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Background: Prehabilitation is gaining increasing interest and shows promising effects on short- and long-term outcomes among patients undergoing major surgery. The effect of multimodal, interdisciplinary prehabilitation has not yet been studied in patients with severe heart failure scheduled for the implantation of a left-ventricular assist device (LVAD). Methods: This randomized controlled multi-center study evaluates the effect of preoperative combined optimization of nutritional and functional status. Patients in the intervention group are prescribed daily in-bed cycling and oral nutrition supplements (ONS) from study inclusion until the day before LVAD-implantation. Patients in the control group receive standard of care treatment. The primary outcomes for the pilot study that involves 48 patients are safety (occurrence of adverse events), efficacy (group separation regarding the intake of macronutrients), feasibility of the trial protocol (compliance (percentage of received interventions) and confirmation of recruitment rates. Secondary outcomes include longitudinal measurements of muscle mass, muscle strength, physical function and quality of life, next to traditional clinical outcomes (30-day mortality, hospital and ICU length of stay, duration of mechanical ventilation and number of complications and infections). If the pilot study is successful, a larger confirmatory, international multicenter study is warranted.

Concise definitive review of how to read and critically appraise a systematic review.None.Current literature describing the conduct, reporting, and appraisal of systematic reviews and meta-analyses.Best practices for conducting, reporting, and appraising systematic review were summarized.A systematic review is a review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant original research, and to collect and analyze data from the studies that are included in the review. Critical appraisal methods address both the credibility (quality of conduct) and rate the confidence in the quality of summarized evidence from a systematic review. The A Measurement Tool to Assess Systematic Reviews-2 tool is a widely used practical tool to appraise the conduct of a systematic review. Confidence in estimates of effect is determined by assessing for risk of bias, inconsistency of results, imprecision, indirectness of evidence, and publication bias.Systematic reviews are transparent and reproducible summaries of research and conclusions drawn from them are only as credible and reliable as their development process and the studies which form the systematic review. Applying evidence from a systematic review to patient care considers whether the results can be directly applied, whether all important outcomes have been considered, and if the benefits are worth potential harms and costs.

ZusammenfassungDieses zweite Positionspapier der Sektion Metabolismus und Ernährung der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI) gibt Empfehlungen zum laborchemischen Monitoring der Makro- und Mikronährstoffzufuhr sowie zum Einsatz der indirekten Kalorimetrie im Rahmen der medizinischen Ernährungstherapie erwachsener Intensivpatient:innen. Zusätzlich werden Empfehlungen zur krankheitsbezogenen bzw. individuellen (Spiegelbestimmung) Substitution und (Hochdosis‑)Pharmakotherapie von Vitaminen und Spurenelementen vorgenommen.

Background A recent landmark randomized controlled trial (RCT) in septic patients demonstrated an increased risk of death and persistent organ dysfunction with intravenous Vitamin C (IVVC) monotherapy, which represents a disparate result from previous systematic reviews and meta-analyses (SRMA). We performed an updated SRMA of IVVC monotherapy to summarize and explore heterogeneity across current trials and conduct trial sequential analysis (TSA) to guard against type-I or type-II statistical errors. Methods RCTs evaluating IVVC in adult critically ill patients were included. Four databases were searched from inception to 22 June 2022 without language restrictions. The primary outcome was overall mortality. Random effect meta-analysis was performed to estimate the pooled risk ratio. TSA for mortality was performed using the DerSimonian–Laird random effect model, alpha 5%, beta 10%, and relative risk reduction (RRR) of 30%, 25%, and 20%. Results We included 16 RCTs (n = 2130). IVVC monotherapy is associated with significant reduction in overall mortality [risk ratio (RR) 0.73, 95% confidence interval (CI) 0.60–0.89; p = 0.002; I2 = 42%]. This finding is supported by TSA using RRR of 30% and 25%, and sensitivity analysis using fixed-effect meta-analysis. However, the certainty of our mortality finding was rated low using GRADE due to the serious risk of bias and inconsistency. In a priori subgroup analyses, we found no differences between single vs multicenter, higher (≥ 10,000 mg/day) vs lower dose and sepsis vs non-sepsis trials. Post-hoc, we found no differences in subgroup analysis of earlier ( 4 days) vs shorter treatment duration, and low vs other risk of bias studies. IVVC may have the greatest benefit in trials that enrolled patients above (i.e., > 37.5%; RR 0.65, 95% CI 0.54–0.79) vs below (i.e., ≤ 37.5%; RR 0.89, 95% CI 0.68–1.16) median control group mortality (test for subgroup differences: p = 0.06), and TSA supported this. Conclusions IVVC monotherapy may be associated with mortality benefits in critically ill patients, particularly in patients with a high risk of dying. Given the low certainty of evidence, this potentially life-saving therapy warrants further studies to identify the optimal timing, dosage, treatment duration, and patient population that will benefit most from IVVC monotherapy. PROSPERO Registration ID: CRD42022323880. Registered 7th May 2022.

