortality concerns. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00876252 . Registered on 3 April 2009.

Macrophage migration inhibitory factor as a potential predictor for requirement of renal replacement therapy after orthotopic liver transplantation.

Acute kidney injury (AKI) after orthotopic liver transplantation (OLT) is associated with a poor clinical outcome. Because there is no specific treatment for postoperative AKI, early recognition and prevention are fundamental therapeutic approaches. Concentrations of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) are elevated in patients with kidney disease. We hypothesized that plasma MIF concentrations would be greater in patients developing AKI after OLT compared with patients with normal kidney function. Twenty-eight patients undergoing OLT were included in the study. Kidney injury was classified according to AKI network criteria. Fifteen patients (54%) developed severe AKI after OLT, 11 (39%) requiring renal replacement therapy (RRT). On the first postoperative day, patients with severe AKI had greater plasma MIF concentrations (237 ± 123 ng/mL) than patients without AKI (95 ± 63 ng/mL; P < 0.001). The area under the receiver operating characteristic (ROC) curve for predicting severe AKI was 0.87 [95% confidence interval (CI), 0.69-0.97] for plasma MIF, 0.61 (95% CI, 0.40-0.79) for serum creatinine (sCr), and 0.90 (95% CI, 0.72-0.98) for delta serum creatinine (ΔsCr). Plasma MIF (P = 0.02) and ΔsCr (P = 0.01) yielded a better predictive value than sCr for the development of severe AKI. Furthermore, the area under the ROC curve to predict the requirement of RRT was 0.87 (95% CI, 0.68-0.96) for plasma MIF, 0.65 (95% CI, 0.44-0.82) for sCr, and 0.72 (95% CI, 0.52-0.88) for ΔsCr. Plasma MIF had a better predictive value than sCr for the requirement of RRT (P = 0.02). In conclusion, postoperative plasma MIF concentrations were elevated in patients who developed severe AKI after OLT. Furthermore, plasma MIF concentrations showed a good prognostic value for identifying patients developing severe AKI or requiring postoperative RRT after OLT.

Extracorporeal liver support.

PURPOSE OF REVIEW: The mortality in patients suffering from liver failure decreased in line with medical progress over the past decades. However, it still remains unacceptably high and liver transplantation still provides the only definite treatment for many patients. The goal of extracorporeal liver support systems is to improve the clinical condition of patients waiting for liver transplantation and/or enhance the regeneration of native injured liver. Nonbiological liver support systems with pure detoxification and biological liver support systems with assumed synthesis and metabolism in addition to detoxification are currently under clinical investigation. Since patient survival is the most significant outcome parameter, we focus in this review on prospective randomized trials with survival rate as primary outcome parameter. RECENT FINDINGS: Although a short-term outcome benefit in patients with acute-on-chronic liver failure was shown in some of these trials, long-term outcome has not been improved significantly with either of the support systems. In spite of more favourable but yet limited data in patients with acute liver failure, it is too early to draw definite conclusions. SUMMARY: The future development of liver support systems may provide different combinations of new adsorbents, integrated regional citrate anticoagulation and eventual substitution of irreversibly damaged albumin.

Regional citrate anticoagulation in patients with liver failure supported by a molecular adsorbent recirculating system.

