[Guideline-conform treatment of sepsis]. / Leitliniengerechte Therapie der Sepsis.

The time to administration of broad-spectrum antibiotics and (secondarily) to the initiation of hemodynamic stabilization are the most important factors influencing survival of patients with sepsis and septic shock; however, the basic prerequisite for the initiation of an adequate treatment is that a suspected diagnosis of sepsis is made first. Therefore, the treatment of sepsis, even before it has begun, is an interdisciplinary and interprofessional task. This article provides an overview of the current state of the art in sepsis treatment and points towards new evidence that has the potential to change guideline recommendations in the coming years. In summary, the following points are critical: (1) sepsis must be diagnosed as soon as possible and the implementation of a source control intervention (in case of a controllable source) has to be implemented as soon as (logistically) possible. (2) In general, intravenous broad-spectrum antibiotics should be given within the first hour after diagnosis if sepsis or septic shock is suspected. In organ dysfunction without shock, where sepsis is a possible but unlikely cause, the results of focused advanced diagnostics should be awaited before a decision to give broad-spectrum antibiotics is made. If it is not clear within 3 h whether sepsis is the cause, broad-spectrum antibiotics should be given when in doubt. Administer beta-lactam antibiotics as a prolonged (or if therapeutic drug monitoring is available, continuous) infusion after an initial loading dose. (3) Combination treatment with two agents for one pathogen group should remain the exception (e.g. multidrug-resistant gram-negative pathogens). (4) In the case of doubt, the duration of anti-infective treatment should rather be shorter than longer. Procalcitonin can support the clinical decision to stop (not to start!) antibiotic treatment! (5) For fluid treatment, if hypoperfusion is present, the first (approximately) 2L (30 ml/kg BW) of crystalloid solution is usually safe and indicated. After that, the rule is: less is more! Any further fluid administration should be carefully weighed up with the help of dynamic parameters, the patient's clinical condition and echo(cardio)graphy.

The prevalence of sepsis-induced coagulopathy in patients with sepsis - a secondary analysis of two German multicenter randomized controlled trials.

BACKGROUND: Sepsis and septic shock are frequently accompanied by coagulopathy. Since the sepsis-induced coagulopathy (SIC) score was first described, subsequent studies from Asia revealed a SIC prevalence of 40-60%. In Europe, however, SIC prevalence in patients fulfilling sepsis criteria according to the third international consensus definition (SEPSIS-3) has not yet been evaluated. METHODS: The Critical Care Trials Group of the German Sepsis Competence Network (SepNet) conducted a secondary analysis of two randomized controlled trials. Only patients fulfilling sepsis criteria according SEPSIS-3 were included in this secondary analysis. In a two step approach, SIC prevalence was determined in 267 patients with sepsis but not septic shock (at the time of inclusion) from the "Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis" (HYPRESS) trial. Then, we estimated SIC prevalence in 1,018 patients from the "Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock" (SISPCT) trial using a simplified SIC score based on the platelet-SIC-subscore (PSSC). Study aims were to assess (i) the prevalence of SIC in patients with SEPSIS-3, (ii) the association of SIC with 90-day mortality and morbidity, (iii) the time when patients become SIC positive during the course of sepsis, and (iv) the value of the PSSC for predicting SIC. RESULTS: In the HYPRESS trial, SIC prevalence was 22.1% (95% confidence interval [CI] 17.5-27.5%). The estimated SIC prevalence in the SISPCT trial was 24.2% (95% CI 21.6-26.9%). In the HYPRESS trial, SIC was associated with significantly higher 90-day mortality (13.9% vs. 26.8%, p = 0.027) and morbidity. Logistic regression analysis adjusted for age, sex, treatment arm, and (SIC-adapted) SOFA score confirmed the negative association of SIC with survival (p = 0.011). In the SISPCT trial, increased PSSCs were associated with higher 90-day mortality (PSSC 0: 34.4%, PSSC 1: 40.5%, PSSC 2: 53.3%; p < 0.001). In both trials, SIC was already present at sepsis diagnosis or occurred during the following 4 days. CONCLUSIONS: SIC is a clinically relevant complication of sepsis. Although it might be less frequent than previously reported, its occurrence is associated with higher morbidity and mortality and should be interpreted as an early warning sign.

