S.J. Klein, A. Brandtner, G.F. Lehner, M. Joannidis P50 Biomarkers for Prediction of Renal Replacement Therapy in Acute Kidney Injury – a Systematic Review and Meta-Analysis IntensivmedizinPurpose: Critically ill patients often develop acute kidney injury (AKI) during their ICU stay. Renal replacement therapy (RRT) is frequently needed for the management of this patients. However, it is still unclear, when to start RRT in critically ill patients. Hope lies in biomarkers to identify the ideal time point for initiation. Methods: We conducted a PRISMA-guided systematic review and meta-analysis including all trials evaluating biomarker performance for prediction of RRT in AKI. A systematic search was applied both in MEDLINE and CENTRAL. All studies reporting an AUC for prediction of RRT were included in a meta-analysis. Results: 48 studies comprising 12583 patients and reporting 55 different biomarkers met the inclusion criteria. A pooled AUC was created if the biomarker was reported in at least two studies. The best predictive value had the combination of urinary TIMP-2 x IGFBP-7 with a pooled AUC of 0.852 (95% Confidence Interval [CI] 0.768-0.935; Heterogeneity I2=47.38%). TIMP-2 alone had a good predictive value with a pooled AUC of 0.805 (95% CI 0.631-0.979; I2=77.62%), also plasma NGAL (pooled AUC 0.786, 95% CI 0.749-0.823; I2=28,46%) as well as plasma Creatinine (pooled AUC 0.771, 95% CI 0.720-0.823; I2=34.38%). Serum Cystatin C had a pooled AUC of 0.763 (95% CI 0.723-0.803; I2=0,00%). The other biomarkers had no good predictive value, with urinary IGFBP-7 alone showing a pooled AUC of 0.734 (95% CI 0.565-0.902; I2=69.45%). Urinary (normalized to urine creatinine concentration [norm.] and concentration alone [conc.]) and serum NGAL had a pooled AUC of 0.712 (95% CI 0.653-771; I2=76.67%), 0.700 (95% CI 0.634-0.767; I2=79.24%) and 0.672 (95% CI 0.533-0.811; I²=87.65%), respectively. Urinary IL-18 showed a pooled AUC of 0.657 (95% CI 0.582-0.731; I²=39.73%) irrespective whether it was normalized to urine creatinine or not. Urinary KIM-1 (norm. and conc.) had a pooled AUC of 0.656 (95% CI 0.528-0.784; I²=0.00%) and 0.642 (95% CI 0.502-0.763; I²=0.00%), respectively. Conclusions: The combination of urinary TIMP-2 and IGFBP-7 showed the best predictive value for initiation of RRT. However, no biomarker showed a very good or even excellent predictive performance. While some promising biomarkers were identified, heterogeneity in the selected studies makes clinical applicability difficult. Figure 1: Forest plot showing pooled AUC of biomarkers from meta-analysis in random effects model [UO = urine output, u = urinary, s = serum, p = plasma, conc. = concentration, norm. = normalized to urinary creatinine concentration, BUN = blood urea nitrogen, Cr = Creatinine, RRT = renal replacement therapy, CI = confidence interval] Correspondence: Dr.med.univ. Sebastian J. Klein Division of Intensive Care and Emergency Medicine, Department of Internal Medicine I, Medical University Innsbruck Anichstrasse 35 6020 Innsbruck, Austria Tel +43 512 504 81499 E-Mail: email@example.com
W. Druml, W. Winnicky, P. Metnitz, P. Zajic, T. Fellinger, B. Metnitz P51 Association of body mass index and outcome in chronic hemodialysis patients requiring intensive care therapy IntensivmedizinBackground and Objective: In patients with end-stage renal disease (ESRD) a positive association of body mass index (BMI) and outcome, the “obesity paradox” has been described. In a large group of intensive care patients we assessed whether a potential beneficial effect of a high body mass is also seen in ESRD patients with critical illness. Setting, Design and Participants: In a retrospective analysis of a prospectively collected data base of 82,323 patients from 