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Hepatic stellate cells (HSCs) surround liver sinusoids and store retinol while they are quiescent. During fibrotic liver diseases and acute-on-chronic liver failure they change to the activated state in which they proliferate, lose their retinol content and deposit extracellular matrix molecules. The process of HSC activation is of utmost interest, but so far only insufficiently understood, because there is a lack of techniques to address the function of single HSCs in the tissue context. In this contribution, the potential of Raman micro-spectroscopy for the label-free detection of HSCs in mouse liver samples is demonstrated. First, culture-induced activation of primary mouse HSCs is followed in vitro and characterized by means of Raman spectroscopy. The HSC activation state is confirmed by immunofluorescence labeling of glial fibrillary acidic protein (GFAP) and α-smooth muscle actin (ASMA). As expected, the unique Raman spectrum of retinol in quiescent HSCs is lost during activation. Nevertheless, successful discrimination of HSCs from primary hepatocytes is possible during all states of activation. A classification model based on principal component analysis followed by linear discriminant analysis (PCA–LDA) of the lipid droplet Raman data yields a prediction accuracy of 99%. The in vitro results are transferred to fresh liver slices and freshly sampled livers. Quiescent HSCs and a HSC transforming from quiescent to activated state are identified based on their Raman signature. This provides valuable information on HSC activation state in the liver.

Renal failure is a common complication among critically ill patients. Timing, dosage, and mode of renal replacement (RRT) are under debate, but also anticoagulation strategies and vascular access interfere with dialysis success. We present a retrospective, five-year evaluation of patients requiring RRT on a multidisciplinary 50-bed surgical intensive care unit of a university hospital with special regard to anticoagulation strategies and vascular access. Anticoagulation was preferably performed with unfractionated heparin or regional citrate application (RAC). Bleeding and suspected HIT-II were most common causes for RAC. In CVVHD mode filter life span was significantly longer under RAC compared to heparin or other anticoagulation strategies (P=0.001). Femoral vascular access was associated with reduced filter life span (P=0.012), especially under heparin anticoagulation (P=0.015). Patients on RAC had higher rates of metabolic alkalosis (P=0.001), required more transfusions (P=0.045), and showed higher illness severity measured by SOFA scores (P=0.001). RRT with unfractionated heparin represented the most common anticoagulation strategy in this study population. However, patients with bleeding risk and severe organ dysfunction were more likely placed on RAC. Citrate provided longer filter life spans regardless of vascular access site. Attention has to be paid to metabolic disturbances.

Eine 50-jahrige Patientin wird nach einem Sturz aus 8 m Hohe in den Schockraum gebracht. Sie war am Unfallort hypoton (Blutdruck 90/50 mmHg), tachykard (130/min), der GCS betrug 12 Punkte. Sie wurde vom Notarzt intubiert und beatmet und hat bei einem Pneumothorax eine Thoraxdrainage erhalten. Die Patientin wird wahrend der Ubergabe reanimationspflichtig. Unter forcierter Volumentherapie, u. a. mit 250 ml HyperHAES und mehreren ungekreuzten Erythrozytenkonzentraten der Blutgruppe Null Rhesus negativ, kann der Kreislauf wiederhergestellt werden. Im Spiral-CT zeigt sich folgendes Verletzungsmuster: kleine traumatische Subarachnoidalblutung, Thoraxtrauma mit Rippenserienfraktur, Pneumothorax und erheblichen Lungenkontusionen, Leberruptur, Lendenwirbelkorperfraktur sowie komplexe Beckenringfraktur. Die Patientin wird direkt operativ versorgt; das Becken wird stabilisiert und bei erheblicher Blutung mit Bauchtuchern gepackt; ebenfalls erfolgt ein Packing im Bereich der Leber. Bis zu diesem Zeitpunkt hat die Patientin 12 EK, 400 ml maschinelles Autotransfusionsblut, 10 FFP, 2 TK, 5 g Fibrinogen sowie 2 g Tranexamsaure erhalten und wird auf die Intensivstation gebracht. Trotz kontinuierlicher Volumentherapie ist die Patientin hoch katecholaminpflichtig; es besteht eine ausgepragte metabolische Azidose (pH-Wert < 7,1) und Hyperlaktatamie, sodass eine Pufferung mit Natriumbikarbonat und TRIS-Puffer erfolgt. Innerhalb einer weiteren Stunde werden weitere 10 EK, 10 FFP und 4 TK sowie 8 g Fibrinogen gegeben. Bei zunehmender Oxygenierungsstorung (paO70 mmHg bei FiO0,8) wird sie in ein Bett zur kontinuierlichen lateralen Rotationstherapie gelagert.

