Valentin Fuhrmann

Liver Dysfunction and Phosphatidylinositol-3-Kinase Signalling in Early Sepsis: Experimental Studies in Rodent Models of Peritonitis

Experimental studies in a rat model of fecal peritonitis conducted by Michael Bauer and colleagues show that in this model, changes in liver function occur early in the development of sepsis, with potential implications for prognosis and development of new therapeutic approaches.

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

Macrophages play a key role in responding to pathogens and initiate an inflammatory response to combat microbe multiplication. Deactivation of macrophages facilitates resolution of the inflammatory response. Deactivated macrophages are characterized by an immunosuppressive phenotype, but the lack of unique markers that can reliably identify these cells explains the poorly defined biological role of this macrophage subset. We identified lipocalin 2 (LCN2) as both a marker of deactivated macrophages and a macrophage deactivator. We show that LCN2 attenuated the early inflammatory response and impaired bacterial clearance, leading to impaired survival of mice suffering from pneumococcal pneumonia. LCN2 induced IL-10 formation by macrophages, skewing macrophage polarization in a STAT3-dependent manner. Pulmonary LCN2 levels were tremendously elevated during bacterial pneumonia in humans, and high LCN2 levels were indicative of a detrimental outcome from pneumonia with Gram-positive bacteria. Our data emphasize the importance of macrophage deactivation for the outcome of pneumococcal infections and highlight the role of LCN2 and IL-10 as determinants of macrophage performance in the respiratory tract.

Prognostic factors for intensive care unit admission, intensive care outcome, and post-intensive care survival in patients with de novo acute myeloid leukemia: a single center experience

Background Acute myeloid leukemia is a life-threatening disease associated with high mortality rates. A substantial number of patients require intensive care. This investigation analyzes risk factors predicting admission to the intensive care unit in patients with acute myeloid leukemia eligible for induction chemotherapy, the outcome of these patients, and prognostic factors predicting their survival. Design and Methods A total of 406 consecutive patients with de novo acute myeloid leukemia (15–89 years) were analyzed retrospectively. Markers recorded at the time of diagnosis included karyotype, fibrinogen, C-reactive protein, and Charlson comorbidity index. In patients requiring critical care, the value of the Simplified Acute Physiology Score II, the need for mechanical ventilation, and vasopressor support were recorded at the time of intensive care unit admission. The independent prognostic relevance of the parameters was tested by multivariate analysis. Results Sixty-two patients (15.3%) required intensive care, primarily due to respiratory failure (50.0%) or life-threatening bleeding (22.6%). Independent risk factors predicting intensive care unit admission were lower fibrinogen concentration, the presence of an infection, and comorbidity. The survival rate was 45%, with the Simplified Acute Physiology Score II being the only independent prognostic parameter (P<0.05). Survival was inferior in intensive care patients compared to patients not admitted to an intensive care unit. However, no difference between intensive care and non-intensive care patients was found concerning continuous complete remission at 6 years or survival at 6 years in patients who survived the first 30 days after diagnosis (non-intensive care patients: 28%; intensive care patients: 20%, P>0.05). Conclusions Ongoing infections, low fibrinogen and comorbidity are predictive for intensive care unit admission in acute myeloid leukemia. Although admission was a risk factor for survival, continuous complete remission and survival of patients alive at day 30 were similar in patients who were admitted or not admitted to an intensive care unit.

