G Marx

RWTH Aachen University, Aachen, North Rhine-Westphalia, Germany

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Publications (153)509.8 Total impact

  • Critical care medicine 05/2014; 42(5):e386-7. · 6.37 Impact Factor
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    ABSTRACT: Purpose: Noninvasive pressure support ventilation is intended to relieve the load on respiratory muscles and to prevent exhaustion. This includes continuous positive airway pressure (CPAP) as well as pressure support ventilation (PSV). Speckle tracking echocardiography (STE) allows quantification of tissue deformation by tracing characteristic grayscale patterns, independent of the acquisition angle. The aim of the present study was to assess the applicability of using STE as a way to investigate diaphragm movement using deformation analysis as a parameter for respiratory workload. Materials and Methods: Healthy male subjects (n = 13, 27 ± 7 years) were treated while in a seated supine position with the following respirator settings: regular breathing, 5 mbar CPAP, CPAP + 5 / + 10 / + 15 mbar PSV. A 2 - 4 MhZ M5S phased array sector transducer was used on a Vivid E 9 (GE, Horton, Norway) to visualize the diaphragm. The inspiratory peak transverse strain was measured as a parameter of maximal inspiratory muscle workload and compared to the M-mode-based fractional thickening (FT). Results: Both the FT and the transverse strain increased significantly under CPAP and PSV. The transverse strain correlated well with the FT (r = 0.753; p < 0.001). Conclusion: The results measured by STE were comparable to the M-mode-based measurements. The capturing of a larger diaphragmatic sample area and movement tracking possibly lead to higher precision compared to one-dimensional M-mode. The use of STE in patients might provide a reproducible, bedside method to analyze the respiratory workload. Due to the larger sampling area, it might prove superior to mere M-mode acquisition.
    Ultraschall in der Medizin 03/2014; · 4.12 Impact Factor
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    ABSTRACT: The purpose of this report was to assess the safety and application of chlorhexidine (CHG)-containing dressings-shown to reduce central line infection rates markedly-for external ventricular drainages (EVDs) and lumbar drainages (LDs). Cerebrospinal fluid samples of patients receiving standard dressings and CHG-containing dressing (ten each) were analyzed by high-performance liquid chromatography for the presence of CHG. The application was evaluated. CHG was not detectable in all samples. The dressings' application for EVDs and LDs worked without problems. Thus, the use of CHG-containing dressings for EVDs and LDs seems to be safe. Further studies addressing their infection reduction potential are warranted.
    Infection 02/2014; · 2.44 Impact Factor
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    ABSTRACT: Calibrated arterial pulse contour analysis has become an established method for the continuous monitoring of cardiac output (PCCO). However, data on its validity in hemodynamically instable patients beyond the setting of cardiac surgery are scarce. We performed the present study to assess the validity and precision of PCCO-measurements using the PiCCOTM-device compared to transpulmonary thermodilution derived cardiac output (TPCO) as the reference technique in neurosurgical patients requiring high-dose vasopressor-therapy. A total of 20 patients (16 females and 4 males) were included in this prospective observational clinical trial. All of them suffered from subarachnoid hemorrhage (Hunt&Hess grade I-V) due to rupture of a cerebral arterial aneurysm and underwent high-dose vasopressor therapy for the prevention/treatment of delayed cerebral ischemia (DCI). Simultaneous CO measurements by bolus TPCO and PCCO were obtained at baseline as well as 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after inclusion. PCCO- and TPCO-measurements were obtained at baseline as well as 2 h, 6 h, 12 h, 24 h, 48 h and 72 h after inclusion. Patients received vasoactive support with (mean +/- standard deviation, SD) 0.57 +/- 0.49 mug . kg-1 . min-1 norepinephrine resulting in a mean arterial pressure of 103 +/- 13 mmHg and a systemic vascular resistance of 943 +/- 248 dyn . s . cm-5. 136 CO-data pairs were analyzed. TPCO ranged from 5.2 to 14.3 l . min-1 (mean +/- SD 8.5 +/- 2.0 l . min-1) and PCCO ranged from 5.0 to 14.4 l . min-1 (mean +/- SD 8.6 +/- 2.0 l . min-1). Bias and limits of agreement (1.96 SD of the bias) were -0.03 +/- 0.82 l . min-1 and 1.62 l . min-1, resulting in an overall percentage error of 18.8%. The precision of PCCO-measurements was 17.8%. Insufficient trending ability was indicated by concordance rates of 74% (exclusion zone of 15% (1.29 l . min-1)) and 67% (without exclusion zone), as well as by polar plot analysis. In neurosurgical patients requiring extensive vasoactive support, CO values obtained by calibrated PCCO showed clinically and statistically acceptable agreement with TPCO-measurements, but the results from concordance and polar plot analysis indicate an unreliable trending ability.