BACKGROUND: Monitoring hepatic blood flow and function might be crucial in treating critically ill patients. Intra-abdominal hypertension is associated with decreased abdominal blood flow, organ dysfunction, and increased mortality. The plasma disappearance rate (PDR) of indocyanine green (ICG) is considered to be a compound marker for hepatosplanchnic perfusion and hepatocellular membrane transport and correlates well with survival in critically ill patients. However, correlation between PDRICG and intra-abdominal pressure (IAP) remains poorly understood. The aim of this retrospective study was to investigate the correlation between PDRICG and classic liver laboratory parameters, IAP and abdominal perfusion pressure (APP). The secondary goal was to evaluate IAP, APP, and PDRICG as prognostic factors for mortality. METHODS: A total of 182 paired IAP and PDRICG measurements were performed in 40 critically ill patients. The mean values per patient were used for comparison. The IAP was measured using either a balloon-tipped stomach catheter connected to an IAP monitor (Spiegelberg, Hamburg, Germany, or CiMON, Pulsion Medical Systems, Munich, Germany) or a bladder FoleyManometer (Holtech Medical, Charlottenlund, Denmark). PDRICG was measured at the bedside using the LiMON device (Pulsion Medical Systems, Munich, Germany). Primary endpoint was hospital mortality. RESULTS: There was no significant correlation between PDRICG and classic liver laboratory parameters, but PDRICG did correlate significantly with APP (R = 0.62) and was inversely correlated with IAP (R = -0.52). Changes in PDRICG were associated with significant concomitant changes in APP (R = 0.73) and opposite changes in IAP (R = 0.61). The IAP was significantly higher (14.6 ± 4.6 vs. 11.1 ± 5.3 mmHg, p = 0.03), and PDRICG (10 ± 8.3 vs. 15.9 ± 5.2%, p = 0.02) and APP (43.6 ± 9 vs. 57.9 ± 12.2 mmHg, p < 0.0001) were significantly lower in non-survivors. CONCLUSIONS: PDRICG is positively correlated to APP and inversely correlated to IAP. Changes in APP areassociated with significant concomitant changes in PDRICG, while changes in IAP are associated with opposite changes in PDRICG, suggesting that an increase in IAP may compromise hepatosplanchnic perfusion. Both PDRICG and IAP are correlated with outcome. Measurement of PDRICG may be a useful additional clinical tool to assess the negative effects of increased IAP on liver perfusion and function.

BACKGROUND: Treatment of septic shock relies on appropriate antimicrobial therapy. Current culture based methods deliver final results after days, which may delay potentially lifesaving adjustments in antimicrobial therapy. This study was undertaken to compare PCR with blood culture results under routine conditions regarding 1. impact on antimicrobial therapy, and 2. time to result, in patients with presumed sepsis. METHODOLOGY/PRINCIPAL FINDINGS: This was an observational study in a 50 beds ICU of a university hospital. In 245 patients with suspected sepsis, 311 concomitant blood cultures and blood for multiplex PCR (VYOO(®)) were obtained. 45 of 311 blood cultures (14.5%) and 94 of 311 PCRs (30.1%) were positive. However, blood culture or microbiological sampling from the presumed site of infection rarely confirmed PCR results and vice versa. Median time to positivity and interquartile range were 24.2 (18.0, 27.5) hours for the PCR and 68 (52.2, 88.5) hours for BC (p