Hypoxic hepatitis - epidemiology, pathophysiology and clinical management

ZusammenfassungHypoxische Hepatitis (HH) – auch unter den Bezeichnungen ichämische Hepatitis oder Schockleber bekannt – ist durch eine zentrilobuläre Leberzellnekrose und einen fulminanten Anstieg der Serumaminotransferasen als Folge von kardialem, zirkulatorischem oder respiratorischem Versagen charakterisiert. Dies ist die häufigste Ursache der akuten Leberschädigung mit einer Prävalenz von bis zu 10 Prozent an Intensivstationen. Kritisch kranke Patienten mit HH und der Notwendigkeit einer Vasopressorentherapie haben ein signifikant erhöhtes Mortalitätsrisiko. Die häufigsten HH auslösenden Ursachen sind erniedrigtes Herzauswurfvolumen und septischer Schock, wobei in der großen Mehrheit der Fälle eine multifaktorielle Ätiologie der HH zugrunde liegt. HH kann verschiedene Komplikationen wie spontane Hypoglykämie, respiratorische Insuffizienz als Folge des hepatopulmonalen Syndroms und Hyperammoniämie verursachen. HH bildet sich nach erfolgreicher Behandlung der zugrunde liegenden Ursachen zurück. Derzeit sind keine Therapieansätze etabliert, die spezifisch die Leberfunktion verbessern. Ein frühestmögliches Erkennen der HH, ihrer zugrunde liegenden Ursachen sowie die unverzügliche Einleitung entsprechender Therapiemaßnahmen sind von zentraler prognostischer Bedeutung. Diese Übersichtsarbeit vermittelt den heutigen Wissensstand hinsichtlich Epidemiologie, Pathophysiologie, sowie diagnostischen und therapeutischen Möglichkeiten der HH.SummaryHypoxic hepatitis (HH), also known as ischemic hepatitis or shock liver, is characterized by centrilobular liver cell necrosis and sharply increasing serum aminotransferase levels in a clinical setting of cardiac, circulatory or respiratory failure. Nowadays it is recognized as the most frequent cause of acute liver injury with a reported prevalence of up to 10% in the intensive care unit. Patients with HH and vasopressor therapy have a significantly increased mortality risk in the medical intensive care unit population. The main underlying conditions contributing to HH are low cardiac output and septic shock, although a multifactorial etiology is found in the majority of patients. HH causes several complications such as spontaneous hypoglycemia, respiratory insufficiency due to the hepatopulmonary syndrome, and hyperammonemia. HH reverses after successful treatment of the basic HH-causing disease. No specific therapies improving the hepatic function in patients with HH are currently established. Early recognition of HH and its underlying diseases and subsequent initiation of therapy is of central prognostic importance. The purpose of this review is to provide an update on the epidemiology, pathophysiology, and diagnostic and therapeutic options of HH.

Coagulation parameters and major bleeding in critically ill patients with cirrhosis

Disturbances of coagulation and hemostasis are common in patients with liver cirrhosis. The typical laboratory pattern mimics disseminated intravascular coagulation (DIC). The aim of this study was to assess the impact of routine coagulation parameters in critically ill cirrhosis patients with regard to new onset of major bleeding and outcome. A total of 1,493 critically ill patients were studied prospectively. Routine coagulation parameters were assessed, and the DIC score was calculated based on platelets, fibrinogen, d‐dimer, and prothrombin index. New onset of major bleeding during the stay at the intensive care unit and mortality were assessed. Patients were followed for 1 year. Two hundred eleven patients of the cohort had liver cirrhosis. Platelets, fibrinogen, prothrombin index, activated partial thromboplastin time, and d‐dimer as well as the DIC score differed significantly between patients with and without cirrhosis (P < 0.001 for all). Moreover, fibrinogen, platelets, and activated partial thromboplastin time (but not prothrombin index) differed significantly between cirrhosis patients with and without major bleeding (P < 0.01 for all). Bleeding on admission, platelet count <30 < 109/L, fibrinogen level <60 mg/dL, and activated partial thromboplastin time values >100 seconds were the strongest independent predictors for new onset of major bleeding in multivariate regression analysis. One‐year mortality in cirrhosis patients with and without major bleeding was 89% and 68%, respectively (P < 0.05 between groups). Conclusion: Abnormal coagulation parameters and high DIC scores (primarily due to fibrinogen and platelets) correspond to increased bleeding risk in patients with liver cirrhosis in the intensive care unit, and fibrinogen and platelet count were identified as the best routine coagulation parameters for prediction of new onset of major bleeding; however, further studies are required to evaluate the potential therapeutic implications of these findings. (Hepatology 2016;64:556‐568)