    Critical care (London, England) 02/2014; 18(1):R25. · 4.72 Impact Factor
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    ABSTRACT: Die mechanische Beatmung ist für Patienten mit respiratorischem Versagen oder im Rahmen der tiefen Sedierung lebensrettend. Während kontinuierlicher mandatorischer Beatmung ist das Diaphragma inaktiviert und unterliegt einer pathophysiologischen Kaskade, die zum Kraftverlust und zur Verringerung der Muskelfasermasse führt. Diese Prozesse sind im Gegensatz zur peripheren Skelettmuskulatur bereits nach 12 h nachweisbar und haben Einfluss auf die Beatmungsentwöhnung von Intensivpatienten – und damit auf Letalität sowie Morbidität. Studien der letzten Jahre haben tierexperimentell die pathophysiologischen Zusammenhänge untersucht und sind durch klinische Untersuchungen bestätigt worden. Diese Übersicht beschreibt die biochemischen Zusammenhänge, Einflüsse von Pharmaka und Interventionen zur Prophylaxe.
    Der Anaesthesist 01/2014; 63(1). · 0.85 Impact Factor
  • Anästhesiologie und Intensivmedizin. 01/2014; 55:316-329.
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    ABSTRACT: Mechanical ventilation is a life-saving intervention for patients with respiratory failure or during deep sedation. During continuous mandatory ventilation the diaphragm remains inactive, which activates pathophysiological cascades leading to a loss of contractile force and muscle mass (collectively referred to as ventilator-induced diaphragm dysfunction, VIDD). In contrast to peripheral skeletal muscles this process is rapid and develops after as little as 12 h and has a profound influence on weaning patients from mechanical ventilation as well as increased incidences of morbidity and mortality. In recent years, animal experiments have revealed pathophysiological mechanisms which have been confirmed in humans. One major mechanism is the mitochondrial generation of reactive oxygen species that have been shown to damage contractile proteins and facilitate protease activation. Besides atrophy due to inactivity, drug interactions can induce further muscle atrophy. Data from animal research concerning the influence of corticosteroids emphasize a dose-dependent influence on diaphragm atrophy and function although the clinical interpretation in intensive care patients (ICU) patients might be difficult. Levosimendan has also been proven to increase diaphragm contractile forces in humans which may prove to be helpful for patients experiencing difficult weaning. Additionally, antioxidant drugs that scavenge reactive oxygen species have been demonstrated to protect the diaphragm from VIDD in several animal studies. The translation of these drugs into the IUC setting might protect patients from VIDD and facilitate the weaning process.