The liver comprises a multitude of parenchymal and nonparenchymal cells with diverse metabolic, hemodynamic and immune functions. Available monitoring options consist of 'static' laboratory parameters, quantitative tests of liver function based on clearance, elimination or metabolite formation and scores, most notably the 'model for end-stage liver disease'. This review aims at balancing conventional markers against 'dynamic' tests in the critically ill.There is emerging evidence that conventional laboratory markers, most notably bilirubin, and the composite model for end-stage liver disease are superior to assess cirrhosis and their acute decompensation, while dynamic tests provide information in the absence of preexisting liver disease. Bilirubin and plasma disappearance rate of indocyanine green reflecting static and dynamic indicators of excretory dysfunction prognosticate unfavorable outcome, both, in the absence and presence of chronic liver disease better than other functions or indicators of injury. Although dye excretion is superior to conventional static parameters in the critically ill, it still underestimates impaired canalicular transport, an increasingly recognized facet of excretory dysfunction.Progress has been made in the last year to weigh static and dynamic tests to monitor parenchymal liver functions, whereas biomarkers to assess nonparenchymal functions remain largely obscure.

Purpose The aim of this study was to investigate the epidemiology of and outcome from heparin-induced thrombocytopenia type II (HIT) in surgical intensive care unit (ICU) patients. Patients and Methods All 13 948 patients admitted to a university hospital surgical ICU between January 2004 and March 2008 were included in this retrospective cohort study. Results Of 349 patients with a clinical suspicion of HIT, 88 patients had platelet factor 4/heparin antibodies using enzyme-linked immunosorbent assay. The prevalence and incidence of HIT were 0.82% and 0.63%, respectively. The complication rate was 43.5%, and the ICU and hospital mortality rates were 23.9% and 33%, respectively. In a multivariable analysis, the nadir platelet count (odds ratio, 1.03; 95% confidence interval, 1.01-1.05; P = .048) was the only factor independently associated with risk of death in these patients. In a nested matched case-control analysis, mortality rates were similar in patients with HIT and in the matched controls. However, complication rates were higher, and ICU and hospital lengths of stay were longer in patients with HIT compared with those of the control group. Conclusions In this cohort of surgical ICU patients, HIT was associated with increased morbidity but not mortality rates compared with a nested matched control group. The nadir platelet count was independently associated with a higher risk of inhospital death in these patients.

Eine 38-jahrige Patientin klagt seit 10 Tagen uber zunehmende Mudigkeit und Schwachegefuhl und wurde bei zunehmendem Ikterus vor 3 Tagen stationar aufgenommen. Bei nichtmessbarem Quickwert unter Phenprocoumontherapie bei Z. n. Lungenembolie vor 5 Monaten erfolgt die Gabe von PPSB. Trotz Absetzen der oralen Antikoagulanzientherapie, Vitamin K-Gabe uber mehrere Tage und weiterer PPSB-Gabe fallt der Quickwert rezidivierend ab, sodass auch von einer erheblichen Synthesestorung ausgegangen werden muss. Die Patientin wird auf die Intensivstation verlegt. Bei Aufnahme ist die Patientin wach, atem- und kreislaufstabil, aber deutlich verlangsamt. Die Laboranalyse ergibt folgenden Befund: Quick 22 (INR 2,8) nach mehrfacher PPSBGabe, nach 10 h Quick 13 (INR 4,4), Bilirubin gesamt 20,6 mg/dl (352 μmol/l), Bilirubin direkt 14,3 mg/dl (244 μmol/l) ALAT (SGPT) 1290 U/l (21,5 μmol/ls), ASAT (SGOT) 720 U/l (12 μmol/ls), GLDH 43,4 U/l (724 nmol/ls), AP 120,6 U/l (2,01 μmol/ls), γGT 442,2 U/l (7,37 μmol/ls), CHE 5700 U/l (95 μmol/ls), Plasmaverschwinderate von Indocyaningrun (PDRICG) 4,2 %/min (Normalwert 18–25%/min). Eine Autoimmun- oder virale Hepatitis kann nicht nachgewiesen werden, sodass am ehesten von einem kumarininduzierten akuten Leberversagen ausgegangen werden muss.