Jaundice increases the rate of complications and one‐year mortality in patients with hypoxic hepatitis

Hypoxic hepatitis (HH) is the most frequent cause of acute liver injury in critically ill patients. No clinical data exist about new onset of jaundice in patients with HH. This study aimed to evaluate the incidence and clinical effect of jaundice in critically ill patients with HH. Two hundred and six consecutive patients with HH were screened for the development of jaundice during the course of HH. Individuals with preexisting jaundice or liver cirrhosis at the time of admission (n = 31) were excluded from analysis. Jaundice was diagnosed in patients with plasma total bilirubin levels >3 mg/dL. One‐year‐survival, infections, and cardiopulmonary, gastrointestinal (GI), renal, and hepatic complications were prospectively documented. New onset of jaundice occurred in 63 of 175 patients with HH (36%). In patients who survived the acute event of HH, median duration of jaundice was 6 days (interquartile range, 3‐8). Patients who developed jaundice (group 1) needed vasopressor treatment (P < 0.05), renal replacement therapy (P < 0.05), and mechanical ventilation (P < 0.05) more often and had a higher maximal administered dose of norepinephrine (P < 0.05), compared to patients without jaundice (group 2). One‐year survival rate was significantly lower in group 1, compared to group 2 (8% versus 25%, respectively; P < 0.05). Occurrence of jaundice was associated with an increased frequency of complications during follow‐up (54% in group 1 versus 35% in group 2; P < 0.05). In particular, infections as well as renal and GI complications occurred more frequently in group 1 during follow‐up. Conclusion: Jaundice is a common finding during the course of HH. It leads to an increased rate of complications and worse outcome in patients with HH. (HEPATOLOGY 2012)

Hypoxic liver injury and cholestasis in critically ill patients.

Purpose of reviewLiver dysfunction frequently complicates the clinical picture of critical illness and leads to increased morbidity and mortality. The purpose of this review is to characterize the most frequent patterns of liver dysfunction at the intensive care unit, cholestasis and hypoxic liver injury (HLI), and to illustrate its clinical impact on outcome in critically ill patients. Recent findingsLiver dysfunction at the intensive care unit can be divided into two main patterns: cholestatic and HLI, also known as ischemic hepatitis or shock liver. Both hepatic dysfunctions occur frequently and early in critical illness. Major issues are the early recognition and subsequent initiation of therapeutic measures. SummaryClinical awareness of the liver not only as a victim, but also as a trigger of multiorgan failure is of central clinical importance. Physicians have to identify the underlying factors that contribute to its development to initiate curative measures as early as possible.

Ventilator-associated pneumonia: Increased bacterial counts in bronchoalveolar lavage by using urea as an endogenous marker of dilution.

Objective:Invasive diagnostic procedures such as bronchoalveolar lavage (BAL) with quantitative microbiological cultures are currently recommended for the diagnosis of nosocomial pneumonia. Commonly, in clinical practice, a threshold of ≥104 colony forming units/mL is used for therapeutic decisions. The use of these measurements in daily practice assumes that their repeatability is acceptable. However, many variations among the positive results have been noted. One of the most important is dilution of BAL, which may influence the quantitative results by minimizing bacterial counts. Knowledge of the extent of dilution may increase dramatically the value of quantitative cultures. The aim of this study was to determine to what extent specimens are diluted in BAL by measuring urea in BAL and blood. Furthermore, the impact of a potential dilution effect on the diagnosis of ventilator-associated pneumonia was studied. Patients and Setting:A total of 47 patients with ventilator-associated pneumonia in two medical intensive care units at the Vienna General Hospital, a university-affiliated facility. Design:Prospective study performed between January 2001 and July 2002. Methods:BAL fluid was divided immediately into two samples: one for direct microscopic examination of cytocentrifuge preparations for Gram staining to determine percentages of cells containing intracellular bacteria and one for quantitative cultures according to the Cumitech 7A guidelines. Epithelial lining fluid volume was calculated using urea as a marker of dilution and correlated with colony forming units per milliliter. Results:Nineteen out of 47 patients (40%) revealed significant bacterial growth (≥104 colony forming units/mL). Eight additional patients (17%) would have reached the cutoff level after correction of the dilution effect, which varied between 1.8- and 130-fold. Conclusions:Data suggest a great variation of dilution during BAL procedures, which influences quantitative results. Using urea to determine the dilution quotient could increase the value of bacterial thresholds in the diagnosis and therapeutic decision of ventilator-associated pneumonia.