98 Austrian intensive care units (ICUs) in whom BMI was available, in 9,869 patients with ESRD the association of 6 groups of BMI and outcome was assessed. Results were adjusted for severity of disease, age, sex and other acute and chronic comorbidities. Main findings: The 9,869 patients with ESRD were older, sicker, had a longer ICU stay and a higher ICU and hospital mortality. Within the group of ESRD patients a high BMI (> 25) was associated with an improved survival in a multivariate analysis, but this was not seen in morbidly obese patients with a BMI > 40. The association was significant in patients with the highest disease severity (SAPS-3 Score > 56) but remarkably, also in those patients without systemic inflammatory response syndrome (SIRS) and those not requiring mechanical ventilation. Conclusions: Also in ESRD patients who have acquired an acute intermittent diseases and are admitted to an ICU an increased BMI is associated with an improved outcome. This association however, is not seen in morbidly obese patients with a BMI > 40. This improved tolerance to acute disease processes may in part explain the “obesity paradox” observed in ESRD patients.-
A. Perez Ruiz de Garibay, B. Ende-Schneider, C. Schreiber, B. Kreymann P52 ADVanced Organ Support (ADVOS) based on albumin dialysis, a new method for CO2 removal and pH stabilization IntensivmedizinGoal of the study: Our group has recently developed an ADVanced Organ Support (ADVOS) system based on albumin dialysis to provide intensive care treatment for multiple organ failure including liver, kidney and lung impairments. The system already demonstrated improved survival in two animal models as well as safety and efficacy to eliminate water and protein-bound toxins in humans with liver failure [1, 2]. In the present work, the ability of the ADVOS procedure to eliminate CO2 and stabilize blood pH together with the reduction of bilirubin and urea levels has been determined. Results were compared to a conventional renal dialysis machine (NIKKISO DBB-03). Methods: An ex vivo model for respiratory acidosis was developed continuously infusing 110 ml/min CO2 into 5 liters swine blood. In addition, liver and kidney detoxification were simulated supplementing blood with bilirubin (275 mg/dl) and urea (30 mg/dl), respectively. Blood was subjected to hemodialysis in the ADVOS system for 4 hours through two dialyzers (2 x 1.9 m2) using a blood flow (BF) of 400 ml/min and a dialysate pH of 10. The NIKKISO machine was run through a dialyzer (2.5 m2) with a BF of 350 ml/min and a dialysate pH of 8. CO2, pH, bilirubin and urea levels were analyzed pre- and post-dialyzer. Blood was checked for hemolysis at the beginning and the end of the experiments. Results and Discussion: The ADVOS procedure reached an average CO2 removal of 108 ± 4 ml/min. 85% was excreted as HCO3-, while 15% was eliminated as dissolved CO2. Additionally, pH was maintained stable between 7.35 and 7.45 during the experiments. In contrast, with the NIKKISO machine pH decreased to 6.60 after one hour, being thereafter continuously below the measuring range. Post-dialyzer blood pH remained in both systems below 8. Urea was efficiently cleared with both machines (97% removal). Moreover, the ADVOS system reduced bilirubin levels about 3 times as much as conventional hemodialysis (59% vs. 21%). No signs for hemolysis were observed. Conclusion: The ADVOS system, in contrast to normal hemodialysis, was able to efficiently remove CO2, bilirubin and urea while maintaining pH in physiological levels in an ex vivo model for respiratory acidosis simulating additional kidney and liver failure. References 1. Al-Chalabi A et al. BMC Gastroenterol 13: 83, 2013. 2. Henschel B et al. Crit Care 19 (Suppl 1):P383, 2015.