Despite improvement in critical care, liver failure is still associated with high mortality. Therapeutic concepts are aimed at restoring endogenous liver function or to bridge the time to liver transplantation. In addition to standard medical treatment, extracorporeal liver support with albumin dialysis is used for this purpose. The aim of this study was to analyze the efficacy of single pass albumin dialysis (SPAD) in comparison to the molecular adsorbent recirculating system (MARS) in patients treated at our university hospital intensive care unit between July 2004 and August 2008. In this retrospective analysis we studied patients presenting with liver failure who were treated with albumin dialysis. Laboratory parameters, daily health scoring, the number of transfusions, and mortality were recorded. The (paired) t-test, Mann-Whitney U-test, and Wilcoxon test were used for statistical analysis. In all, 163 albumin dialysis treatments, 126 with MARS and 37 with SPAD, in 57 patients were performed. MARS resulted in a significant decrease in bilirubin (-38 +/- 66.5 micromol/L from a baseline of 301 +/- 154.6 micromol/L), gamma-glutamyltransferase (gamma-GT), alanine aminotransferase, creatinine, and urea. SPAD resulted in a significant decrease in bilirubin (-41 +/- 111.2 micromol/L from a baseline of 354 +/- 189.4 micromol/L) and gamma-GT, while lactate levels increased. No differences in the need for blood transfusion, health scoring, or mortality between the two treatment modalities were detected. This retrospective analysis suggests equal efficacy of MARS and SPAD; however, prospective assessment to further define the role of SPAD in the treatment of acute or acute-on-chronic liver failure is needed.

Disorders of fluid and electrolyte balance in the critically ill are volume-related, compositional, or both. Targeting 'normal' values for plasma volume, osmolality and electrolytes might not be optimal in conditions as diverse as intracranial trauma/haemorrhage, hepatic encephalopathy, abdominal hypertension, or major surgery, because a hyperosmolar state seems to favourably affect tissue (brain and intestinal) oedema formation. However, adequately powered studies regarding the impact of hypertonic saline on outcome are lacking. Isotonic crystalloids are the cornerstone of resuscitation and must be balanced against natural or artificial colloids and vasopressors. Crystalloid resuscitation is superior to vasopressors in shock associated with blunt trauma, and is at least not inferior to colloids in septic shock. Traditional rules of thumb indicating the need for three to four times the amount of crystalloids for the plasma volume to be replaced are probably erroneous and might have contributed to association of overly aggressive crystalloid resuscitation with poor outcome.

Liver dysfunction affects a variety of metabolic pathways in the critically ill, but mechanisms remain poorly understood. We prospectively assessed markers of hepatic injury and function in sepsis and I/R injury in vivo and molecular mechanisms in human liver tissue ex vivo. Markers of hepatocellular injury, synthesis, and excretion, including plasma disappearance rate of indocyanine green (ICG), were measured in 48 patients with severe sepsis. Incidence of liver dysfunction was 42% as assessed by hyperbilirubinemia but 74% by impaired dye excretion. Conventional markers for liver injury failed to predict outcome, whereas dye excretion of less than 8% per minute predicted death with high sensitivity and specificity. Potential mechanisms were assessed via (a) gene expression analysis of transporter proteins for bilirubin and ICG in cultured human liver tissue, and (b) monitoring uptake and excretion of the dye after I/R injury in 12 patients receiving a biliary T-tube during liver transplantation. Ex vivo gene expression of transporters was differentially affected for bilirubin and ICG with upregulation of basolateral and downregulation of canalicular ICG transporters. Consistently, patients with unfavorable course after liver transplantation displayed almost complete cessation of biliary dye excretion, whereas uptake into the hepatocyte was reduced by only 40%. In conclusion, standard liver tests lack the required sensitivity to assess hepatic injury and function in the critically ill. Dye excretion better reflects excretory and/or microvascular dysfunction but still underestimates impaired canalicular transport. The observed differential susceptibility of the polar surfaces of human hepatocytes has potential implications for monitoring liver function and drug-induced liver injury.