IntroductionVarious clinical scores have been developed to predict organ dysfunction and mortality in patients undergoing cardiac surgery, but outcome prediction may be inaccurate for some patient groups. Proenkephalin A (penKid) and bioactive adrenomedullin (bio-ADM) have emerged as promising biomarkers correlating with shock and organ dysfunction. This imposes the question of whether they can be used as prognostic biomarkers for risk stratification in the perioperative setting of cardiac surgery.MethodsPatients undergoing cardiac surgery were prospectively enrolled in this observational study. PenKid and bio-ADM plasma levels, as well as markers evaluating inflammation and organ dysfunction, were measured at five perioperative time points from before the induction of anesthesia to up to 48 h postoperatively. Clinical data regarding organ dysfunction and patient outcomes were recorded during the intensive care unit (ICU)-stay with a special focus on acute kidney injury (AKI).ResultsIn 136 patients undergoing cardiac surgery, the bio-ADM levels increased and the penKid levels decreased significantly over time. PenKid was associated with chronic kidney disease (CKD), the incidence of AKI, and renal replacement therapy (RRT). Bio-ADM was associated with lactate and the need for vasopressors. PenKid was useful to predict an ICU-length of stay (LOS)>1 day and added prognostic value to the European System for Cardiac Operative Risk Evaluation Score (EuroSCORE) II when measured after the end of cardiopulmonary bypass and 24 h after cardiac surgery. For bio-ADM, the same was true when measured 24 h after surgery. PenKid also added prognostic value to the EuroSCORE II for the combined outcome “ICU length of stay >1 day and in-hospital mortality.”ConclusionThe combination of preoperative EuroSCORE II and intraoperative measurement of penKid may be more useful to predict a prolonged ICU LOS and increased mortality than EuroSCORE II alone. Bio-ADM correlates with markers of shock. More research is encouraged for early risk stratification and validation of penKid and bio-ADM as a tool involved in clinical decisions, which may enable the early initiation of organ protective strategies.

ObjectiveInflammation is increasingly recognized to be involved in the pathophysiology of aneurysmal subarachnoid hemorrhage (aSAH) and may increase the susceptibility to delayed cerebral ischemia (DCI). Macrophage migration inhibitory factor (MIF) has been shown to be elevated in serum and cerebrospinal fluid (CSF) after aSAH. Here, we determined MIF levels in serum, CSF and cerebral microdialysate (MD) at different time-points after aSAH and evaluated their clinical implications.MethodsMIF levels were measured in serum, CSF and MD obtained from 30 aSAH patients during early (EPd1−4), critical (CPd5−15) and late (LPd16−21) phase after hemorrhage. For subgroup analyses, patients were stratified based on demographic and clinical data.ResultsMIF levels in serum increased during CPd5−15 and decreased again during LPd16−21, while CSF levels showed little changes over time. MD levels peaked during EPd1−4, decreased during CPd5−15 and increased again during LPd16−21. Subgroup analyses revealed significantly higher serum levels in patients with aneurysms located in the anterior vs. posterior circulation during CPd5−15 (17.3 [15.1–21.1] vs. 10.0 [8.4–11.5] ng/ml, p = 0.009) and in patients with DCI vs. no DCI during CPd5−15 (17.9 [15.1–22.7] vs. 11.9 [8.9–15.9] ng/ml, p = 0.026) and LPd16−21 (17.4 [11.7–27.9] vs. 11.3 [9.2–12.2] ng/ml, p = 0.021). In addition, MIF levels in MD during CPd5−15 were significantly higher in patients with DCI vs. no DCI (3.6 [1.8–10.7] vs. 0.2 [0.1–0.7] ng/ml, p = 0.026), while CSF levels during the whole observation period were similar in all subgroups.ConclusionOur findings in a small cohort of aSAH patients provide preliminary data on systemic, global cerebral and local cerebral MIF levels after aSAH and their clinical implications.Clinical trial registrationClinicalTrials.gov, identifier: NCT02142166.

Many critically ill patients are vitamin D and vitamin C deficient and the current international guidelines state that hypovitaminoses should be compensated. However, uncertainty about optimal dosage, timing and indication exists in clinical routine, mainly due to the conflicting evidence. This narrative review discusses both micronutrients with regards to pathophysiology, clinical evidence of benefits, potential risks, and guideline recommendations. Evidence generated from the most recent clinical trials are summarized and discussed. In addition, pragmatic tips for the application of these vitamins in the clinical routine are given. The supplementations of vitamin D and C represent cost-effective and simple interventions with excellent safety profiles. Regarding vitamin D, critically ill individuals require a loading dose to improve 25(OH)D levels within a few days, followed by a daily or weekly maintenance dose, usually higher doses than healthy individuals are needed. For vitamin C, dosages of 100–200 mg/d are recommended for patients receiving parenteral nutrition, but needs may be as high as 2–3 g/d in acutely ill patients.

Journal of parenteral and enteral nutrition : JPEN 47(2), 220-235 (2023). doi:10.1002/jpen.2467, Published by Wiley, Hoboken, NJ

Over the past decade, the use of supraphysiologic doses of micronutrients (also called metabolic resuscitation) in critically ill patients has gained significant attention. Building upon preclinical and observational human data, numerous randomized controlled trials have tested the impact of multiple micronutrients on various outcomes in critically ill patients. At the 2022 American Society for Parenteral and Enteral Nutrition Preconference Course, three world-renowned speakers delivered talks on the (1) overall role of micronutrients and, specifically, (2) selenium and vitamin C and (3) vitamin D and zinc in critically ill patients. Here, the case presentation and discussion from the postsession question and answer period are presented. The moderator for this session was Jose Pimiento, MD, and the speakers and panelists were Christian Stoppe, MD, Todd Rice, MD, and Daren Heyland, MD.