    Der Anaesthesist 12/2013; · 0.85 Impact Factor
  • Johannes Bickenbach, Gernot Marx
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    ABSTRACT: Independent from the mode of mechanical ventilation, particularly a quick termination of mechanical ventilation is essential for the weaning progress. Respirator-associated complications need to be early detected and treated. Thus it is important to know correspondent pathomechanisms as they have a crucial influence on the weaning process.To facilitate a holistic treatment approach for patients in prolonged weaning, a tight junction of intensive care within specialized units seems mandatory.
    ains · Anästhesiologie · Intensivmedizin 10/2013; 48(10):626-32. · 0.39 Impact Factor
  • J Bickenbach, G Marx
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    ABSTRACT: Ventilator associated pneumonia (VAP) is one of the most common nosocomial infections in critically ill patients, especially in those being mechanically ventilated. Beside increased healthcare costs due to prolonged hospital stay, VAP is associated with a consistently high morbidity and mortality. Although pathomechanisms leading to VAP are well known, it remains challenging to diagnose VAP accurately and in a timely manner. It has been suggested that the Clinical Pulmonary Infection Score (CPIS) may help to resolve these difficulties however, its use is questionable. Several evidence based strategies have been described for the diagnosis of ventilator associated pneumonia, potentially leading to better or faster treatment and thereby influencing the outcome. Current diagnostic approaches and the value of the CPIS are therefore considered within this article. A bundle approach, regarding time management and several diagnostic pathways should be evaluated in further studies.
    Minerva anestesiologica 07/2013; · 2.82 Impact Factor
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    ABSTRACT: BACKGROUND: /st>A new calibrated pulse wave analysis method (VolumeView™/EV1000™, Edwards Lifesciences, Irvine, CA, USA) has been developed to continuously monitor cardiac output (CO). The aim of this study was to compare the performance of the VolumeView method, and of the PiCCO2™ pulse contour method (Pulsion Medical Systems, Munich, Germany), with reference transpulmonary thermodilution (TPTD) CO measurements. METHODS: /st>This was a prospective, multicentre observational study performed in the surgical and interdisciplinary intensive care units of four tertiary hospitals. Seventy-two critically ill patients were monitored with a central venous catheter, and a thermistor-tipped femoral arterial VolumeView™ catheter connected to the EV1000™ monitor. After initial calibration by TPTD CO was continuously assessed using the VolumeView-CCO software (CCOVolumeView) during a 72 h period. TPTD was performed in order to obtain reference CO values (COREF). TPTD and arterial wave signals were transmitted to a PiCCO2™ monitor in order to obtain CCOPiCCO values. CCOVolumeView and CCOPiCCO were recorded over a 5 min interval before assessment of COTPTD. Bland-Altman analysis, %(errors), and concordance (trend analysis) were calculated. RESULTS: /st>A total of 338 matched sets of data were available for comparison. Bias for CCOVolumeView-COREF was -0.07 litre min(-1) and for CCOPiCCO-COREF +0.03 litre min(-1). Corresponding limits of agreement were 2.00 and 2.48 litre min(-1) (P<0.01), %(errors) 29 and 37%, respectively. Trending capabilities were comparable for both techniques. CONCLUSIONS: /st>The performance of the new VolumeView™-CCO method is as reliable as the PiCCO2™-CCO pulse wave analysis in critically ill patients. However, an improved precision was observed with the VolumeView™ technique.Clinicaltrials.gov identifierNCT01405040.
    BJA British Journal of Anaesthesia 04/2013; · 4.24 Impact Factor
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    ABSTRACT: Perioperative hemodynamic optimisation improves postoperative outcome for patients undergoing high-risk surgery (HRS). In this prospective randomized multicentre study we studied the effects of an individualized, goal-directed fluid management based on continuous stroke volume variation (SVV) and stroke volume (SV) monitoring on postoperative outcomes. 64 patients undergoing HRS were randomized either to a control group (CON, n = 32) or a goal-directed group (GDT, n = 32). In GDT, SVV and SV were continuously monitored (FloTrac/Vigileo) and patients were brought to and maintained on the plateau of the Frank-Starling curve (SVV <10 % and SV increase <10 % in response to fluid loading). Organ dysfunction was assessed using the SOFA score and resource utilization using the TISS score. Patients were followed up to 28 days for postoperative complications. Main outcome measures were the number of complications (infectious, cardiac, respiratory, renal, hematologic and abdominal post-operative complications), maximum SOFA score and cumulative TISS score during ICU stay, duration of mechanical ventilation, length of ICU stay, and time until fit for discharge. 12 patients had to be excluded from final analysis (6 in each group). During surgery, GDT received more colloids than CON (1,589 vs. 927 ml, P < 0.05) and SVV decreased in GDT (from 9.0 to 8.0 %, P < 0.05) but not in CON. The number of postoperative wound infections was lower in GDT (0 vs. 7, P < 0.01). Although not statistically significant, the proportion of patients with at least one complication (46 vs. 62 %), the number of postoperative complications per patient (0.65 vs. 1.40), the maximum sofa score (5.9 vs. 7.2), and the cumulative TISS score (69 vs. 83) tended to be lower. This multicentre study shows that fluid management based on a SVV and SV optimisation protocol is feasible and decreases postoperative wound infections. Our findings also suggest that a goal-directed strategy might decrease postoperative organ dysfunction.