Epidural blockade in major abdominal surgery bears the potential to increase gastrointestinal perfusion and thus to improve patient outcome. The aim of this study was to assess the differential influence of thoracic and lumbar epidural anaesthesia and analgesia (EAA) on blood lactate levels and central venous oxygen saturation (ScvO2) as parameters of global oxygen supply/demand ratio, as well as on the plasma disappearance rate of indocyanine green (PDR(ICG)), a noninvasive method to evaluate liver perfusion.We enrolled 17 patients receiving thoracic and 17 patients receiving lumbar EAA in addition to general anaesthesia for major abdominal surgery. Lactate, ScvO2 and PDR(ICG) were measured postoperatively on the ICU. Subsequently, epidural application of local anaesthetics was started with a bolus of bupivacaine 0.25% (thoracic 10 ml, lumbar 12 ml) followed by continuous infusion of bupivacaine (thoracic 8 ml h(-1) 0.175%, lumbar 10 ml h(-1) 0.125%) and fentanyl (2 microg ml(-1)). Central venous pressure was maintained by titrated volume replacement. Lactate, ScvO2 and PDR(ICG) were measured again after 2 h.In both the groups, the mean arterial pressure and heart rate as well as lactate levels and ScvO2 did not change significantly. Although there was a slight but not significant decrease of PDR(ICG) in patients with lumbar EAA (from 25.9 +/- 7.68 to 23.2 +/- 5.90; NS), thoracic EAA resulted in a significant increase of PDR(ICG) (from 21.3 +/- 5.13 to 24.0 +/- 6.66; P0.05) for the group mean, but with substantial variability in individual patients in the lumbar EAA group.Liver perfusion was increased with thoracic but not lumbar EAA after major abdominal surgery in most patients. PDR(ICG) allows assessment of individual changes of liver blood flow due to therapeutic intervention, for example, EAA.

Liver failure is a rare but life-threatening condition affecting a multitude of other organ systems, most notably the brain and kidneys, following severe hepatocellular injury. Liver failure may develop in the absence ('acute') or presence ('acute-on-chronic') of liver disease with substantial differences in pathophysiology and therapeutic options. Within the last 12 months substantial progress has been made in identifying patients who will potentially benefit from extracorporeal support of their failing liver.In addition to traditional 'static' laboratory tests to assess liver function, the significance of 'dynamic' tests, such as indocyanine green clearance, has been better defined, and these tests are becoming more easily available. Transplantation remains the treatment of choice for fulminant, acute and subacute liver failure with predicted unfavorable outcome according to King's College or Clichy criteria, most notably in the absence of pre-existing liver disease, and should be performed before extrahepatic complications emerge. Encouraging results have been obtained with the use of support systems in patients with acute and acute-on-chronic liver failure in relatively small patient collectives, making well-conducted randomized trials a necessity to define their role in this high-risk population. Current (pre)clinical data suggest that programmed cell death is an important mechanism for the pathogenesis of acute and acute-on-chronic liver failure and, thus, antiapoptotic strategies are promising pharmacologically.Although mortality remains high, substantial progress has been made in 2004 regarding the understanding of pathophysiology, and the monitoring and support of the patient presenting with a failing liver.