[SEPSIS-3.0-Is intensive care medicine ready for ICD-11?] / SEPSIS-3.0 ­ Ist die Intensivmedizin bereit für die ICD-11?

BACKGROUND: The 11th revision of the International Classification of Diseases (ICD-11) will come into effect in January 2022. Among other things, The Third International Consensus Definitions for Sepsis and Septic Shock (SEPSIS­3 definition) will be implemented in it. This defines sepsis as a "life-threatening organ dysfunction caused by a dysregulated host response to infection". The aim of the present secondary analysis of a survey on the topic of "sepsis-induced coagulopathy" was to evaluate whether the SEPSIS­3 definition, 4 years after its international introduction, has arrived in everyday clinical practice of intensive care units (ICU) run by anesthesiologists in Germany and thus the requirements for its use of the ICD-11 are given. METHODS: Between October 2019 and May 2020, we carried out a nationwide survey among German medical directors of ICUs. In a separate block of questions we asked about the definition of sepsis used in daily practice. In addition, we asked whether the quick-sequential (sepsis-related) organ failure assessment (qSOFA) score is used in screening for sepsis in the hospital to which to the participating ICU belongs. RESULTS: A total of 50 medical directors from anesthesiological ICUs took part in the survey. In total, the ICUs evaluated stated that they had around 14% of the high-care beds registered in Germany. The SEPSIS­3 definition is integrated into everyday clinical practice at 78.9% of the university hospitals and 84.0% of the participating teaching hospitals. In contrast, the qSOFA screening test is only used by 26.3% of the participating university hospitals, but at least 52% of the teaching hospitals and 80% of the other hospitals. CONCLUSION: The data show that both SEPSIS­3 and qSOFA have become part of everyday clinical practice in German hospitals. The cautious use of qSOFA at university hospitals with simultaneous broad acceptance of the SEPSIS­3 definition can be interpreted as an indication that the search for a suitable screening test for sepsis has not yet been completed.

[Practice of pharmaceutical thrombosis prophylaxis and anticoagulation in patients with sepsis and pre-existing anticoagulation or heparin-induced type II thrombocytopenia-Results of a nationwide survey in German intensive care units]. / Praxis der medikamentösen Thromboseprophylaxe und Antikoagulation bei Patienten mit Sepsis und vorbestehender Antikoagulation oder Heparin-induzierter Thrombozytopenie Typ II ­ Ergebnisse einer deutschlandweiten Umfrage auf Intensivstationen.

BACKGROUND: A pre-existing anticoagulation treatment and predisposing diseases for thromboembolic events represent common problems in patients with sepsis or septic shock; however, these conditions are not addressed in current national guidelines for sepsis and septic shock. One of the aims of this nationwide survey in Germany was therefore to determine how intensive care physicians deal with these problems. METHODS: From October 2019 to May 2020, we conducted a nationwide survey among German medical directors of intensive care units (ICU) addressing anticoagulation and drug-based prophylaxis of venous thromboembolism (VTE) in patients with sepsis and sepsis-induced coagulopathy. One focus was the procedure for patients with a pre-existing anticoagulation treatment or a previously known heparin-induced thrombocytopenia (HIT) type 2 (acute symptomatic vs. dating back years). RESULTS: In most of the participating ICUs pre-existing anticoagulation is largely continued with low molecular weight heparin preparations or unfractionated heparin. In patients with pre-existing HIT type 2 both acute symptomatic and dating back years, argatroban represents the drug of choice. There is a high degree of variability in the definition of the target values, usually being well above the range for pure VTE prophylaxis. CONCLUSION: Data on the continuation of anticoagulation beyond VTE prophylaxis with a subsequently increased risk of bleeding in patients with sepsis and septic shock is limited and treatment decisions are in many cases subject to individual consideration by the practitioner. The results of our survey imply the need for a systematic work-up of this topic in order to support daily practice in many ICUs with the required evidence.

Next-generation sequencing diagnostics of bacteremia in pediatric sepsis.