Jejunal tube placement in critically ill patients: A prospective, randomized trial comparing the endoscopic technique with the electromagnetically visualized method.

Objective:Head-to-head comparison of the success rate of jejunal placement of a new electromagnetically visualized jejunal tube with that of the endoscopic technique in critically ill patients. Design:Prospective, randomized clinical trial. Setting:Two intensive care units at a university hospital. Patients:A total of 66 critically ill patients not tolerating intragastric nutrition. Interventions:Patients were randomly assigned (2:1 ratio) to receive an electromagnetically visualized jejunal feeding tube or an endoscopically placed jejunal tube. The success rate of correct jejunal placement after 24 hrs was the main outcome parameter. Measurements and Main Results:The correct jejunal tube position was reached in 21 of 22 patients using the endoscopic technique and in 40 of 44 patients using the electromagnetically visualized jejunal tube (95% vs. 91%; relative risk 0.9524, confidence interval 0.804–1.127, p = .571). In the remaining four patients, successful endoscopic jejunal tube placement was performed subsequently. The implantation times, times in the right position, and occurrences of nose bleeding were not different between the two groups. The electromagnetically visualized technique resulted in the correct jejunal position more often at the first attempt. Factors associated with successful placement at the first attempt of the electromagnetically visualized jejunal tube seem to be a higher body mass index and absence of emesis. This trial is registered at ClinicalTrials.gov, number NCT00500851. Conclusions:In a head-to-head comparison correct jejunal tube placement using the new electromagnetically visualized method was as fast, safe, and successful as the endoscopic method in a comparative intensive care unit patient population.

Statin therapy is associated with reduced incidence of hypoxic hepatitis in critically ill patients

BACKGROUND & AIMS Hypoxic hepatitis (HH) is a frequent and life-threatening complication associated with states of oxygen depletion in critically ill patients. Ischemia and reperfusion contribute to liver injury in HH. Experimental data suggest beneficial effects of statins in hepatic ischemia/reperfusion injury. This study was conducted to investigate whether statin treatment prior to intensive care unit (ICU) admission affects incidence rates and severity of HH. METHODS Eight hundred fifty-one patients admitted consecutively to three medical ICUs between December 2008 and December 2009 were prospectively screened for new occurrence of HH within 48 h following ICU admission. Statin treatment prior to ICU admission was assessed. 28-day-, 90-day-, and 1-year-survival as well as new-onset of complications in HH patients were prospectively documented. RESULTS Eighty-seven patients (10%) developed HH. Statin treatment prior to ICU admission was significantly associated with decreased incidence of HH within 48 h after ICU admission in the multivariate analysis (adjusted OR=0.42 (95% CI 0.19-0.95); p<0.05). Cardiogenic shock (p<0.001), septic shock (p<0.001) and active alcohol consumption (p<0.01) were identified as independent risk factors for development of HH. 28-day-, 90-day-, and 1-year-mortality rates in HH were 58%, 67%, and 74%, respectively. Statins were associated with improved 28-day-survival in the total study cohort (p<0.05), but did not affect 90-day- and 1-year-mortality, respectively. CONCLUSIONS Cardiogenic shock, septic shock, and active alcohol consumption were independent factors predisposing patients to new onset of HH. Statin treatment prior to ICU admission was the only protective factor regarding the new occurrence of HH in critically ill patients.