To assess the impact of an algorithm defining resuscitation according to early goal-directed therapy, glycemic control, administration of stress doses of hydrocortisone, and use of recombinant human activated protein C (rhAPC) on measures of organ dysfunction and outcome in septic shock.Retrospective cohort study.Multidisciplinary ten-bed intensive care unit of a university hospital.Sixty patients were analyzed: 30 consecutive patients fulfilling criteria for diagnosis of septic shock, treated from September 2002 until December 2003 after implementation of a standard operating procedure (SOP) for severe sepsis and septic shock; and 30 patients with septic shock treated from January until August 2002 in the same unit, who served as controls.Data for blood gas analysis, lactate, glucose, serum creatinine, bilirubin, white blood cells, platelets, and C-reactive protein were obtained from patient files on admission or at time of diagnosis of septic shock and at 7:00 a.m. on days 2 and 4; Sequential Organ Failure Assessment scores were calculated and 28-day survival was assessed. With implementation of the SOP, use of dobutamine (12/30 vs. 2/30), insulin (blood glucose150 mg/dL, day 4: 26/28 vs. 13/25), hydrocortisone (30/30 vs. 13/30), and rhAPC (7/30 vs. 0/30) significantly increased, whereas volume for resuscitation and use of packed red blood cells were unaffected. Mortality was 53% in the historical control group and 27% after implementation of the SOP (p.05).The combined approach of early goal-directed therapy, intensive insulin therapy, hydrocortisone administration, and additional application of rhAPC in selected cases seems to favorably influence outcome. The implementation of a "sepsis bundle" can be facilitated by a standardized protocol while significantly reducing the time until the defined therapeutic measures are realized in daily practice.

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., Background Hepatic dysfunction and jaundice are traditionally viewed as late features of sepsis and portend poor outcomes. We hypothesized that changes in liver function occur early in the onset of sepsis, yet pass undetected by standard laboratory tests. Methods and Findings In a long-term rat model of faecal peritonitis, biotransformation and hepatobiliary transport were impaired, depending on subsequent disease severity, as early as 6 h after peritoneal contamination. Phosphatidylinositol-3-kinase (PI3K) signalling was simultaneously induced at this time point. At 15 h there was hepatocellular accumulation of bilirubin, bile acids, and xenobiotics, with disturbed bile acid conjugation and drug metabolism. Cholestasis was preceded by disruption of the bile acid and organic anion transport machinery at the canalicular pole. Inhibitors of PI3K partially prevented cytokine-induced loss of villi in cultured HepG2 cells. Notably, mice lacking the PI3Kγ gene were protected against cholestasis and impaired bile acid conjugation. This was partially confirmed by an increase in plasma bile acids (e.g., chenodeoxycholic acid [CDCA] and taurodeoxycholic acid [TDCA]) observed in 48 patients on the day severe sepsis was diagnosed; unlike bilirubin (area under the receiver-operating curve: 0.59), these bile acids predicted 28-d mortality with high sensitivity and specificity (area under the receiver-operating curve: CDCA: 0.77; TDCA: 0.72; CDCA+TDCA: 0.87). Conclusions Liver dysfunction is an early and commonplace event in the rat model of sepsis studied here; PI3K signalling seems to play a crucial role. All aspects of hepatic biotransformation are affected, with severity relating to subsequent prognosis. Detected changes significantly precede conventional markers and are reflected by early alterations in plasma bile acids. These observations carry important implications for the diagnosis of liver dysfunction and pharmacotherapy in the critically ill. Further clinical work is necessary to extend these concepts into clinical practice. Please see later in the article for the Editors' Summary, Editors' Summary Background Sepsis (blood poisoning)—a life-threatening condition caused by an inappropriate immune response to an infection—is a major global cause of death. Normally, when bacteria or other microbes enter the human body, the immune system efficiently destroys the invaders. In sepsis the immune system goes into overdrive, and the chemicals it releases into the blood to combat the infection trigger widespread inflammation (swelling). This leads to the formation of small blood clots and leaky blood vessels that block the flow of blood to vital organs such as the kidneys and liver. In the most severe cases, multiple