INTRODUCTION: Sepsis and septic shock are the most severe forms of infection affecting predominantly elderly people, preterm and term neonates, and young infants. Even in high-income countries sepsis causes about 8% of admissions to pediatric intensive care units (PICUs). Early diagnosis, rapid anti-infective treatment, and prompt hemodynamic stabilization are crucial for patient survival. In this context, it is essential to identify the causative pathogen as soon as possible to optimize antimicrobial treatment. To date, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care. However, they have 2 major problems: on the one hand, in the case of very small sample volumes (and thus usually in children), they are not sufficiently sensitive. On the other hand, with a time-to-result of 2 to 5 days, blood cultures need a relatively long time for the anti-infective therapy to be calculated. To overcome these problems, culture-independent molecular diagnostic procedures such as unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) have been tested successfully in adult septic patients. However, these results still need to be transferred to the pediatric setting. METHODS: The Next GeneSiPS-Trial is a prospective, observational, non-interventional, multicenter study used to assess the diagnostic performance of an NGS-based approach for the identification of causative pathogens in (preterm and term) neonates (d1-d28, n = 50), infants (d29 to <1 yr, n = 50), and toddlers (1 yr to <5 yr, n = 50) with suspected or proven severe sepsis or septic shock (according to the pediatric sepsis definition) by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard of care (culture-based) microbiological diagnostics. Potential changes in anti-infective treatment regimens based on these NGS results will be estimated retrospectively by a panel of 3 independent clinical specialists. DISCUSSION: Neonates, infants, and young children are significantly affected by sepsis. Fast and more sensitive diagnostic approaches are urgently needed. This prospective, observational, non-interventional, multicenter study seeks to evaluate an NGS-based approach in critically ill children suffering from sepsis. TRIAL REGISTRATION: DRKS-ID: DRKS00015705 (registered October 24, 2018). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00015705.

[Treatment of sepsis-induced coagulopathy : Results of a Germany-wide survey in intensive care units]. / Therapie der sepsisinduzierten Koagulopathie : Ergebnisse einer deutschlandweiten Umfrage auf Intensivstationen.

BACKGROUND: In the context of sepsis and septic shock, coagulopathy often occurs due to the close relationship between coagulation and inflammation. Sepsis-induced coagulopathy (SIC) is the most severe and potentially fatal form. Anticoagulants used in prophylactic or therapeutic doses are discussed to potentially exert beneficial effects in patients with sepsis and/or SIC; however, due to the lack of evidence recent guidelines are limited to recommendations for drug prophylaxis of venous thromboembolism (VTE), while treatment of SIC has not been addressed. METHODS: In order to determine the status quo of VTE prophylaxis as well as treatment of SIC in German intensive care units (ICU), we conducted a Germany-wide online survey among heads of ICUs from October 2019 to May 2020. In April 2020, the survey was supplemented by an additional block of questions on VTE prophylaxis and SIC treatment in coronavirus disease 2019 (COVID-19) patients. RESULTS: A total of 67 senior doctors took part in the survey. The majority (n = 50; 74.6%) of the responses were from ICU under the direction of an anesthesiologist and/or a department of anesthesiology. Most of the participants worked either at a university hospital (n = 31; 47.8%) or an academic teaching hospital (n = 27; 40.3%). The survey results show a pronounced heterogeneity in clinical practice with respect to the prophylaxis of VTE as well as SIC treatment. In an exemplary case of pneumogenic sepsis, low molecular weight heparins (LMWH) were by far the most frequently mentioned group of medications (n = 51; 76.1% of the responding ITS). In the majority of cases (n = 43; 64.2%), anti-FXa activity is not monitored with the use of LMWH in prophylaxis doses. Unfractionated heparin (UFH) was listed as a strategy for VTE prophylaxis in 37.3% of the responses (n = 25). In an exemplary case of abdominal sepsis 54.5% of the participants (n = 36; multiple answers possible) stated the use of UFH or LMWH and UFH with dosage controlled by PTT is used on two participating ICUs. The anti-FXa activity under prophylactic anticoagulation with LMWH is monitored in 7 participating clinics (10.6%) in abdominal sepsis. Systematic screening for sepsis-associated coagulation disorders does not take place in most hospitals and patterns in the use of anticoagulants show significant variability between ICUs. In the case of COVID-19 patients, it is particularly noticeable that in three quarters of the participating ICUs the practice of drug-based VTE prophylaxis and SIC treatment does not differ from that of non-COVID-19 patients. CONCLUSION: The heterogeneity of answers collected in the survey suggests that a systematic approach to this topic via clinical trials is urgently needed to underline individualized patient care with the necessary evidence.