OBJECTIVE: Regional citrate anticoagulation has emerged as a promising method in critically ill patients at high risk of bleeding. However, in patients with liver failure, citrate accumulation may lead to acid-base and electrolyte imbalances, notably of calcium. The aim of this study was to evaluate the feasibility and safety of regional citrate anticoagulation during liver support using a molecular adsorbent recirculating system as well as its effects on electrolyte and acid-base balance in patients with liver failure. DESIGN: Prospective observational study. SETTING: University hospital. PATIENTS: Twenty critically ill patients supported by molecular adsorbent recirculating system resulting from liver failure between January 2007 and May 2009. MEASUREMENTS AND MAIN RESULTS: The median duration of molecular adsorbent recirculating system treatment was 20 hrs (interquartile range, 18-22 hrs). Two of 77 molecular adsorbent recirculating system treatments (2%) were prematurely discontinued as a result of filter clotting and bleeding, respectively. The median citrate infusion rate, necessary to maintain the postfilter ionized calcium between 0.2 and 0.4 mmol/L, was 3.1 mmol/L (interquartile range, 2.3-4 mmol/L) blood flow. The median calcium chloride substitution rate was 0.9 mmol/L (0.3-1.7 mmol/L) dialysate. Total serum calcium remained stable during molecular adsorbent recirculating system treatments. There was a statistically significant increase of the ratio of total calcium to systemic ionized calcium (2.04 ± 0.32 mmol/L to 2.17 ± 0.35; p = .01), which reflected citrate accumulation resulting from liver failure. Under close monitoring, no clinically relevant electrolytes or acid-base disorders were observed. CONCLUSIONS: Our results suggest that regional citrate anticoagulation is a safe and feasible method to maintain adequate circuit lifespan without increasing the risk of hemorrhagic complications while maintaining a normal acid-base as well as electrolyte balance in patients with liver failure supported by molecular adsorbent recirculating system.

Current approach to intraoperative monitoring in liver transplantation.

PURPOSE OF REVIEW: Although liver transplantation has become a standardized treatment and the only established definite therapy for end-stage liver disease it remains a unique clinical procedure. Increased understanding of the specific pathophysiological changes in end-stage liver disease and the transplantation procedure have led to the adaptation of concepts including overall monitoring of the patient and assessment of specific organ function. RECENT FINDINGS: Major emphasis is placed on adequate monitoring during perioperative care of liver transplantation patients in order to ensure optimal hemodynamic and respiratory performance. The immediate assessment of metabolism and graft function will also serve to guide therapy according to the individual patient's needs. SUMMARY: The evolution of monitoring during standardized liver transplantation, as well as currently recommended novel devices and concepts, are described and discussed.

Caspase-cleaved cytokeratin 18 and 20 S proteasome in liver degeneration.

Apoptosis of epithelial hepatocytes plays a pivotal role in acute as well as in chronic liver diseases. The cleavage of cytokeratin-18 (CK-18) by caspases is an early event in the apoptotic process. We therefore sought to investigate serum levels of CK-18 and 20S proteasome in patients with liver cirrhosis, primary graft dysfunction (PDF), and acute liver failure (ALF), and in healthy volunteers. Enzyme-linked immunosorbent assay (ELISA) was utilized to measure the concentration of M30, a fragment of CK-18 cleaved at Asp396 (M30 neoantigen), and the concentration of 20S proteasome. Serum levels of the CK-18 neoepitope M30 were significantly increased in ALF, primary graft dysfunction, and liver cirrhosis vs. healthy controls (1,993.6+/-124.7 U/L, 2,238.1+/-235.9 U/L, and 673.6+/-86.5 U/L vs. 66.8+/-29.1 U/L, respectively, P<0.001). Similar results were detected with the evaluation of 20S proteasome (124,014.5+/-13,235.6 ng/mL, 76,993.2+/-15,720.1 ng/mL, and 2,395.9+/-1,098.2 ng/mL vs. 1,074.5+/-259.4 ng/mL, respectively; P<0.001). Detection of CK-18 neoepitope M30 and 20S proteasome may represent a novel marker of tracing apoptotic epithelium, respectively mirroring degenerative liver processes in affected patient population.

Molecular adsorbent recirculating system in patients with early allograft dysfunction after liver transplantation: a pilot study.

Early allograft dysfunction (EAD) after orthotopic liver transplantation (OLT) causes marked morbidity and mortality. We conducted a prospective pilot study to assess the safety and efficacy of molecular adsorbent recirculating system (MARS) in treatment of EAD after OLT. Twelve consecutive adult liver allograft recipients with a median age of 48 years, 9 of whom were male, were prospectively included and supported with MARS. EAD was defined as the presence of at least 2 of the following: serum bilirubin >10 mg/dL, prothrombin time <40%, aspartate aminotransferase or alanine transferase >1,000 U/L, and plasma disappearance rate of indocyanine green (PDR(ICG)) <10% per minute within 72 hours after reperfusion. One-year patient and graft survival was 66%. There was a significant decrease in serum bilirubin (P = 0.002), serum creatinine (P = 0.006), and aspartate aminotransferase (P = 0.005) and a significant increase in PDR(ICG) (P = 0.007) after MARS treatment. Prothrombin time, albumin level, and platelet count remained stable. Sustained improvement of renal and neurological function and of mean arterial pressure were observed. No MARS-related adverse effects occurred. MARS treatment provides a safe approach to the treatment of EAD after OLT. On the basis of this pilot study, a multicenter randomized clinical trial that uses MARS treatment in EAD after OLT has been initiated.