A. Perez Ruiz de Garibay, B. Ende-Schneider, C. Schreiber, B. Kreymann P53 Combined removal of 4.5 mol/day of protons and protein bound and water soluble substances in an ex vivo model for metabolic acidosis using an ADVanced Organ Support (ADVOS) system based on albumin dialysis IntensivmedizinGoal of the study: Metabolic acidosis is a common event among patients with multiple organ failure. In case of impaired carbohydrate metabolism due to hypoxia, lactic acidosis may occur increasing blood lactate and reducing pH. We integrated the treatment of acidosis into an ADVanced Organ Support (ADVOS) system based on albumin dialysis. It consists of 3 circuits that allow elimination of water and protein bound toxins, regeneration of the albumin used in the process and stabilization of pH . The aim of this work is to show the ability of the ADVOS system to eliminate lactate, stabilize pH and clear bilirubin in an ex vivo model. Results were compared with a normal renal dialysis machine (NIKKISO DBB-03). Methods: An ex vivo model for metabolic acidosis with liver involvement was designed setting a continuous infusion of lactic acid into 5 liters porcine blood, which was spiked with bilirubin (275 mg/dl) before. Blood was dialyzed through the ADVOS system for 2 hours at 200 and 400 ml/min blood flow (BF). A dialysate pH of 9 was set. To determine the maximum lactate addition and removal, lactic acid infusion was progressively increased until blood pH was out of physiological ranges. Once the maximum addition was determined, tests were repeated with the NIKKISO machine (BF 400 ml/min). Lactate, pH and bilirubin levels were analyzed pre- and post-dialyzer every 15 minutes. Blood was checked for hemolysis at the beginning and the end of the experiments. Results and Discussion: The ADVOS system stabilized blood pH (7.35-7.45) till a maximum lactic acid addition of 3.1 mmol/min (BF 400 ml/min), which would result into a proton elimination of 4,464 mmol/day. Moreover, up to 75% of lactate (BF 200 ml/min) was eliminated and the ADVOS system removed significantly more bilirubin than the NIKKISO DBB-03 machine (66% vs. 21%). Although the NIKKISO DBB-03 machine achieved 80% lactate elimination, blood pH decreased to 6.90. Conclusion: During a continuous infusion of up to 3.1 mmol/min of lactic acid in an ex vivo model for metabolic acidosis, blood pH decreased to 6.90 under conventional hemodialysis. With the ADVOS system, blood pH remained stable between 7.35 and 7.45 and additionally an efficient elimination of bilirubin was achieved. References Henschel B et al. Crit Care 19 (Suppl 1):P383, 2015.
G. F. Lehner, U. Harler, C. Feistritzer, J. Hasslacher, R. Bellmann, M. Joannidis P54 Hemofiltration induces generation of microvesicles and tissue factor in sepsis Intensivmedizin Goal of the study: Microvesicles (MV) are extracellular vesicles known to be associated with cellular activation and inflammation. Hemofiltration is an effective blood purification technique for patients with renal failure and possibly also eliminates inflammatory mediators in the setting of sepsis. On the other hand, proinflammatory stimuli are induced by blood contacting the artificial membrane during extracorporeal blood purification. In chronic dialysis patients a systemic increase of MV has been described. The aim of the study was to investigate if hemofilter passage of blood in CVVH alters MV composition and levels in critically ill patients with sepsis. Methods: Pre- and postfilter blood as well as ultrafiltrate samples from intensive care unit patients with severe sepsis were obtained during continuous veno-venous hemofiltration (CVVH). MV subtypes in blood were analyzed by high-sensitivity flow cytometry. Additionally, tissue factor (TF) levels and MV-associated TF-activities as well as MV-activities were quantified. All parameters were corrected for hemoconcentration applied during CVVH. Results