Nature Communications 13, 3027 (2022). doi:10.1038/s41467-022-30682-0, Published by Nature Publishing Group UK, [London]

Glutamine is thought to have beneficial effects on the metabolic and stress response to severe injury. Clinical trials involving patients with burns and other critically ill patients have shown conflicting results regarding the benefits and risks of glutamine supplementation.In a double-blind, randomized, placebo-controlled trial, we assigned patients with deep second- or third-degree burns (affecting ≥10% to ≥20% of total body-surface area, depending on age) within 72 hours after hospital admission to receive 0.5 g per kilogram of body weight per day of enterally delivered glutamine or placebo. Trial agents were given every 4 hours through a feeding tube or three or four times a day by mouth until 7 days after the last skin grafting procedure, discharge from the acute care unit, or 3 months after admission, whichever came first. The primary outcome was the time to discharge alive from the hospital, with data censored at 90 days. We calculated subdistribution hazard ratios for discharge alive, which took into account death as a competing risk.A total of 1209 patients with severe burns (mean burn size, 33% of total body-surface area) underwent randomization, and 1200 were included in the analysis (596 patients in the glutamine group and 604 in the placebo group). The median time to discharge alive from the hospital was 40 days (interquartile range, 24 to 87) in the glutamine group and 38 days (interquartile range, 22 to 75) in the placebo group (subdistribution hazard ratio for discharge alive, 0.91; 95% confidence interval [CI], 0.80 to 1.04; P = 0.17). Mortality at 6 months was 17.2% in the glutamine group and 16.2% in the placebo group (hazard ratio for death, 1.06; 95% CI, 0.80 to 1.41). No substantial between-group differences in serious adverse events were observed.In patients with severe burns, supplemental glutamine did not reduce the time to discharge alive from the hospital. (Funded by the U.S. Department of Defense and the Canadian Institutes of Health Research; RE-ENERGIZE ClinicalTrials.gov number, NCT00985205.).

Objectives Cardiac support systems are being used increasingly more due to the growing prevalence of heart failure and cardiogenic shock. Reducing cardiac afterload, intracardiac pressure, and flow support are important factors. Extracorporeal membrane oxygenation (ECMO) and intracardiac microaxial pump systems (Impella) as non-permanent MCS (mechanical circulatory support) are being used increasingly. Methods We reviewed the recent literature and developed an international European registry for non-permanent MCS. Results Life-threatening conditions that are observed preoperatively often include reduced left ventricular function, systemic hypoperfusion, myocardial infarction, acute and chronic heart failure, myocarditis, and valve vitia. Postoperative complications that are commonly observed include severe systemic inflammatory response, ischemia-reperfusion injury, trauma-related disorders, which ultimately may lead to low cardiac output (CO) syndrome and organ dysfunctions, which necessitates a prolonged ICU stay. Choosing the appropriate device for support is critical. The management strategies and complications differ by system. The “heart-team” approach is inevitably needed.However despite previous efforts to elucidate these topics, it remains largely unclear which patients benefit from certain systems, when is the right time to initiate (MCS), which support system is appropriate, what is the optimal level and type of support, which therapeutic additive and supportive strategies should be considered and ultimately, what are the future prospects and therapeutic developments. Conclusion The European cardiac surgical register ImCarS has been established as an IIT with the overall aim to evaluate data received from the daily clinical practice in cardiac surgery. Interested colleagues are cordially invited to join the register. Clinical registration number: DRKS00024560. Positive Ethics Vote: AZ 246/20 Faculty of Medicine, Justus-Liebig-University-Gießen.

Clinical nutrition; Intensive care unit; Nutrition care Nutrició clínica; Unitat de cures intensives; Cura de la nutrició Nutrición Clínica; Unidad de cuidados intensivos; Cuidado de la nutrición A multidisciplinary group of international physicians involved in the medical nutrition therapy (MNT) of adult critically ill patients met to discuss the value, role, and open questions regarding supplemental parenteral nutrition (SPN) along with oral or enteral nutrition (EN), particularly in the intensive care unit (ICU) setting. This manuscript summarizes the discussions and results to highlight the importance of SPN as part of a comprehensive approach to MNT in critically ill adults and for researchers to generate new evidence based on well-powered randomized controlled trials (RCTs). The experts agreed on several key points: SPN has shown clinical benefits, resulting in this strategy being included in American and European guidelines. Nevertheless, its use is heterogeneous across European countries, due to the persistence of uncertainties, such as the optimal timing and the risk of overfeeding in absence of indirect calorimetry (IC), which results in divergent opinions and barriers to SPN implementation. Education is also insufficient. The experts agreed on actions needed to increase evidence quality on SPN use in specific patients at a given time point during acute critical illness or recovery. The organization of the Virtual Meeting that motivated this publication was funded by Baxter Healthcare SA. The authors received no financial support for the research, authorship, and/or publication of this article. MPC receives funding from the Research Foundation Flanders (FWO) (Grant No. 1832817N) and Onderzoeksraad, KU Leuven (Grant No. C24/17/070) and from the Private Charity Organization “Help Brandwonden Kids.

Introduction A need exists to improve the efficiency of clinical trials in burn care. The objective of this study was to validate “Persistent Organ Dysfunction” plus death as endpoint in burn patients and to demonstrate its statistical efficiency. Methods This secondary outcome analysis of a dataset from a prospective international multicenter RCT (RE-ENERGIZE) included patients with burned total body surface area >20% and a 6-month follow-up. Persistent organ dysfunction was defined as persistence of organ dysfunction with life-supportiing technologies and ICU care. Results In the 539 included patients, the prevalence of 0p p+ pdeath was 40% at day 14 and of 27% at day 28. At both timepoints, survivors with POD (vs. survivors without POD) had a higher mortality rate, longer ICU- and hospital-stays, and a reduced quality of life. POD + death as an endpoint could result in reduced sample size requirements for clinical trials. Detecting a 25% relative risk reduction in 28-day mortality would require a sample size of 4492 patients, whereas 1236 patients would be required were 28-day POD + death used. Conclusions POD + death represents a promising composite outcome measure that may reduce the sample size requirements of clinical trials in severe burns patients. Further validation in larger clinical trials is warranted. Study type Prospective cohort study, level of evidence: II