    International Journal of Clinical Monitoring and Computing 04/2013;
  • Critical Care 03/2013; 17(2). · 4.93 Impact Factor
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    ABSTRACT: BACKGROUND: /st>Xenon has profound neuroprotective effects after neurological injury and is currently undergoing phase 2 clinical trials in cardiac arrest patients. However, xenon is very costly, which might preclude its widespread use. We hypothesized argon, which is more available, might also protect central nervous tissues and allow better functional recovery in a rodent model of global cerebral ischaemia. METHODS: /st>Fourteen male Sprague-Dawley rats were subjected to 7 min of cardiac arrest and 3 min of cardiopulmonary resuscitation (CPR). One hour after successful CPR, animals were randomized to either ventilation with 70% argon in oxygen (n = 7) for 1 h or 70% nitrogen (controls, n=7). A neurological deficit score (NDS) was calculated daily for the following 7 days, then the animals were killed and the brains harvested for histopathological analyses. RESULTS: /st>All animals survived. Control rats had severe neurological dysfunction, while argon-treated animals showed significant improvements in the NDS at all time points. This was paralleled by a significant reduction in the neuronal damage index in the neocortex and the hippocampal CA 3/4 region. CONCLUSIONS: /st>Our study demonstrates that a single 1 h application of 70% argon significantly reduced histopathological damage of the neocortex and hippocampus, associated with a marked improvement in functional neurological recovery.
    BJA British Journal of Anaesthesia 02/2013; · 4.24 Impact Factor
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    ABSTRACT: INTRODUCTION: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. METHODS: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. RESULTS: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2].[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2].[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2].[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. CONCLUSIONS: Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration: ClinicalTrials.gov number NCT01209169.
    Critical care (London, England) 02/2013; 17(1):R25. · 4.72 Impact Factor
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    ABSTRACT: INTRODUCTION: Increasing rates of multi-resistant bacteria are a major problem in the treatment of critically ill patients. Furthermore, conventional antibiotics lead to the release of bacterial derived membrane parts initiating pro-inflammatory cascades with potential harm to the patient. Antimicrobial peptides (AMP) may kill bacteria without releasing pro-inflammatory factors. Thus, we compared three newly developed synthetic anti-lipopolysaccharide peptides (SALPs) with a broader range of efficacy to suppress cytokine release in plasma and CD14 mRNA expression in organ tissue in a murine, polymicrobial sepsis model. METHODS: Randomized, experimental trial in an animal research facility. Male NMRI mice (n=90; 8-12 weeks) were randomized to the following six groups: (i) sham operation and parenteral vehicle (NaCl 0.9%) administration (sham); (ii) cecal ligation and puncture (CLP) and vehicle infusion (sepsis-control), (iii) CLP and polymyxin B infusion (polyB), or (iv-vi) CLP and infusion of three different synthetic antimicrobial peptides Pep19-2.5 (Pep2.5), Pep19-4 (Pep4) or Pep19-8 (Pep8). All animals underwent arterial and venous catheterization for hemodynamic monitoring 48 hours prior to CLP or sham-operation. Physical appearance and behavior (activity), plasma cytokine levels, and CD14 mRNA expression in heart, lung, liver, spleen and kidney tissue were determined 24 hours after CLP or sham operation. RESULTS: Only Pep2.5 significantly enhanced the activity after CLP, whereas none of the therapeutic regimen elevated the mean arterial pressure or heart rate. The strongly elevated IL-6, IL-10 and MCP serum levels in septic animals were significantly reduced after Pep2.5 administration (p<0.001, p<0.001, and p<0.001, respectively). Similarly, Pep2.5 significantly reduced the sepsis-induced CD14 mRNA expression in heart (p=0.003), lung (p=0.008), and spleen tissue (p=0.009) but not in kidney and liver. CONCLUSIONS: Structurally variable SALPs exhibit major differences in their anti-inflammatory effect in vivo. Continuous parenteral administration of Pep2.5 is able to reduce sepsis-induced cytokine release and tissue inflammation.