and Discussion: Twelve patients with severe sepsis on hemofiltration were analyzed. Significant increases of platelet-derived CD41+ MV (1.13 (1.07-2.08) fold, p=0.0335) and presumably mostly leukocyte-derived CD31+/CD41- MV (1.65 (1.22–2.24) fold, p=0.0015) as well as significantly higher TF-activities (1.20 (1.06–1.50) fold, p=0.0076) and TF-levels (1.12 (0.99–1.15) fold, p=0.0376) were detected postfilter compared to prefilter. No significant differences concerning AnnexinV+ MV or MV-Activity were detected. No MV-activity was measurable in ultrafiltrate samples. Increments of AnnexinV+, CD41+, CD42b+ and CD31+/CD41- MV post- to prefilter correlated with filtration fraction (all p < 0.01). Conclusions: Hemofiltration induces the release of MV subsets, indicating platelet and presumably leukocyte activation during hemofilter passage. Moreover, TF is generated within the hemofilter. Increases of MV subsets within the hemofilter correlate with filtration fraction. No significant clearance of MV by a single hemofilter passage during CVVH could be detected. Acknowledgements: Supported by funds of the Oesterreichische Nationalbank (Oesterreichische Nationalbank, Anniversary Fund, project numbers 13861 and 15708)
J. Frick, M. Möckel, M. Schmiedhofer, J. Searle, A. Slagman P55 Fragebogenentwicklung zur Inanspruchnahme der Notaufnahmen durch Patienten mit nicht-dringlichem Behandlungsbedarf - Implikationen für die Patientenbefragung NotfallmedizinZielsetzung: Die Notaufnahmen in Deutschland verzeichnen seit Jahren eine steigende Zahl an Patienten mit der Folge einer zunehmenden Überfüllung der Notaufnahmen. In qualitativen Befragungen wurde das Spektrum der Gründe für die Inanspruchnahme der Notaufnahmen durch nicht-dringliche Patienten erfasst. Das Ziel der vorliegenden Arbeit ist die Entwicklung eines Fragebogens zur quantitativen Erfassung dieser Gründe für die Inanspruchnahme der Notaufnahme und die Beschreibung der damit verbundenen Implikationen für eine Patientenbefragung in der Notaufnahme. Methode: Die Fragebogenentwicklung basiert auf einer Literaturrecherche sowie der qualitativ durchgeführten EPICS-2 Studie. In drei Notaufnahmen der Charité – Universitätsmedizin Berlin wurden zwei Pretests durchgeführt. Rekrutiert wurden ambulant behandelte Patienten ≥18 Jahre mit den MTS Triage-Kategorien blau, grün und gelb. Die Patienten im ersten Pretest wurden vom Studienteam interviewt, während im zweiten Pretest Fragebögen zum Selbstausfüllen an die Patienten ausgehändigt wurden. Ergebnisse und Diskussion: Insgesamt konnten in den Pretests 189 Patienten rekrutiert werden (Pretest 1: n=89, Pretest 2: n=100). Der finale Fragebogen enthält 24 Items, die im Verlauf beider Pretests evaluiert und angepasst wurden. Sie beziehen sich auf die klinischen Charakteristika der gesundheitlichen Beschwerden, die Gründe für die Inanspruchnahme der Notaufnahme, vorherige Kontakte mit niedergelassenen Praxen und mit dem Bereitschaftsdienst der Kassenärztlichen Vereinigung sowie die soziodemographischen Charakteristika der Patienten. Die erhobenen Fragebogendaten konnten zusätzlich mit den Daten des Klinikinformationssystem (KIS) abgeglichen und so um klinische Charakteristika ergänzt werden. Für die Durchführung der Befragung empfiehlt sich ein schriftlicher Fragebogen, der von den Patienten selbst ausgefüllt wird. Die heterogenen Studienbedingungen in der Notaufnahme erfordern während der Datenerhebung eine hohe Flexibilität. Schlussfolgerung: Der entwickelte Fragebogen eignet sich zur routinemäßigen, quantitativen Erfassung der individuellen Gründe für die Inanspruchnahme der Notaufnahme. Hohe Rekrutierungsraten sind nur realisierbar, wenn Mitarbeiter ausschließlich für die Begleitung der Datenerhebung eingesetzt werden. Die diesem Beitrag zugrunde liegende Machbarkeitsstudie wurde mit Stiftungsmitteln des Zentralinstituts der kassenärztlichen Versorgung in Deutschland (ZI) gefördert.