Molecular adsorbent recirculating system and hemostasis in patients at high risk of bleeding: an observational study.

INTRODUCTION: Liver failure is associated with reduced synthesis of clotting factors, consumptive coagulopathy, and platelet dysfunction. The aim of the study was to evaluate the effects of liver support using a molecular adsorbent recirculating system (MARS) on the coagulation system in patients at high risk of bleeding. METHODS: We studied 61 MARS treatments in 33 patients with acute liver failure (n = 15), acute-on-chronic liver failure (n = 8), sepsis (n = 5), liver graft dysfunction (n = 3), and cholestasis (n = 2). Standard coagulation tests, standard thromboelastography (TEG), and heparinase-modified and abciximab-fab-modified TEG were performed immediately before and 30 minutes after commencement of MARS, and after the end of MARS treatment. Prostaglandin I2 was administered extracorporeally to all patients; 17 patients additionally received unfractioned heparin. RESULTS: Three moderate bleeding complications in three patients, requiring three to four units of packed red blood cells, were observed. All were sufficiently managed without interrupting MARS treatment. Although there was a significant decrease in platelet counts (median, 9 G/l; range, -40 to 145 G/l) and fibrinogen concentration (median, 15 mg/dl; range, -119 to 185 mg/dl) with a consecutive increase in thrombin time, the platelet function, as assessed by abciximab-fab-modified TEG, remained stable. MARS did not enhance fibrinolysis. CONCLUSION: MARS treatment appears to be well tolerated during marked coagulopathy due to liver failure. Although MARS leads to a further decrease in platelet count and fibrinogen concentration, platelet function, measured as the contribution of the platelets to the clot firmness in TEG, remains stable. According to TEG-based results, MARS does not enhance fibrinolysis.

Endothelin activation and postoperative renal failure after human liver transplantation.

Renal failure is an established risk factor for impaired patient outcome after orthotopic liver transplantation (OLT). As the endothelin pathway is known to be involved in the development of acute renal failure (ARF), we designed a study to clarify its role in ARF following OLT. Twenty consecutive patients with intact kidney function scheduled for their first OLT were prospectively studied. Plasma big endothelin-1 (ET-1) levels were measured before surgery, after graft reperfusion, and on the first and second postoperative day. According to postoperative glomerular filtration rate (GFR), patients were assigned to the acute renal dysfunction group (ARDF) and the non-ARDF group. Each patient's GFR was estimated according to the 4-variable formula used in the modification of diet in renal disease before surgery, daily within the first postoperative week, and at 1, 3, 12, and 24 months after surgery. Postoperative mean big ET-1 levels correlated significantly with the maximum percent decrease of GFR within 3 days after OLT (P < 0.01). The proportion of patients who developed ARDF was significantly correlated to mean postoperative big ET-1 quartiles (P < 0.01). In the ARDF group, the percent decrease of GFR within 24 months was significantly higher (P < 0.05) as compared to the non-ARDF group. In conclusion, patients who develop ARDF immediately after OLT do not fully recover to baseline regarding long-term kidney function. Short-term GFR was significantly correlated with postoperative big ET-1 plasma levels, suggesting renal dysfunction is mediated by the activated endothelin system.

Comparison of invasive and noninvasive measurement of plasma disappearance rate of indocyanine green in patients undergoing liver transplantation: a prospective investigator-blinded study.