The anesthetist's choice of inhalational vs. intravenous anesthetics has no impact on survival of glioblastoma patients.

Recent data suggest that the type of anesthesia used during the resection of solid tumors impacts the long-term survival of patients favoring total-intravenous-anesthesia (TIVA) over inhalative-anesthesia (INHA). Here we sought to query this impact on survival in patients undergoing resection of glioblastoma (GBM). All patients receiving elective resection of a newly diagnosed, isocitrate-dehydrogenase-1-(IDH1)-wildtype GBM under general anesthesia between January 2010 and June 2017 in the Department of Neurosurgery, Heidelberg University Hospital, were included. Patients were grouped according to the applied anesthetic technique. To adjust for potential prognostic confounders, patients were matched in a 1:2 ratio (TIVA vs. INHA), taking into account the known prognostic factors: age, extent of resection, O-6-methylguanine-DNA-methyltransferase-(MGMT)-promoter-methylation-status, pre-operative Karnofsky-performance-index and adjuvant radio- and chemotherapy. The primary endpoint was progression-free-survival (PFS) and the secondary endpoint was overall-survival (OS). In the study period, 576 patients underwent resection of a newly diagnosed, IDH-wildtype GBM. Patients with incomplete follow-up-data, on palliative treatment, having emergency or awake surgery; 54 patients remained in the TIVA-group and 417 in the INHA-group. After matching, 52 patients remained in the TIVA-group and 92 in the INHA-group. Median PFS was 6 months in both groups. The median OS was 13.5 months in the TIVA-group and 13.0 months in the INHA-group. No significant survival differences associated with the type of anesthesia were found either before or after adjustment for known prognostic factors. This retrospective study supports the notion that the current anesthetic approaches employed during the resection of IDH-wildtype GBM do not impact patient survival.

[Diagnostic Approaches in Sepsis - Part 1: General Diagnostic Principles, Focus Identification and Source Control]. / Diagnostik der Sepsis ­ Teil 1: allgemeine Diagnostik und Fokussuche-/sanierung.

Sepsis and septic shock represent medical emergencies with persistently high mortality rates. According to the lately revised Surviving Sepsis Campaign (SSC) guidelines, focus identification/pathogen detection and the initial administration of broad-spectrum antibiotics are to be secluded within one hour after recognition of the symptoms of sepsis. However, there is dispute concerning the so called hour-1 bundle. Being a core aspect of focus identification, imaging modalities mainly depend on the suspected site of infection and the individual patient. Contrast agent-enhanced computed tomography (CT) is the modality usually used in critically ill patients. The microbiological pathogen detection still largely remains culture-based. This emphasizes the significance of microbiological specimen obtained from easily accessible body compartments and at least 2 blood culture sets. If possible, blood cultures should be drawn prior to antibiotic administration. Intraoperatively obtained swabs of otherwise sterile body compartments are of utmost importance with regard to microbiological pathogen detection. Catheters and implanted medical devices (i.e. cardiac pacemakers or defibrillators) suspicious of infection should be explanted and sent in for microbiological workup as soon as possible. All necessary source control measures should be realized as soon as medically possible but at least within 6 - (12) hours after the onset of symptoms. There is no specific biomarker for sepsis so far. Procalcitonin (PCT) and C-reactive protein (CRP) are crucial biomarkers in terms of infectious disease management and guidance of antimicrobial therapy in the ICU. Positive clinical trials showed that biomarkers like the midregional pro-adrenomedullin (MR-proADM) or presepsin might be promising candidates in the diagnosis of sepsis in the future. As an important marker of microcirculatory failure and disrupted cell metabolism, lactate serum concentrations (and lactate-clearance, respectively) are of prognostic value in septic patients.

[Diagnostic Approaches in Sepsis - Part 2: Pathogen Detection]. / Diagnostik der Sepsis ­ Teil 2: Erregeridentifikation.

Despite the dissemination of innovative, molecular biology-based and commercially available devices for pathogen detection, culture-based methods with susceptibility testing remain the key principles for guiding antimicrobial treatment of patients suffering from sepsis or septic shock on the ICU. Culture-based methods are able to facilitate pathogen detection from a diversity of specimen (respiratory secretion, intraoperatively obtained smears, aspirates, and so forth). However, the latency from obtainment of the specimen up to pathogen detection with susceptibility testing is a major disadvantage of culture-based methods in critical illness. Molecular biology-based methods like Polymerase Chain Reaction (PCR) and especially Next-Generation Sequencing (NGS) based methods promise faster pathogen and resistance detection, but are not used in clinical routine yet. With more clinical trials to come, these innovative diagnostic tools may have the potential to lead to a paradigm shift within the context of pathogen identification in sepsis.

