Impact of carbohydrate-reduced nutrition in septic patients on ICU: study protocol for a prospective randomised controlled trial

Introduction: Sepsis is defined as detrimental immune response to an infection. This overwhelming reaction often abolishes a normal reconstitution of the immune cell homeostasis that in turn increases the risk for further complications. Recent studies revealed a favourable impact of ketone bodies on resolution of inflammation. Thus, a ketogenic diet may provide an easy-to-apply and cost-effective treatment option potentially alleviating sepsis-evoked harm. This study is designed to assess the feasibility, efficiency and safety of a ketogenic diet in septic patients. Methods and analysis: This monocentric study is a randomised, controlled and open-label trial, which is conducted on an intensive care unit of a German university hospital. As intervention enteral nutrition with reduced amount of carbohydrates (ketogenic) or standard enteral nutrition (control) is applied. The primary endpoint is the detection of ketone bodies in patients' blood and urine samples. As secondary endpoints, the impact on important safety-relevant issues (eg, glucose metabolism, lactate serum concentration, incidence of metabolic acidosis, thyroid function and 30-day mortality) and the effect on the immune system are analysed. Ethics and dissemination The study has received the following approvals: Ethics Committee of the Medical Faculty of Ruhr-University Bochum (No. 18-6557-BR). Results will be made available to critical care survivors, their caregivers, the funders, the critical care societies and other researchers by publication in a peer-reviewed journal

Decreased protein binding of moxifloxacin in patients with sepsis?

The mean (SD) unbound fraction of moxifloxacin in plasma from patients with severe sepsis or septic shock was determined by ultrafiltration to 85.5±3.0% (range 81.9 and 91.6%) indicating a decreased protein binding of moxifloxacin in this population compared with the value of 58–60% provided in the Summary of Product Characteristics. However, previous investigations neglected the influence of pH and temperature on the protein binding of moxifloxacin. Maintaining physiological conditions (pH 7.4, 37°C) – as in the present study – the unbound fraction of moxifloxacin in plasma from healthy volunteers was 84%. In contrast, the unbound fraction of moxifloxacin was 77% at 4°C and 66–68% in unbuffered plasma or at pH 8.5 in fair agreement with previously published data. PK/PD parameters e.g. fAUC/MIC or ratios between interstitial fluid and free plasma concentrations, which were obtained assuming a protein binding rate of moxifloxacin of 40% or more, should be revised

Hypoxia Inducible Factor-2Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS)

Hypoxia-inducible-factor-2 alpha (HIF-2 alpha) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2 alpha (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T;SNP rs516651 and T/C;SNP rs480902) are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs' prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2 alpha or PHD2 genes are (1) common, and (2) independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay) and HIF-2 alpha-polymorphism (restriction digest + agarose-gel visualization), and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2 alpha CC-carriers (CG: 0.38%;GG: 0%), 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%;CC: 78.8%), and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%;CC: 52.4%). PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09-10.22;p = 0.034) within 30-days, whereas the other SNPs had no significant impact (p = ns). The homozygous HIF-2 alpha GG-genotype was not present in our Caucasian ARDS cohort;however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS

German-wide prospective DACAPO cohort of survivors of the acute respiratory distress syndrome (ARDS): a cohort profile

Purpose While most research focuses on the association between medical characteristics and residual morbidity of survivors of the acute respiratory distress syndrome (ARDS), little is known about the relation between potentially modifiable intensive care unit (ICU) features and the course of health-related quality of life (HRQoL). Accordingly, the DACAPO study was set up to elucidate the influence of quality of intensive care on HRQoL and return to work (RtW) in survivors of ARDS. The continued follow-up of these former ICU patients leads to the establishment of the DACAPO (survivor) cohort. Participants Sixty-one ICUs all over Germany recruited patients with ARDS between September 2014 and April 2016. Inclusion criteria were: (1) age older than 18 years and (2) ARDS diagnosis according to the ‘Berlin definition’. No further inclusion or exclusion criteria were applied. 1225 patients with ARDS could be included in the DACAPO ICU sample. Subsequently, the 876 survivors at ICU discharge form the actual DACAPO cohort. Findings to date The recruitment of the participants of the DACAPO cohort and the baseline data collection has been completed. The care-related data of the DACAPO cohort reveal a high proportion of adverse events (in particular, hypoglycaemia and reintubation). However, evidence-based supportive measures were applied frequently. Future plans Three months, 6 months and 1 year after ICU admission a follow-up assessment is conducted. The instruments of the follow-up questionnaires comprise the domains: (A) HRQoL, (B) RtW, (C) general disability, (D) psychiatric symptoms and (E) social support. Additionally, an annual follow-up of the DACAPO cohort focusing on HRQoL, psychiatric symptoms and healthcare utilisation will be conducted. Furthermore, several add-on projects affecting medical issues are envisaged

German-wide prospective DACAPO cohort of survivors of the acute respiratory distress syndrome (ARDS): a cohort profile

Purpose While most research focuses on the association between medical characteristics and residual morbidity of survivors of the acute respiratory distress syndrome (ARDS), little is known about the relation between potentially modifiable intensive care unit (ICU) features and the course of health-related quality of life (HRQoL). Accordingly, the DACAPO study was set up to elucidate the influence of quality of intensive care on HRQoL and return to work (RtW) in survivors of ARDS. The continued follow-up of these former ICU patients leads to the establishment of the DACAPO (survivor) cohort. Participants Sixty-one ICUs all over Germany recruited patients with ARDS between September 2014 and April 2016. Inclusion criteria were: (1) age older than 18 years and (2) ARDS diagnosis according to the 'Berlin definition'. No further inclusion or exclusion criteria were applied. 1225 patients with ARDS could be included in the DACAPO ICU sample. Subsequently, the 876 survivors at ICU discharge form the actual DACAPO cohort. Findings to date The recruitment of the participants of the DACAPO cohort and the baseline data collection has been completed. The care-related data of the DACAPO cohort reveal a high proportion of adverse events (in particular, hypoglycaemia and reintubation). However, evidence-based supportive measures were applied frequently. Future plans Three months, 6 months and 1 year after ICU admission a follow-up assessment is conducted. The instruments of the follow-up questionnaires comprise the domains: (A) HRQoL, (B) RtW, (C) general disability, (D) psychiatric symptoms and (E) social support. Additionally, an annual follow-up of the DACAPO cohort focusing on HRQoL, psychiatric symptoms and healthcare utilisation will be conducted. Furthermore, several add-on projects affecting medical issues are envisaged

Personalized medicine with IgGAM compared with standard of care for treatment of peritonitis after infectious source control (the PEPPER trial): study protocol for a randomized controlled trial

Background: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum). Methods/design: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival. Discussion: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine. Trial registration: EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017. Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort)

Biomarker-guided intervention to prevent acute kidney injury after major surgery (BigpAK-2 trial): study protocol for an international, prospective, randomised controlled multicentre trial

IntroductionPrevious studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysisThe BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and disseminationThe BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration numberNCT04647396