Elevated hydrogen sulfide (HIn adults with septic shock, is comparing high-dose IV hydroxocobalamin with placebo feasible?We conducted a phase 2 single-center, double-blind, allocation-concealed, placebo-controlled, parallel-group pilot randomized controlled trial comparing high-dose IV hydroxocobalamin with placebo in critically ill adults with septic shock. Patients meeting Sepsis 3 criteria were randomized 1:1 to receive a single 5-g dose of high-dose IV hydroxocobalamin or equivalent volume 0.9% saline solution as placebo. The primary outcome was study feasibility (enrollment rate, clinical and laboratory compliance rate, and contamination rate). Secondary outcomes included between-group differences in plasma HTwenty patients were enrolled over 19 months, establishing an enrollment rate of 1.05 patients per month. Protocol adherence rates were 100% with zero contamination. In the high-dose IV hydroxocobalamin group, compared to placebo, there was a greater reduction in vasopressor dose between randomization and postinfusion (-36% vs 4%, P .001) and randomization and 3-h postinfusion (-28% vs 10%, P = .019). In the high-dose IV hydroxocobalamin group, the plasma HThis pilot trial established favorable feasibility metrics. Consistent with the proposed mechanism of benefit, high-dose IV hydroxocobalamin compared with placebo was associated with reduced vasopressor dose and HClinicalTrials.gov; No.: NCT03783091; URL: www.gov.

Background: Minimally invasive surgery for left ventricular assist device implantation may have advantages over conventional sternotomy (CS). Additionally, ultra-fast-track anesthesia has been linked to better outcomes after cardiac surgery. This study summarizes our early experience of combining minimally invasive surgery with ultra-fast-track anesthesia (MIFTA) in patients receiving HeartMate 3 devices and compares the outcomes between MIFTA and CS. Methods: From October 2015 to January 2019, 18 of 49 patients with Interagency Registry for Mechanically Assisted Circulatory Support profiles >1 underwent MIFTA for HeartMate 3 implantation. For bias reduction, propensity scores were calculated and used as a covariate in a regression model to analyze outcomes. Weighted parametric survival analysis was performed. Results: In the MIFTA group, intensive care unit stays were shorter (mean difference, 8 days [95% CI, 4–13]; P P =0.016, respectively). At 6 and 12 hours postoperatively, MIFTA patients had a better hemodynamic performance with lower pulmonary wedge pressure (mean difference, 2.23 mm Hg [95% CI, 0.41–4.06]; P =0.028) and a higher right ventricular stroke work index (mean difference, −1.49 g·m/m 2 per beat [95% CI, −2.95 to −0.02]; P =0.031). CS patients had a worse right heart failure–free survival rate (hazard ratio, 2.35 [95% CI, 0.96–5.72]; P Conclusions: Compared with CS, MIFTA is a beneficial approach for non–Interagency Registry for Mechanically Assisted Circulatory Support 1 HeartMate 3 patients with lower adverse event incidences, better hemodynamic performance, and preserved right heart function. Future large multicentric investigations are required to verify MIFTA’s effects on outcomes.

Frontiers in immunology 13, 886421 (2022). doi:10.3389/fimmu.2022.886421 special issue: "Organ Cross Talk and its Impact on the Clinical Course in Multiple Trauma and Critical Illness", Published by Frontiers Media, Lausanne

Summary Background & aims Burn patients pose a number of clinical challenges for doctors and dietitians to achieve optimal nutrition practice. The objective of this study was to describe nutrition practices in burn center intensive care units (ICUs) compared to the most recent ESPEN and SCCM/ASPEN guidelines (hereafter referenced as “the Guidelines”) and highlight the variation in practice and what is “best achievable.” Methods In 2014–15, we prospectively enrolled 283 mechanically ventilated patients who were admitted to one of 14 burn ICUs for at least 72 h. Data collected included information on the estimation of energy and protein requirements, their actual delivery as well as route and time of feeding, and administration of micronutrients. We describe site practices and data per patient-day. Results Adherence to the Guidelines for the use of enteral nutrition (EN) over parenteral nutrition (PN) was 90.5% of patient-days (site range 79.2%–97.0%). However, adherence to the Guidelines for the measurement of energy requirements was 6.0% of patient-days (site range 0.0%–93.3%), supplementation with glutamine took place in 22.4% of patient-days (site range 0.0%–61.8%). Provision of 80% of energy requirements within 48–72 h was achieved in 35.3% of patients (site range 0.0%–80.0%), and provision of 80% of protein needs within 48–72 h was achieved in 34.3% of patients (site range 0.0%–80.0%). Average nutritional adequacy was 64.9 ± 40.0% for energy (best site: 80.2%, worst site: 42.0%) and 65.6 ± 42.1% for protein (best site: 87.3%, worst site: 43.6%). Conclusion The present findings indicate that despite high adherence to providing EN over PN, there is still a large gap between many recommendations and clinical practice, and the achievement of nutrition goals for patients in burn centers is suboptimal.