Cell cycle arrest and cell death correlate with the extent of ischaemia and reperfusion injury in patients following kidney transplantation - results of an observational pilot study.

A prolonged cold ischaemia time (CIT) is suspected to be associated with an increased ischaemia and reperfusion injury (IRI) resulting in an increased damage to the graft. In total, 91 patients were evaluated for a delayed graft function within 7 days after kidney transplantation (48 deceased, 43 living donors). Blood and urine samples were collected before, immediately after the operation, and 1, 3, 5, 7 and 10 days later. Plasma and/or urine levels of total keratin 18 (total K18), caspase-cleaved keratin 18 (cc K18), the soluble receptor for advanced glycation end products (sRAGE), tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein-7 (IGFBP7) were measured. As a result of prolonged CIT and increased IRI, deceased donor transplantations were shown to suffer from a more distinct cell cycle arrest and necrotic cell death. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 were therefore demonstrated to be of value for the detection of a delayed graft function (DGF), as they improved the diagnostic performance of a routinely used clinical scoring system. Plasmatic total K18 and urinary TIMP-2 and IGFBP7 measurements are potentially suitable for early identification of patients at high risk for a DGF following kidney transplantation from deceased or living donors.

Next-generation sequencing diagnostics of bacteremia in sepsis (Next GeneSiS-Trial): Study protocol of a prospective, observational, noninterventional, multicenter, clinical trial.

BACKGROUND: Sepsis remains a major challenge, even in modern intensive care medicine. The identification of the causative pathogen is crucial for an early optimization of the antimicrobial treatment regime. In this context, culture-based diagnostic procedures (e.g., blood cultures) represent the standard of care, although they are associated with relevant limitations. Accordingly, culture-independent molecular diagnostic procedures might be of help for the identification of the causative pathogen in infected patients. The concept of an unbiased sequence analysis of circulating cell-free DNA (cfDNA) from plasma samples of septic patients by next-generation sequencing (NGS) has recently been identified to be a promising diagnostic platform for critically ill patients suffering from bloodstream infections. Although this new approach might be more sensitive and specific than culture-based state-of-the-art technologies, additional clinical trials are needed to exactly define the performance as well as clinical value of a NGS-based approach. METHODS: Next GeneSiS is a prospective, observational, noninterventional, multicenter study to assess the diagnostic performance of a NGS-based approach for the detection of relevant infecting organisms in patients with suspected or proven sepsis [according to recent sepsis definitions (sepsis-3)] by the use of the quantitative sepsis indicating quantifier (SIQ) score in comparison to standard (culture-based) microbiological diagnostics. The clinical value of this NGS-based approach will be estimated by a panel of independent clinical specialists, retrospectively identifying potential changes in patients' management based on NGS results. Further subgroup analyses will focus on the clinical value especially for patients suffering from a failure of empiric treatment within the first 3 days after onset [as assessed by death of the patient or lack of improvement of the patient's clinical condition (in terms of an inadequate decrease of SOFA-score) or persistent high procalcitonin levels]. DISCUSSION: This prospective, observational, noninterventional, multicenter study for the first time investigates the performance as well as the clinical value of a NGS-based approach for the detection of bacteremia in patients with sepsis and may therefore be a pivotal step toward the clinical use of NGS in this indication. TRIAL REGISTRATION: DRKS-ID: DRKS00011911 (registered October 9, 2017) https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011911; ClinicalTrials.gov Identifier: NCT03356249 (registered November 29, 2017) https://clinicaltrials.gov/ct2/show/NCT03356249.

The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology.