organs fail and the patient dies. Anyone can get sepsis, but people with weakened immune systems, the very young, and the elderly are most vulnerable. Symptoms of sepsis include fever, chills, rapid breathing, a fast heart rate, and confusion. In its early stages, sepsis can be treated with antibiotics alone, but people with severe sepsis need to be admitted to an intensive care unit where the vital organs can be supported while the infection is treated. Why Was This Study Done? Thirty to fifty percent of people who develop severe sepsis die. If sepsis could be diagnosed in its early stages, it might be possible to save more people. Unfortunately, the symptoms of sepsis mimic those of other conditions, and, because sepsis tends to develop very quickly, it is often not diagnosed until it is too late to save the patient's life. The development of liver (hepatic) dysfunction and jaundice are both regarded as late features of sepsis (jaundice is yellowing of the skin and eyes caused by a build-up of bilirubin in the blood). However, the researchers hypothesized that changes in liver function occur early in sepsis and could, therefore, be used to improve the diagnosis and management of sepsis. What Did the Researchers Do and Find? The researchers induced sepsis in rats by injecting bacteria into the peritoneal cavity (the gap between the abdominal wall and the abdominal organs), separated the infected animals into predicted survivors and non-survivors based on their heart stroke volume measured using cardiac ultrasound, and then examined their liver function. The expression of genes encoding proteins involved in “biotransformation” and “hepatobiliary transport” (the processes that convert waste products and toxic chemicals into substances that can be conjugated to increase solubility and then excreted) was down-regulated within six hours of sepsis induction in the predicted non-survivors compared to the predicted survivors. Functional changes such as bilirubin and bile acid accumulation in the liver (cholestasis), poor excretion of xenobiotics (molecules not usually found in the body such as antibiotics), and disturbed bile acid conjugation were also seen in predicted non-survivors but not in survivors. Moreover, phosphatidylinositol-3-kinase (PI3K) signaling (which is involved in several immune processes) increased soon after sepsis induction in non-survivor but not in survivor animals. Notably, mice lacking the PI3Kγ gene did not develop cholestasis or show impaired bile acid conjugation after induction of sepsis. Finally, in human patients, plasma bile acids were increased in 48 patients on the day that severe sepsis was diagnosed, and these increases accurately predicted death in these patients. What Do These Findings Mean? These findings show that liver dysfunction is an early event in animal models of sepsis and that PI3K signalling plays a crucial role in the development of liver dysfunction. They show that all aspects of liver biotransformation are affected during sepsis and suggest that outcomes are related to the severity of these changes. The limited clinical data included in this study also support the hypothesis that changes in liver function occur early in sepsis, although these data need confirming and extending. Taken together, these findings suggest that liver function tests might aid early diagnosis of sepsis and might also provide information about likely outcomes. They also have important implications for the use of drugs in patients who are critically ill with sepsis, in that some of the drugs routinely administered to such patients may not be adequately detoxified and may, therefore, contribute to organ injury. Finally, these findings suggest that inhibition of PI3Kγ may alleviate sepsis-associated cholestasis. Additional Information Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001338. This study is further discussed in a PLOS Medicine Perspective by John Marshall The US National Institute of General Medical Sciences has a fact sheet on sepsis The UK National Health Service Choices website has information about sepsis and about jaundice The Surviving Sepsis Campaign, which was developed to improve the management, diagnosis, and treatment of sepsis, provides basic information about sepsis The Sepsis Alliance, a US not-for-profit organization, also provides information about sepsis for patients and their families, including personal stories about sepsis The not-for profit UK Sepsis Trust is another useful source of information about sepsis that includes patient stories MedlinePlus provides links to additional resources about sepsis and jaundice (in English and Spanish)