    Critical care (London, England) 01/2013; 17(1):R3. · 4.72 Impact Factor
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    Anästh Intensivmed. 01/2013; 54:522-524.
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    ABSTRACT: Critical care medicine in severely burned patients should be adapted to the different pathophysiological phases. Accordingly, surgical and non-surgical therapy must be coordinated adequately. Initial stabilization of the burn victim during the first 24 hours (Surgical therapy and critical care medicine in severely burned patients - Part 1: the first 24 ours, AINS 9/12) is followed by a long lasting reconstructive period. During this time calculated fluid replacement to compensate evaporative losses by large bourn wounds is as essential as reconstruction of the integrity of the skin and the modulation of metabolic consequences following severe burn injury. Special attention has to be paid to local and systemic infections.
    ains · Anästhesiologie · Intensivmedizin 01/2013; 48(1):18-27. · 0.39 Impact Factor
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    ABSTRACT: Quality indicators are key elements of quality management. The quality indicators for intensive care medicine of the German Interdisciplinary Society of Intensive Care Medicine (DIVI) from the year 2010 were recently evaluated when their validity time expired after two years. Overall one indicator was replaced and further three were in part changed. The former indicator I "elevation of head of bed" was replaced by the indicator "Daily multi-professional ward rounds with the documentation of daily therapy goals" and added to the indicator IV "Weaning and other measures to prevent ventilator associated pneumonias (short: Weaning/VAP Bundle)" (VAP = ventilator-associated pneumonia) which aims at the reduction of VAP incidence. The indicator VIII "Documentation of structured relative-/next-of-kin communication" was refined. The indicator X "Direction of the ICU by a specially trained certified intensivist with no other clinical duties in a department" was also updated according to recent study results. These updated quality indicators are part of the Peer Review in intensive care medicine. The next update of the quality indicators is due in 2016.
    German medical science : GMS e-journal 01/2013; 11:Doc09.
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    ABSTRACT: BACKGROUND:There is evidence suggesting that early fluid resuscitation is beneficial in treatment of sepsis. Previously we demonstrated that HES 130/0.42 attenuated capillary leakage better than HES 200/0.5. Using a similar porcine fecal sepsis model we tested the effects of two new synthetic high molecular weight (700kD) hydroxyethyl starches with the same molar substitution of 0.42 but a different C2/C6 ratio compared to 6%HES 130/0.42 on plasma volume, systemic and tissue oxygenation. METHODS: Prospective randomized, controlled animal study. 25 anesthetized and mechanically ventilated pigs (28.4±2.3kg) were observed over 8h. Septic shock was induced with fecal peritonitis. Animals were randomized to volume- replacement therapy with HES 700/0.42 C2/C6/2.5:1 (n=5), HES 700/0.42 C2/C6/6:1 (n=5), HES 130/0.42 C2/C6/5:1 (n=5) or Ringer's Solution (RS, n=5), and compared to non-septic controls receiving RS (n=5). Albumin- escape-rate was calculated and plasma volume was determined at end of study. Tissue Oxygen Saturation was measured with the InSpectra™ Device (InSpectra Tissue Spectrometer, Hutchinson Technology Inc., Hutchinson, Minn.) RESULTS: AER increased in all groups compared to control. All colloids (HES700/6:1 68±15; HES130 67±4; HES700/2.5:1 71±12; p<0.05) but not RS (44±7) stabilized PV [mLkg-1BW-1] after eight hours of sepsis. Systemic oxygenation was significantly lower in the RS group (44±17%; p<0.05) compared to all other groups at study end (p<0.05). CONCLUSION: In this porcine faecal peritonitis model the high molecular weight artificial colloids HES700/2.5:1 and HES700/6:1 could maintain plasma volume, systemic and tissue oxygenation not more effective than HES 130. In comparison to the crystalloid RS all HES solutions were more effective to maintain plasma volume, MAP, systemic and tissue oxygenation.