B. Hofer, S. Dunzendorfer, R. Beer, M. Joannidis P56 Cardiac arrest - favorable functional outcome despite high NSE levels and early brain swelling Intensivmedizin A 50-year-old woman was admitted to the ER after having suffered a witnessed cardiac arrest, following respiratory distress and consecutive apnoea during sleep. She received immediate basic life support by her husband. Upon arrival of emergency medical service advanced cardiovascular life support was provided with 5 defibrillations due to ventricular fibrillation as initial rhythm. After a resuscitation time of 35 minutes the patient achieved ROSC. In total 5 mg epinephrine and 300 mg amiodarone were administered prior to ROSC. After admission to the ER the patient developed progressive arterial hypotension and decreasing arterial oxygen saturation. There was no evidence for pulmonary embolism, pericardial effusion or aortic dissection on diagnostic workup. Emergency CT revealed extensive infiltrations of both lungs. Neuroimaging showed acute brain swelling but no catastrophic intracranial cause for the arrest. Because of abnormal ECG findings (ST depressions in V3-V6), elevated troponin (cTnT 2308 ng/ml) and creatine kinase (CK 2169 ng/ml) the patient underwent acute CAG. Intriguingly, no signs of stenosing coronary artery disease were detected, however, 2 weeks later transmural posterior myocardial infarction was diagnosed on cardiac MR imaging. The patient then was transferred to the ICU where she presented with deep coma (GCS 3) and bilaterally dilated and fixed pupils. Targeted temperature management was instituted for 24 hours. Repeated measurements of blood levels of NSE and S100B were performed. NSE peaked at 100.7 ng/ml (Figure) and S100B at 0.43 ng/ml on day 2. Notably, after rewarming blood biomarkers gradually returned to baseline (Figure). Concurrently a significant improvement of all neurological tests (clinical examination, SSEP, EEG) was observed. After successful weaning from the ventilator the patient was transferred to the regular ward 3 weeks after CA and then discharged to a rehabilitation facility with moderate residual cognitive problems (corresponding to CPC 2). Our case emphasizes that neurological prognostication of comatose CA victims should be multimodal and interpreted with caution within the first 72 hours after ROSC since accepted predictors of poor outcome  diagnosed during that time period may be consistent with recovery. To the best of our knowledge, the simultaneous observation of acute brain swelling and such a high NSE level but still favorable neurological recovery has not been reported so far. This again adds a question mark to the reliability of the currently recommended NSE cutoff levels for prediction of poor neurological outcome of comatose CA survivors . Consequently, we performed a multicenter study including 1053 patients to investigate the kinetics of NSE in the first days after CA and identified a NSE threshold of 90 ng/ml enabling prediction of poor outcome with almost no false positives at acceptable sensitivity . References 1. Wijdicks E. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006. 2. Sandroni C, Cariou A, Cavallaro F, et al. Prognostication in comatose sur-vivors of cardiac arrest: an advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine. Resuscitation. 2014. 3. Streitberger K, Joannidis M, Ploner C, Storm. Neuron specific enolase (NSE) predicts poor outcome after cardiac arrest and targeted temperature management: a multicenter study on 1053 patients. Critical Care Medicine. in press.