To determine the incidence of enteral feed intolerance, identify factors associated with enteral feed intolerance, and assess the relationship between enteral feed intolerance and key nutritional and clinical outcomes in critically ill patients.Analysis of International Nutrition Survey database collected prospectively from 2007 to 2014.Seven-hundred eighty-five ICUs from around the world.Mechanically ventilated adults with ICU stay greater than or equal to 72 hours and received enteral nutrition during the first 12 ICU days.None.We defined enteral feed intolerance as interrupted feeding due to one of the following reasons: high gastric residual volumes, increased abdominal girth, distension, subjective discomfort, emesis, or diarrhea. The current analysis included 15,918 patients. Of these, 4,036 (24%) had at least one episode of enteral feed intolerance. The enteral feed intolerance rate increased from 1% on day 1 to 6% on days 4 and 5 and declined daily thereafter. After controlling for site and patient covariates, burn (odds ratio 1.46; 95% CIs, 1.07-1.99), gastrointestinal (odds ratio 1.45; 95% CI, 1.27-1.66), and sepsis (odds ratio 1.34; 95% CI, 1.17-1.54) admission diagnoses were more likely to develop enteral feed intolerance, as compared to patients with respiratory-related admission diagnosis. enteral feed intolerance patients received about 10% less enteral nutrition intake, as compared to patients without enteral feed intolerance after controlling for important covariates including severity of illness. Enteral feed intolerance patients had fewer ventilator-free days and longer ICU length of stay time to discharge alive (all p0.0001). The daily mortality hazard rate increased by a factor of 1.5 (1.4-1.6; p0.0001) once enteral feed intolerance occurred.Enteral feed intolerance occurs frequently during enteral nutrition delivery in the critically ill. Burn and gastrointestinal patients had the highest risk of developing enteral feed intolerance. Enteral feed intolerance is associated with lower enteral nutrition delivery and worse clinical outcomes. Identification, prevention, and optimal management of enteral feed intolerance may improve nutrition delivery and clinical outcomes in important "at risk" populations.

This review provides an overview for health care teams involved in the perioperative care of cardiac surgery patients. The intention is to summarize key determinants of delirium, its impact on short- and long-term outcomes as well as to discuss effective management strategies. The first component of this review examines the prevalence and the factors associated with an increased risk of postoperative delirium. A multitude of predisposing (eg, baseline vulnerability and comorbidities) and precipitating (eg, type of cardiac surgery and postoperative care) factors that contribute to the occurrence of delirium are discussed.

Cardiac surgery is performed more often in a population with an increasing number of comorbidities. Although these surgeries can be lifesaving, they disturb homeostasis and may induce a temporary overall loss of physiologic function. The required postoperative intensive care unit and hospital stay often lead to a mid- to long-term decline of nutritional and physical status, mental health, and health-related quality of life. Prehabilitation before elective surgery might be an opportunity to optimize the state of the patient. This article discusses current evidence and potential effects of preoperative optimization of nutrition and physical status before cardiac surgery.

OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) initiates a deleterious cascade activating multiple inflammatory processes, which can contribute to delayed cerebral ischemia (DCI). Procalcitonin (PCT) is an established marker for sepsis treatment monitoring, and its time course in the context of DCI after aSAH remains unclear. The aim of this trial was to assess the predictive and confirmative value of PCT levels in the context of DCI. METHODS All patients admitted to the authors’ institution with aSAH between 2014 and 2018 were prospectively screened for eligibility. Daily PCT levels were recorded alongside relevant aSAH characteristics. The predictive and confirmative values of PCT levels were assessed using a receiver operating characteristic and area under the curve (AUC) analysis. The course of PCT levels around the DCI event was evaluated in an infection-free subgroup of patients. RESULTS A total of 132 patients with aSAH were included. Early PCT levels (first 3 days post-aSAH) had a low predictive value for the development of DCI (AUC 0.661, standard error [SE] 0.050; p = 0.003) and unfavorable long-term outcome (i.e., Glasgow Outcome Scale–Extended scores 1–4; AUC 0.674, SE 0.054; p = 0.003). In a subgroup analysis of infection-free patients (n = 72), PCT levels were higher in patients developing DCI (p = 0.001) and DCI-related cerebral infarction (p = 0.002). PCT concentrations increased gradually after DCI and decreased with successful intervention. In refractory cases progressing to cerebral infarction, PCT levels showed a secondary increase. CONCLUSIONS Early higher PCT levels were associated with the later development of DCI and unfavorable outcome. Analysis of PCT beyond the first couple of days after hemorrhage is hampered by nosocomial infections. In infection-free patients, however, PCT levels rise during DCI and an additional increase develops in patients developing cerebral infarction. Clinical trial registration no.: NCT02142166 (clinicaltrials.gov)

While medical nutrition therapy is an essential part of the care for critically ill patients, uncertainty exists about the right form, dosage, timing and route in relation to the phases of critical illness. As enteral nutrition (EN) is often withheld or interrupted during the intensive care unit (ICU) stay, combined EN and parenteral nutrition (PN) may represent an effective and safe option to achieve energy and protein goals as recommended by international guidelines. We hypothesise that critically ill patients at high nutritional risk may benefit from such a combined approach during their stay on the ICU. Therefore, we aim to test if an early combination of EN and high-protein PN (EN+PN) is effective in reaching energy and protein goals in patients at high nutritional risk, while avoiding overfeeding. This approach will be tested in the here-presented EFFORTcombo trial. Nutritionally high-risk ICU patients will be randomised to either high (≥2·2 g/kg per d) or low protein (≤1·2 g/kg per d). In the high protein group, the patients will receive EN+PN; in the low protein group, patients will be given EN alone. EN will be started in accordance with international guidelines in both groups. Efforts will be made to reach nutrition goals within 48–96 h. The efficacy of the proposed nutritional strategy will be tested as an innovative approach by functional outcomes at ICU and hospital discharge, as well as at a 6-month follow-up.