Differential diagnosis of systemic inflammation versus sepsis is based primarily on clinical criteria and laboratory tests that lack the required sensitivity and specificity. This dilemma holds true for medical as well as surgical patients, for example after bypass surgery or autoimmune disease. Both populations are characterized by the presence of signs of systemic inflammation or by increased risk for nosocomial infection and, thus, reflect patient populations at risk for sepsis with significant diagnostic uncertainty. Novel and robust biomarkers are urgently needed to correctly and timely identify infection as the underlying cause of a systemic host response because each hour of delay of anti-infectious therapy leads to increased mortality.

Blood cultures are often negative even in patients with clinical signs of severe sepsis. Furthermore, the long time to result of culture-based methods does not allow the results to guide empiric antimicrobial therapy. PCR-based pathogen detection promises a higher rate of positivity and a faster time to result.

Background The aim of extracorporeal albumin dialysis (ECAD) is to reduce endogenous toxins accumulating in liver failure. To date, ECAD is conducted mainly with the Molecular Adsorbents Recirculating System (MARS). However, single-pass albumin dialysis (SPAD) has been proposed as an alternative. The aim of this study was to compare the two devices with a prospective, single-centre, non-inferiority crossover study design with particular focus on reduction of bilirubin levels (primary endpoint) and influence on paraclinical and clinical parameters (secondary endpoints) associated with liver failure. Methods Patients presenting with liver failure were screened for eligibility and after inclusion were randomly assigned to be started on either conventional MARS or SPAD (with 4 % albumin and a dialysis flow rate of 700 ml/h). Statistical analyses were based on a linear mixed-effects model. Results Sixty-nine crossover cycles of ECAD in 32 patients were completed. Both systems significantly reduced plasma bilirubin levels to a similar extent (MARS: median −68 μmol/L, interquartile range [IQR] −107.5 to −33.5, p = 0.001; SPAD: −59 μmol/L, −84.5 to +36.5, p = 0.001). However, bile acids (MARS: −39 μmol/L, −105.6 to −8.3, p p = 0.131), creatinine (MARS: −24 μmol/L, −46.5 to −8.0, p p = 0.314) and urea (MARS: −0.9 mmol/L, −1.93 to −0.10, p = 0.024; SPAD: −0.1 mmol/L, −1.0 to +0.68, p = 0.523) were reduced and albumin-binding capacity was increased (MARS: +10 %, −0.8 to +20.9 %, p p = 0.137) only by MARS. Cytokine levels of interleukin (IL)-6 and IL-8 and hepatic encephalopathy were altered by neither MARS nor SPAD. Conclusions Both procedures were safe for temporary extracorporeal liver support. While in clinical practice routinely assessed plasma bilirubin levels were reduced by both systems, only MARS affected other paraclinical parameters (i.e., serum bile acids, albumin-binding capacity, and creatinine and urea levels). Caution should be taken with regard to metabolic derangements and electrolyte disturbances, particularly in SPAD using regional citrate anti-coagulation. Trial registration German Clinical Trials Register (www.drks.de) DRKS00000371. Registered 8 April 2010.

Introduction Hepatobiliary elimination of endo- and xenobiotics is affected by different variables including hepatic perfusion, hepatocellular energy state and functional integrity of transporter proteins, all of which are altered during sepsis. A particular impairment of hepatocellular transport at the canalicular pole resulting in an accumulation of potentially hepatotoxic compounds would have major implications for critical care pharmacology and diagnostics. Methods Hepatic transcellular transport, that is, uptake and hepatobiliary excretion, was studied in a rodent model of severe polymicrobial sepsis by two different biophotonic techniques to obtain insights into the handling of potentially toxic endo- and xenobiotics in sepsis. Direct and indirect in vivo imaging of the liver was performed by intravital multifluorescence microscopy and non-invasive whole-body near-infrared (NIRF) imaging after administration of two different, primarily hepatobiliary excreted xenobiotics, the organic anionic dyes indocyanine green (ICG) and DY635. Subsequent quantitative data analysis enabled assessment of hepatic uptake and fate of these model substrates under conditions of sepsis. Results Fifteen hours after sepsis induction, animals displayed clinical and laboratory signs of multiple organ dysfunction, including moderate liver injury, cholestasis and an impairment of sinusoidal perfusion. With respect to hepatocellular transport of both dyes, excretion into bile was significantly delayed for both dyes and resulted in net accumulation of potentially cytotoxic xenobiotics in the liver parenchyma (for example, specific dye fluorescence in liver at 30 minutes in sham versus sepsis: ICG: 75% versus 89%; DY635 20% versus 40% of maximum fluorescence; P < 0.05). Transcutaneous assessment of ICG fluorescence by whole body NIRF imaging revealed a significant increase of ICG fluorescence from the 30th minute on in the bowel region of the abdomen in sham but not in septic animals, confirming a sepsis-associated failure of canalicular excretion. Conclusions Hepatocytes accumulate organic anions under conditions of sepsis-associated organ dysfunction. These results have potential implications for monitoring liver function, critical care pharmacology and the understanding of drug-induced liver injury in the critically ill.