Andreas Kortgen

Implementation of an evidence-based standard operating procedure and outcome in septic shock

Objective: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. Design:Retrospective cohort study. Setting:Multidisciplinary ten-bed intensive care unit of a university hospital. Patients: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. Measurements and Results: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 glucose <150 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). Conclusion: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.

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.

Prospective assessment of hepatic function and mechanisms of dysfunction in the critically ill.

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.

Evaluation of a Polymerase Chain Reaction Assay for Pathogen Detection in Septic Patients under Routine Condition: An Observational Study

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<0.01). PCR median time to result was dependent on technician availability (53.5 hours on Saturdays, 7.2 hours under optimal logistic conditions). PCR results showed good correlation with procalcitonin (p<0.001). In 34% of patients with positive PCRs antimicrobial therapy was considered inadequate according to assessment of clinical arbitrators including 5 patients with vancomycin-resistant enterococci (VRE), 3 cases with multiresistant staphylococci, and 4 patients with fungi. Conclusions The results of this observational study support the hypothesis that PCR results are available faster, are more frequently positive, and may result in earlier adjustment of antimicrobial therapy. However, shorter time to result can only be fully exploited when the laboratory is adequately staffed for a 24 hour/7 day service, or when point of care/automated assay systems become available.

Thoracic but not lumbar epidural anaesthesia increases liver blood flow after major abdominal surgery.

Background and objective 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 (PDRICG), a noninvasive method to evaluate liver perfusion. Methods We enrolled 17 patients receiving thoracic and 17 patients receiving lumbar EAA in addition to general anaesthesia for major abdominal surgery. Lactate, ScvO2 and PDRICG 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 μg ml−1). Central venous pressure was maintained by titrated volume replacement. Lactate, ScvO2 and PDRICG were measured again after 2 h. Results 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 PDRICG in patients with lumbar EAA (from 25.9 ± 7.68 to 23.2 ± 5.90; NS), thoracic EAA resulted in a significant increase of PDRICG (from 21.3 ± 5.13 to 24.0 ± 6.66; P < 0.05) for the group mean, but with substantial variability in individual patients in the lumbar EAA group. Conclusion Liver perfusion was increased with thoracic but not lumbar EAA after major abdominal surgery in most patients. PDRICG allows assessment of individual changes of liver blood flow due to therapeutic intervention, for example, EAA.

Relationship between intra-abdominal pressure and indocyanine green plasma disappearance rate: hepatic perfusion may be impaired in critically ill patients with intra-abdominal hypertension

AbstractBackgroundMonitoring 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.MethodsA 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.ResultsThere 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.ConclusionsPDRICG is positively correlated to APP and inversely correlated to IAP. Changes in APP are associated 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.

Albumin Dialysis in Liver Failure: Comparison of Molecular Adsorbent Recirculating System and Single Pass Albumin Dialysis—A Retrospective Analysis

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 µmol/L from a baseline of 301 ± 154.6 µmol/L), γ‐glutamyltransferase (γ‐GT), alanine aminotransferase, creatinine, and urea. SPAD resulted in a significant decrease in bilirubin (−41 ± 111.2 µmol/L from a baseline of 354 ± 189.4 µmol/L) and γ‐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.

Attributable costs of patients with candidemia and potential implications of polymerase chain reaction–based pathogen detection on antifungal therapy in patients with sepsis

PURPOSE The purposes of this study were to calculate attributable costs of candidemia in patients with severe sepsis and to obtain preliminary data regarding the potential effects of polymerase chain reaction-based pathogen detection on antifungal therapy for these patients. METHODS Patients treated between 2004 and 2010 because of severe sepsis were included into this retrospective analysis. The hospital management provided annual fixed costs per patient-day; data for variable intensive care unit costs were taken from the literature. Multiplex polymerase chain reaction (PCR) was used (VYOO, SIRS-Lab, Jena, Germany) for pathogen detection in the blood. RESULTS Thirty-two patients with candidemia were identified. Of 874 patients with sepsis, propensity score matching found 32 corresponding patients with sepsis but without candida infection but similar risk factors for developing candidemia. Attributable costs of candidemia were 7713.79 Euro (cost increase, 19.4%). Initiation of antifungal therapy was reduced from 67.5 (52.4, 90) hours in the group, where candida infection was determined by blood culture, to 31.0 (28.0, 37.5; P < .01) hours after detection by multiplex PCR. CONCLUSIONS Candidemia increases costs of care in patients with septic shock. Polymerase chain reaction-based pathogen detection significantly reduces the time to initiation of antifungal therapy. This might impact on the clinical course of the disease but need to be confirmed in further trials.

How to assess liver function

Purpose of reviewThe 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. Recent findingsThere 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. SummaryProgress 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.

Molecular adsorbent recirculating system and single-pass albumin dialysis in liver failure--a prospective, randomised crossover study.

BackgroundThe 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.MethodsPatients 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.ResultsSixty-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 < 0.001; SPAD: −9 μmol/L, −36.9 to +11.4, p = 0.131), creatinine (MARS: −24 μmol/L, −46.5 to −8.0, p < 0.001; SPAD: −2 μmol/L, −9.0 to +7.0/L, 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 < 0.001; SPAD: +7 %, −7.5 to +15.5 %, 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.ConclusionsBoth 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 registrationGerman Clinical Trials Register (www.drks.de) DRKS00000371. Registered 8 April 2010.