Background and objectives Coronary artery disease (CAD) is the number one cause of death worldwide. The If channel inhibitor ivabradine serves as second line medication for the CAD leading symptom angina pectoris. This systematic review and meta-analysis assess the existing evidence of ivabradine in angina pectoris. Methods We systematically searched MEDLINE, Embase, CENTRAL, and Web of Science (September 2019) for randomized controlled trials (RCTs) that compared ivabradine versus placebo, standard therapy (ST) or other anti-anginal drugs. Two review authors independently assessed trials for inclusion and performed data extraction. We completed a 'risk of bias' assessment for all studies and assessed quality of the trial evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. We meta-analysed data were applicable and calculated mean differences (MDs) and risk ratios using a random-effects model. Results A total of 11 RCTs (n=16,039) were included. Compared to placebo/ST, we found significant effects on the frequency of hospitalisation in a small cohort (n=90; hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.04, -0.92; p=0.04), but no effects on cardiovascular mortality (n=19,102; HR, 1.10; 95% CI, 0.94, 1.28; p=0.25) or the frequency of angina pectoris episodes (n=167; weighted MD, -1.06; 95% CI, -2.74, -0.61; p=0.21). Conclusions The present work makes an important contribution to optimal patient care in angina pectoris by complementing the current European Society of Cardiology guideline-recommending class IIa with evidence level B-decisively with 8 further studies.

ZusammenfassungDie Ernährungstherapie des einzelnen Intensivpatienten stellt im klinischen Alltag oft eine Herausforderung dar: Nicht nur die Schwere der akuten Erkrankung – auch das Alter, Komorbiditäten, Ernährungszustand und der erwartete Verlauf sind zu berücksichtigen. Dieser Beitrag beschreibt basierend auf nationalen und internationalen Leitlinien die zurzeit empfohlene Ernährungstherapie für verschiedene Patientengruppen in der Intensivmedizin.

Der ethische Bezugsrahmen zur Durchfuhrung einer Flussigkeitstherapie in der palliativmedizinischen Versorgung am Lebensende kann sehr unterschiedlich gewahlt werden. Welche ethischen Implikationen gilt es wahrend einer Dehydration am Lebensende zu beachten und gibt es besondere Anforderungen im Umgang mit der „terminalen“ Dehydration? Es wurde eine umfassende Literatursuche durchgefuhrt, um relevante Artikel in englischer und deutscher Sprache zu identifizieren. Unsere Schlussfolgerungen reprasentieren eher eine Haltung als eine evidenzbasierte Position – eine Tatsache, die auf den zugrunde liegenden normativen und ethischen Bezugen basiert, die einer statistischen Auswertung kaum zuganglich sind. Unsere ethischen Erwagungen werden vom Fehlen einer klaren Evidenzlage gepragt, die es nach unserer Auffassung auch am Lebensende nicht rechtfertigt, sich von etablierten Konzepten der klinisch assistierten Flussigkeitszufuhr („clinically assisted hydration“, CAH) zu entfernen, solange therapeutische Masnahmen wirksam umgesetzt werden konnen. Die „permissive“ Dehydration darf am Lebensende nicht als eine Option zur Verkurzung des Sterbeprozesses betrachtet werden. In der Palliativmedizin ist die Dehydration auch weiterhin als „Symptom“ zu betrachten, das zu „kontrollieren“ ist, solange dieses mit therapeutischen Mitteln beherrscht werden kann und solange der Patient diesem Vorgehen nicht ablehnend gegenubersteht. Bleibt die Dehydration aber therapeutisch refraktar, ist es gerechtfertigt, die CAH entweder nicht zu initiieren oder die laufende Therapie zu stoppen.

Der rechtliche Bezugsrahmen zur Durchfuhrung einer Flussigkeitstherapie in der palliativmedizinischen Versorgung am Lebensende kann auf verschiedenen Kontinenten und sogar in benachbarten Landern sehr unterschiedlich sein. Welche rechtlichen Implikationen mussen in Deutschland im Umgang mit der „terminalen“ Dehydration beachtet werden? Es wurden relevante Publikationen in englischer und deutscher Sprache identifiziert. Insbesondere wurden die in Deutschland gultigen Empfehlungen herangezogen und mit den Vorgehensweisen in England und Kanada verglichen. Unsere rechtlichen Erwagungen entsprechen den Empfehlungen der Bundesarztekammer. Als zentrale Bestandteile sind die Patientenautonomie, die bestmogliche Symptomkontrolle und die standige therapeutische Nutzen-Risiko-Abschatzung zu nennen. Die Dehydration ist danach auch weiterhin als „Symptom“ zu betrachten, das zu „kontrollieren“ ist, solange dieses mit therapeutischen Mitteln beherrscht werden kann und solange der Patient diesem Vorgehen nicht ablehnend gegenubersteht. Bleibt die Dehydration aber therapeutisch refraktar, ist es gerechtfertigt, die klinisch assistierte („Clinically assisted hydration“, CAH) entweder nicht zu initiieren oder die laufende Therapie zu stoppen. Diesem Vorgehen steht das in Kanada praktizierte „shared decision-making model“ diametral gegenuber, bei dem eine paternalistische Entscheidungsfindung moglich ist, sofern die Patienten oder Angehorigen schlecht informiert und unvorbereitet erscheinen, um nach Expertenmeinung „richtig“ zu entscheiden. Eine nichtrefraktare Dehydration am Lebensende darf nach deutschem Recht nicht untherapiert bleiben und darf nicht als Option zur Verkurzung des Sterbeprozesses genutzt werden, wenn die Entstehung einer Dehydration nicht dem Patientenwillen entspricht oder dieser Wille nicht ermittelbar ist.