Plasma disappearance rate of indocyanine green (PDRICG) has been proposed for assessment of liver function in liver transplants donors and recipients, in patients with chronic liver failure, and as a prognostic factor in critically ill patients. The assessment of PDRICG using a newly developed noninvasive digital pulse densitometry method was simultaneously compared to invasive aortic fiber-optic method in patients undergoing orthotopic liver transplantation (OLT). Fourteen consecutive liver transplant candidates (11 male, 3 female) were prospectively enrolled into the study. A 4F aortic catheter with an integrated fiber-optic device and a thermistor was inserted via a femoral artery sheath for invasive aortic (INV) PDRICG assessment in all patients. The fiber-optic device was connected to a computer system (COLD-Z021, PULSION Medical Systems, Munich, Germany). A finger-piece sensor was used for non-invasive (NINV) pulse-densitometric PDRICG assessment. For the PDRICG assessment.5 mg/kg of ICG in cooled saline (10-15 mL) was injected through a central venous catheter. The assessments of PDRICG were performed after induction of anesthesia, after clamping of the hepatic artery, after clamping of the inferior vena cava, after reperfusion of the graft, and on the first postoperative day. During the PDRICG measurements, the investigators were blinded for the results of the noninvasive monitoring. Seventy-one pairs of measurements were performed successfully. PDRICG ranged from 0%/min to 43.8 %/min (11.6%/min +/- 9.6 %/min, mean +/- SD) for invasive and from 2.6%/min to 36.1 %/min (10%/min +/- 7.6 %/min, mean +/- SD) for noninvasive assessment method. The linear regression analysis yielded the equation: PDRICG(NINV) = 1.493 +/- 0.735 x PDRICG(INV), with a correlation coefficient of r = 0.93 (P <.0001). The analysis according to Bland and Altman showed a good agreement between the PDRICG(NINV) and PDRICG(INV) with a mean bias 1.5 +/- 3.8 for all measurements. In conclusion, according to these results, the noninvasive transcutaneous pulse-densitometric method correlates well with the invasive aortic fiber-optic method and thus can be used in patients undergoing liver transplantation.

Iced versus room temperature injectate for assessment of cardiac output, intrathoracic blood volume, and extravascular lung water by single transpulmonary thermodilution.

PURPOSE: To assess the accuracy of iced versus room (RT) temperature single transpulmonary thermodilution (STPD) measurements for cardiac output, intra-thoracic blood, volume and extravascular lung water. MATERIALS AND METHODS: We studied 15 critically ill patients in a surgical intensive care unit with sepsis/septic shock (n = 8), pancreatitis (n = 2), acute liver failure (n = 2), orthotopic liver transplantation (n = 2) and lung resection (n = 1). All patients were sedated and mechanically ventilated. A 4-French femoral arterial catheter was inserted into each patient and connected to the pulse contour computer system (PiCCO). The pulse contour computer was then consecutively calibrated by triplicate STPD with 20 mL of RT and iced saline solution. The measurements with RT injectate were performed with a special in-line sensor adapted for measurement with RT injectate. All measurements were completed in less than 10 min. RESULTS: A total of 144 measurements were carried out. Linear regression analysis revealed good correlation between the two methods [r = 0.95; r = 0.91 and r = 0.97 for iced v RT cardiac index (CI), intrathoracic blood volume index (ITBVI) and extravascular lung water index (ELWI) respectively]. The bias +/- 2 * standard deviation of difference was -0.2 +/- 0.7 L/min/m2 for CIIT v CIRT; -4,9 +/- 194 mL/m2 for ITBVIIT v ITBVIRT and -0.535 +/- 1,5 mL/kg for ELWIIT v ELWIRT. CIRT and ELWIRT were measured slightly higher compared to IT injectate (P <.05). CONCLUSIONS: CI, ITBVI, and ELWI assessed by STPD with RT injectate are well correlated with measurements by iced injectates. According to our results room temperature injectates can be used in critically ill patients for assessment of CI, ITBVI and ELWI, which is more convenient for both the patients and medical staff and is also less expensive.

Living-related liver transplantation: implication for the anaesthetist.