J. Hasslacher, M. Gashi, F. Steinkohl, U. Harler, M. Joannidis P57 Influence of mild therapeutic hypothermia on the incidence of ventilator associated pneumonia after cardiopulmonary resuscitation IntensivmedizinIntroduction: The aim of the study was to investigate the possible influence of mild therapeutic hypothermia (MTH) on the incidence of ventilator associated pneumonia. Methods: We prospectively included patients after successful cardiopulmonary resuscitation (CPR) at our ICU. Daily chest X –rays were performed at bed-side routinely in every patient. Ventilator associated pneumonia (VAP) was defined as an infiltration in the chest X-ray ≥ 48 hours after admission in patients with invasive ventilation. Mild therapeutic hypothermia (MTH) was applied for 24 hours targeting a temperature of 33°C using an intravascular cooling device. Neurological outcome was assessed with the Cerebral Performance Categories (CPC) score at hospital discharge. Results: In total 134 patients were included in the study, 69 patients (51 %) had a poor outcome (CPC 3–5) at hospital discharge, 59 (44%) were treated with MTH. The median age was 64 (range 53–75) years, 35 patients were female. 20 patients (16%) developed VAP after 48 hours. There was no statistical difference between patients treated with MTH or normothermia. When treated with MTH significantly more patients developed a new infiltration in the chest X -ray only at day 4 after admission (3 vs 0; p=0.047). There was no difference observed between patients with good or poor neurological outcome. At admission 18 (13%) patients had pneumonia. When treated with MTH pneumonia occurred significantly less often in those patients (2 vs. 16; p= 0.003). There was also a significant difference in the incidence of pneumonia at day 1 between patients with good and poor neurological outcome (5 vs 13; p=0.047). Conclusion: At admission the incidence of pneumonia was significantly higher in patients with poor neurological outcome treated with normothermia. At day 4 the incidence of VAP was significantly higher in patients treated with MTH, but in total the development of VAP was independent of outcome or temperature management.
K. Roedl, C. Wallmüller, H. Herkner, F. Sterz, V. Fuhrmann P58 Cholestase bei Patienten mit Herzkreislaufstillstand: Epidemiologie und Outcome IntensivmedizinZielsetzung: Bisher sind keine Daten zur kardiopulmonalen Reanimation (CPR) und Entwicklung einer Cholestase verfügbar. Zielsetzung dieser Studie war es die Häufigkeit und das Outcome von Patienten mit Cholestase nach erfolgreicher CPR zu untersuchen. Methodik: Aus 1068 erfolgreich reanimierten Patienten an der Medizinischen Universität Wien konnten 266 (25%) mit Entwicklung einer Cholestase identifiziert werden. Es wurden die Patientencharakteristika, Aufnahmediagnose, Schwere der Erkrankung und 28-Tages-Mortalität erhoben. Die Entwicklung einer Cholestase wurde als Anstieg des Bilirubins > 2mg/dl definiert. Ergebnisse: Insgesamt entwickelten 266 Patienten im Verlauf nach erfolgreicher CPR eine Cholestase. Der mediane SOFA-Score bei Aufnahme betrug 10 (7 – 13) Punkte, SAPS II betrug 80 (74 – 87) Punkte. Der Herzkreislaufstillstand war bei 176 (66%) Patienten kardialer Genese. 213 (80%) Patienten erlitten den Herzkreislaufstillstand außerhalb des Krankenhauses. Die Zeit bis zur Wiedererlangung des Kreislaufes betrug 18 (9 – 28) Minuten. Der beobachtete Erstrhythmus war schockbar (VT/VF) in 150 (56%), nicht schockbar (PEA/Asystolie) in 107 (40%) und unbekannt in 9 (4%) der Patienten. 133 (50%) Patienten waren nach 28 Tagen verstorben oder hatten ein schlechtes neurologisches Outcome (CPC III/IV). Schlussfolgerungen: Nach erfolgreicher Reanimation ist die Cholestase eine häufige Komplikation, die in einem Viertel der Patienten auftritt. Die Ursache des Herzkreislaufstillstandes ist häufig kardial. Bei Patienten mit Cholestase zeigte sich eine hohe Sterberate sowie ein schlechtes neurologisches Outcome.