At the time of admission to an intensive or intermediate care unit, assessment of the patients' nutritional status may have both prognostic and therapeutic relevance with regard to the planning of individualized medical nutrition therapy (MNT). MNT has definitely no priority in the initial treatment of a critically ill patient, but is often also neglected during the course of the disease. Especially with prolonged length of stay, there is an increasing risk of malnutrition with considerable prognostic macro- and/or micronutrient deficit. So far, there are no structured, evidence-based recommendations for assessing nutritional status in intensive or intermediate care patients. This position paper of the Section Metabolism and Nutrition of the German Interdisciplinary Association for Intensive and Emergency Medicine (DIVI) presents consensus-based recommendations for the assessment and technical monitoring of nutritional status of patients in intensive and intermediate care units. These recommendations supplement the current S2k guideline "Clinical Nutrition in Intensive Care Medicine" of the German Society for Nutritional Medicine (DGEM) and the DIVI.Die Erhebung des Ernährungsstatus zum Zeitpunkt der Aufnahme im Intensiv- oder Intermediate Care Bereich hat sowohl prognostische als auch therapeutische Relevanz im Hinblick auf die Planung einer individualisierten medizinischen Ernährungstherapie (engl. „medical nutrition therapy“, MNT). Diese Planung wird im Rahmen der Erstversorgung eines vital bedrohlichen Krankheitsbilds nachvollziehbar nicht priorisiert, jedoch im weiteren Verlauf häufig auch oft nicht mehr angemessen durchgeführt. Vor allem bei längerer Verweildauer besteht das Risiko einer Mangelernährung mit Aufbau eines kumulativen, prognoserelevanten Makro- und/oder Mikronährstoffdefizits. Bisher gibt es für Patient*innen auf Intensiv- und Intermediate Care Einheiten keine strukturierten Empfehlungen zur Erhebung des Ernährungsstatus. Das vorliegende Positionspapier der Sektion Metabolismus und Ernährung der Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI) beinhaltet konsensbasierte Empfehlungen zur Erfassung und zum apparativen Monitoring des Ernährungsstatus von Patient*innen auf Intensiv- und Intermediate Care Stationen. Diese Empfehlungen ergänzen die aktuelle S2k-Leitlinie „Klinische Ernährung in der Intensivmedizin“ der Deutschen Gesellschaft für Ernährungsmedizin (DGEM) und der DIVI.

Critical care 26(1), 268 (2022). doi:10.1186/s13054-022-04139-1, Published by BioMed Central, London

in press

Cardiac surgery (CSX) can be lifesaving in elderly patients (age &ge, 80 years) but may still be associated with complications and functional decline. Frailty represents a determinant to outcomes in critically ill patients, but little is known about its influence on elderly CSX-patients. This is a secondary exploratory analysis of a multi-center, prospective observational cohort study of 610 elderly patients admitted to the ICU and followed for one year to document long-term outcomes. CSX-ICU-patients (n = 49) were compared to surgical ICU patients (n = 184) with regard to demographics, frailty, and outcomes. Of all surgical patients, 102 (43%) were considered vulnerable or frail. The subdistribution hazard ratio (SHR) of time to discharge home (TTDH) for vulnerable/frail vs. fit/well patients was 0.54 (95% confidence interval (CI), 0.34, 0.86, p = 0.007). The p-value for effect modification between surgery group (CSX vs. surgical ICU patients) and Clinical Frailty Scale (CFS) group was not significant (p = 0.37) suggesting that the observed difference in the CFS effect between the CSX and surgical ICU patients is consistent with random error. A further subgroup analysis shows that among surgical ICU patients, the SHR of time to discharge home (TTDH) for vulnerable/frail vs. fit/well patients was 0.49 (95% CI, 0.29, 0.83) while the corresponding SHR for CSX patients was 0.77 (0.32&ndash, 1.88). In conclusion, preoperative frailty reduced the rate of discharge to home in both surgical and CSX patients, but a larger sample of CSX patients is needed to adequately address this question in this patient group.

Facial burns frequently occur in occupational or household accidents. While dysphagia and dysphonia are known sequelae, little is known about impaired smell and taste after facial burns.In a prospective observational controlled study, we evaluated hyposmia via the Sniffin' Stick Test (SnS), hypogeusia via a taste strip test, and dysphonia and dysphagia via validated questionnaires acutely and one-year after burn, respectively. A matched control group consisting of a convenience sample of healthy volunteers underwent the same assessments.Fifty-five facial burn patients (FB) and 55 healthy controls (CTR) were enrolled. Mean burn size was 11 (IQR: 29) % total body surface area (TBSA); CTR and FB were comparable regarding age, sex and smoking status. Acutely, hyposmia was present in 29% of the FB group (CTR: 9%, p = 0.014) and burn patients scored worse on the SnS than CTR (FB: 10; CTR: 11; IQR: 2; p = 0.013). Hyposmia per SnS correlated with subjective self-assessment. Hyposmia and SnS scores improved over time (FB acute: 10.5 IQR: 2; FB one year: 11; IQR: 2; p = 0.042) and returned to normal at one-year post burn in most patients who completed the study (lost to follow-up: 21 patients). Taste strip scores were comparable between FB and CTR, as was the acute prevalence of dysphagia and dysphonia.Hyposmia acutely after facial thermal trauma appeared frequently in this study, especially when complicated by inhalation trauma or large TBSA involvement. Of all complete assessments, a fraction of burn patients retained hyposmia after one year while most improved over time to normal. Prevalence of dysphonia, dysphagia and hypogeusia was comparable to healthy controls in this study, perhaps due to overall minor burn severity.