    Minerva anestesiologica 10/2012; · 2.82 Impact Factor
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    ABSTRACT: OBJECTIVES: We recently reported that cardiac surgical patients in our institution exhibited low selenium blood levels preoperatively, which were further aggravated during surgery and independently associated with the development of postoperative multiorgan failure. Low circulating selenium levels result in a decreased antioxidant capacity. Both can be treated effectively by sodium-selenite administration. Little is known about the kinetics of exogenously administered sodium-selenite during acute perioperative oxidative stress. The aim of this study was to assess the effects of perioperative high-dose sodium-selenite administration on selenium blood concentrations in cardiac surgical patients. METHODS: One hundred four cardiac surgical patients were enrolled in this prospective observational trial. Patients received an intravenous bolus of 2000 μg selenium after an induction of anesthesia and 1000 μg selenium every day further during their intensive care unit (ICU) stay. Selenium blood levels were measured at regular intervals. RESULTS: Preoperative sodium-selenite administration increased selenium blood concentrations to normal values on ICU admission, but failed to prevent a significant decrease of circulating selenium on the first postoperative day. During the further ICU stay, selenium blood levels were normalized by the administration strategy and did not exceed the German reference range. No acute selenium-specific side effects occurred. When matching the participating patients to a historical control group without sodium-selenite administration, the chosen strategy was associated with a decrease in SAPS II (23 ± 7 versus 29 ± 8, P = 0.005) and SOFA scores (4 ± 3 versus 7 ± 2, P = 0.007) on the first postoperative day, but was unable to improve the postoperative outcome in patients staying >1 d in ICU. CONCLUSIONS: Despite preemptive high-dose sodium-selenite administration, cardiac surgical patients experienced a significant decrease in circulating selenium levels on the first postoperative day.
    Nutrition 09/2012; · 2.86 Impact Factor

Publication Stats

1k Citations
509.80 Total Impact Points

Institutions

  • 2009–2014
    • RWTH Aachen University
      • Surgical Intensive Care
      Aachen, North Rhine-Westphalia, Germany
  • 2013
    • University of Groningen
      • Department of Anaesthesiology
      Groningen, Province of Groningen, Netherlands
  • 2008–2013
    • University Hospital RWTH Aachen
      • Department of Neurology
      Aachen, North Rhine-Westphalia, Germany
  • 2012
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 1996–2012
    • Hannover Medical School
      • Clinic for Anaesthesiology and Intensive Care Medicine
      Hanover, Lower Saxony, Germany
  • 2004–2010
    • Friedrich-Schiller-University Jena
      • Department of Anaesthesiology and Intensive Care Medicine
      Jena, Thuringia, Germany
  • 2006–2008
    • Universitätsklinikum Jena
      • Klinik für Anästhesiologie und Intensivmedizin
      Jena, Thuringia, Germany
  • 2001–2005
    • Royal Liverpool and Broadgreen University Hospitals NHS Trust
      • Department of Anaesthesia
      Liverpool, England, United Kingdom
  • 2001–2004
    • University of Liverpool
      Liverpool, England, United Kingdom