Sepsis remains one of the leading causes of death in intensive care units. Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death. The concomitant profound metabolic changes are characterized by hyperglycemia, insulin resistance, and profound transformations of the intracellular energy supply in both peripheral and immune cells. A further hallmark of the early phases of sepsis is a massive formation of reactive oxygen (ROS; e.g., superoxide) as well as nitrogen (RNS; e.g., nitric oxide) species. Reactive carbonyl species (RCS) form a third crucial group of highly reactive metabolites, which until today have been not the focus of interest in sepsis. However, we previously showed in a prospective observational clinical trial that patients suffering from septic shock are characterized by significant methylglyoxal (MG)-derived carbonyl stress, with the glyoxalase system being downregulated in peripheral blood mononuclear cells. In this review, we give a detailed insight into the current state of research regarding the metabolic changes that entail an increased MG-production in septicemia. Thus, we point out the special role of the glyoxalase system in the context of sepsis.

Soluble TREM-1 as a diagnostic and prognostic biomarker in patients with septic shock: an observational clinical study.

OBJECTIVES: The impact of TREM-1-mediated inflammation was investigated in different inflammatory settings. METHODS: Secondary analyses of an observational clinical pilot study, including 60 patients with septic shock, 30 postoperative controls and 30 healthy volunteers. RESULTS: Plasma levels of sTREM-1 were found to identify patients with septic shock more effectively than procalcitonin and C-reactive protein. Moreover, sTREM-1 was identified to be an early predictor for survival in patients with septic shock. CONCLUSION: Due to its diagnostic as well as prognostic value in sepsis syndrome, implementation of sTREM-1 measurements in routine diagnostics should be taken into account.

RAGE-mediated inflammation in patients with septic shock.

BACKGROUND: The receptor for advanced glycation end-products (RAGE)-pathway is described to be a crucial component of the innate immune response in sepsis. The aims of the present study were, therefore, to delineate the kinetics of membrane-bound RAGE expression, to quantify its soluble isoforms, and to determine the extent of metabolic (e.g., AGE-CML) as well as immunologic (e.g., S100A8/A9) ligands in different inflammatory settings in humans. MATERIALS AND METHODS: The presented data result from secondary analyses of an observational clinical pilot study, including patients with septic shock (n = 60), postoperative controls (n = 30), and healthy volunteers (n = 30). Surface-bound expression of RAGE by peripheral blood leukocytes was determined by flow cytometry. In addition, plasma levels of sRAGE, esRAGE, AGE-CML, S100A8/A9, S100A8/A9-CML, RBP, RBP-CML, HSA-CML, HMBG-1, and ß-Amyloid were measured using ELISA. RESULTS: In patients with septic shock, RAGE expression was significantly increased in comparison to both control groups, which was paralleled by a significant increase in sRAGE plasma levels. Formation of AGE-CML was shown to be dependent on the availability of the unmodified protein. However, the total amount of AGE-CML did not differ significantly between septic patients and healthy volunteers at early stages or was even lower in patients with sepsis at later stages. In contrast, immunologic ligands (e.g., S100A8/A9) were shown to be significantly elevated in septic patients within the entire study period. CONCLUSIONS: Activation of the RAGE-pathway was shown to be of relevance in patients with septic shock, mainly driven by an increase in immunologic (e.g., S100A8/A9) rather than metabolic ligands (e.g., CML-derived AGE-formation).

Combined Treatment of ATRA with Epigenetic Drugs Increases Aggressiveness of Glioma Xenografts.

BACKGROUND/AIM: Recently, anti-tumourigenic effects of all-trans-retinoic-acid (ATRA) on glioblastoma stem cells were demonstrated. Therefore we investigated if these beneficial effects could be enhanced by co-medication with epigenetic drugs such as the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) or the DNA-methyltransferase inhibitor 5-aza-2'deoxycytidine (5-AZA). MATERIALS AND METHODS: Glioma stem cell xenografts were treated for 42 days with ATRA plus SAHA or ATRA plus 5-AZA or the correspondent monotherapies. Tumour sizes, histological features, proliferation and apoptosis rates were assessed. RESULTS: Neither SAHA nor 5-AZA were able to enhance the anti-tumourigenic effect of ATRA. Instead, tumours became more aggressive. Combination of ATRA plus 5-AZA increased tumour size (p<0.05) and induced more frequent and larger necroses (p<0.05) and tumours were more invasive (p<0.05) in comparison to controls. A similar trend was observed for the combination of ATRA plus SAHA. CONCLUSION: Combining ATRA with epigenetic drug therapies led to the unwanted opposite effect and increased aggressiveness of glioma xenografts, arguing against future clinical applications of such combinations.