PURPOSE OF REVIEW: Living donor liver transplantation, originally introduced about a decade ago to overcome paediatric cadaveric organ shortage, has rapidly gained acceptance within the transplant community and is nowadays almost routinely applied to the growing number of adult and paediatric patients awaiting a live-saving liver transplantation. In fact its introduction has contributed to a continuing decrease of waiting list deaths. RECENT FINDINGS: The risk of potential complications and even death for the donor increases with the extent of liver tissue resected. Better preoperative evaluation of suitability, refinement of surgical technique and smarter anaesthetic management, based on extended knowledge of underlying pathophysiology, have made the procedure safer for donors, with low morbidity and even lower mortality rates, tending towards zero in experienced centres. Despite these improvements, a certain risk is inherent. Yet from an ethical point of view it has to remain unacceptable especially because donors are otherwise healthy people and their only motives are altruistic. The procedure of living donor liver transplantation like conventional liver transplantation involves various disciplines, each of which contributes in a specific manner. There is a broad scope of issues that anaesthetists are responsible for and these largely depend on the department and hospital requirements. These issues may range from perioperative anaesthetic management and pain relief, to--and there are definite continental differences--the coordination of donor evaluation, intensive care management, postoperative complication management, as well as psychological support for donors, recipients and their relatives. SUMMARY: In this paper we review and summarize the potential impact of findings and advances made in this particular field as described by the most important articles published during the past year.

Liver support in fulminant liver failure after hemorrhagic shock.

Acute liver failure (ALF) is a rare clinical syndrome associated with a mortality of up to 80% and its management remains an interdisciplinary challenge. Despite recent improvements in intensive care management, the mortality of patients with ALF remains high and is related to complications such as cerebral edema, sepsis and multiple organ failure. Emergency orthotopic liver transplantation (OLT) is currently the only effective treatment for those patients who are unlikely to recover spontaneously. Nevertheless, OLT is not always possible because of the shortage of the organs and/or complications related to ALF. Newly introduced liver-assist devices can temporarily support the patient's liver until native liver recovers or can serve as a bridging device until a liver graft is available. The support devices use both cell-based and non-cell-based techniques. One of the latest non-cell-based extracorporeal hepatic support devices, the molecular adsorbent recycling system (MARS), is based on the concept of albumin dialysis. MARS utilises selective hemodiafiltration with countercurrent albumin dialysis aiming to selectively remove both water-soluble and albumin-bound toxins of the low and middle molecular-weight range. We report on a young patient who presented with clinical symptoms of ischemic hepatitis and multi-organ failure (APACHE II score 38-->predicted postoperative mortality 87%) due to prolonged hemorrhagic shock. OLT was contraindicated because of history of pancreas cancer with metastases. It was necessary to use aggressive conservative therapy and an extracorporeal liver-assist device until liver regeneration began and hemodynamic conditions were stable. The patient underwent five treatments with MARS. During the treatment, there were improvements of hemodynamics, respiratory function, acid-base disturbances and laboratory parameters. The plasma disappearance rate of indocyanine green, a parameter of dynamic liver function, improved during MARS treatment. Although repeated neurological examination predicted diffuse brain damage (brain oedema, decreased cerebral blood flow), the patient recovered without any neurological deficits. The patient survived and was discharged from the hospital in good condition. In this case MARS treatment was successful in supporting the patient through the most critical period of ALF.

Extracorporeal albumin dialysis in patients with Amanita phalloides poisoning.

BACKGROUND: Ingestion of Amanita phalloides is the most common cause of lethal mushroom poisoning. The relative late onset of symptoms is a distinct diagnostic feature of Amanita intoxication and also the main reason of failure for extracorporeal removal of Amanita-specific toxins from the gut and circulation. PATIENTS AND METHODS: Extracorporeal albumin dialysis (ECAD) has been used on six consecutive patients admitted after A. phalloides poisoning with acute liver failure (ALF). RESULTS: Six patients, with mean age of 46 years (range: 9-70 years), underwent one to three ECAD treatments. The mean time from mushroom ingestion until the first ECAD treatment was 76 h. Two patients regenerated spontaneously under ECAD treatment and orthotopic liver transplantation (OLT) could be avoided. Two patients were successfully bridged to OLT and one patient died because of cerebral herniation. One patient was treated with ECAD immediately after OLT because of the graft dysfunction and survived without re-transplantation. CONCLUSION: ECAD appeared to be a successful treatment perspective in supporting liver regeneration or in sufficient bridging to OLT and also in treatment of graft dysfunction after OLT in patients with A. phalloides poisoning.