BMJ Open 11(11), e053148 (2021). doi:10.1136/bmjopen-2021-053148, Published by BMJ Publishing Group, London

OBJECTIVES To conduct a systematic review and meta-analysis to evaluate the impact of IV vitamin C on outcomes in critically ill patients. DATA SOURCES Systematic search of MEDLINE, EMBASE, CINAHL, and the Cochrane Register of Controlled Trials. STUDY SELECTION Randomized controlled trials testing IV vitamin C in critically ill patients. DATA ABSTRACTION Two independent reviewers abstracted patient characteristics, treatment details, and clinical outcomes. DATA SYNTHESIS Fifteen studies involving 2,490 patients were identified. Compared with placebo, IV vitamin C administration is associated with a trend toward reduced overall mortality (relative risk, 0.87; 95% CI, 0.75-1.00; p = 0.06; test for heterogeneity I2 = 6%). High-dose IV vitamin C was associated with a significant reduction in overall mortality (relative risk, 0.70; 95% CI, 0.52-0.96; p = 0.03), whereas low-dose IV vitamin C had no effect (relative risk, 0.94; 95% CI, 0.79-1.07; p = 0.46; test for subgroup differences, p = 0.14). IV vitamin C monotherapy was associated with a significant reduction in overall mortality (relative risk, 0.64; 95% CI, 0.49-0.83; p = 0.006), whereas there was no effect with IV vitamin C combined therapy. No trial reported an increase in adverse events related to IV vitamin C. CONCLUSIONS IV vitamin C administration appears safe and may be associated with a trend toward reduction in overall mortality. High-dose IV vitamin C monotherapy may be associated with improved overall mortality, and further randomized controlled trials are warranted.

Background: Macrophage migration inhibitory factor (MIF) is an important stress-regulating mediator of acute ischemia/reperfusion (I/R) injury and ischemic conditioning. The present study aimed to investigate whether MIF is involved in the effects of remote ischemic conditioning (RIC) in a rat model of orthotopic liver transplantation (OLT). Methods: OLTs were performed in male Lewis rats (245 g-340 g). Recipients were allocated in a randomized fashion into three experimental groups: remote preconditioning-RIPC, remote post-conditioning-RIPOST, control. RIC was applied as 4x5-5 min I/R via clamping of the infrarenal aorta. Animals were followed for 1, 3, 24, 168 h post-reperfusion (n = 6 recipient/group/time point). Graft micro- and macrocirculation and hepatocellular damage were assessed. Messenger ribonucleic acid (mRNA) expression, serum, and tissue protein levels of MIF, as well as additional markers of I/R injury, were measured. Results: RIC resulted in a prominent downregulation of MIF mRNA, serum, and tissue protein. Compared with control, hepatocellular damage was significantly mitigated after RIPC or RIPOST (serum ALT; RIPC, RIPOST vs. Control, P = 0.008, P = 0.030, respectively). Graft circulation was better preserved in the RIC groups. Furthermore, there was a significant positive correlation between serum MIF and transaminase levels (r = 0.330; P = 0.02). RIC showed a significant effect on iNOS and STAT5 mRNA expressions. Supporting findings were obtained from the measurements of tissue CXCL12 mRNA expression and pAkt/Akt, pErk/Erk. Conclusion: In this sophisticated experimental model of OLT, RIC-induced hepatoprotective effects were associated with a downregulation of MIF at mRNA and protein levels, suggesting the role of MIF as a mediator in RIC-induced protection following OLT.

Summary Purpose Enteral and parenteral nutrition of adult critically ill patients varies in terms of the route of nutrient delivery, the amount and composition of macro- and micronutrients, and the choice of specific, immune-modulating substrates. Variations of clinical nutrition may affect clinical outcomes. The present guideline provides clinicians with updated consensus-based recommendations for clinical nutrition in adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function. Methods The former guidelines of the German Society for Nutritional Medicine (DGEM) were updated according to the current instructions of the Association of the Scientific Medical Societies in Germany (AWMF) valid for a S2k-guideline. According to the S2k-guideline classification, no systematic review of the available evidence was required to make recommendations, which, therefore, do not state evidence- or recommendation grades. Nevertheless, we considered and commented the evidence from randomized-controlled trials, meta-analyses and observational studies with adequate sample size and high methodological quality (until May 2018) as well as from currently valid guidelines of other societies. The liability of each recommendation was described linguistically. Each recommendation was finally validated and consented through a Delphi process. Results In the introduction the guideline describes a) the pathophysiological consequences of critical illness possibly affecting metabolism and nutrition of critically ill patients, b) potential definitions for different disease phases during the course of illness, and c) methodological shortcomings of clinical trials on nutrition. Then, we make 69 consented recommendations for essential, practice-relevant elements of clinical nutrition in critically ill patients. Among others, recommendations include the assessment of nutrition status, the indication for clinical nutrition, the timing and route of nutrient delivery, and the amount and composition of substrates (macro- and micronutrients); furthermore, we discuss distinctive aspects of nutrition therapy in obese critically ill patients and those treated with extracorporeal support devices. Conclusion The current guideline provides clinicians with up-to-date recommendations for enteral and parenteral nutrition of adult critically ill patients who suffer from at least one acute organ dysfunction requiring specific drug therapy and/or a mechanical support device (e.g., mechanical ventilation) to maintain organ function. The period of validity of the guideline is approximately fixed at five years (2018–2023).