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Abstract Background The clinical significance of vitamin D administration in critically ill patients remains inconclusive. The purpose of this systematic review with meta-analysis was to investigate the effect of vitamin D and its metabolites on major clinical outcomes in critically ill patients, including a subgroup analysis based on vitamin D status and route of vitamin D administration. Methods Major databases were searched through February 9, 2022. Randomized controlled trials of adult critically ill patients with an intervention group receiving vitamin D or its metabolites were included. Random-effect meta-analyses were performed to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Risk of bias assessment included the Cochrane tool for assessing risk of bias in randomized trials. Results Sixteen randomized clinical trials with 2449 patients were included. Vitamin D administration was associated with lower overall mortality (16 studies: risk ratio 0.78, 95% confidence interval 0.62–0.97, p = 0.03; I 2 = 30%), reduced intensive care unit length of stay (12 studies: mean difference − 3.13 days, 95% CI − 5.36 to − 0.89, n = 1250, p = 0.006; I 2 = 70%), and shorter duration of mechanical ventilation (9 studies: mean difference − 5.07 days, 95% CI − 7.42 to − 2.73, n = 572, p

Abstract Background Medical nutrition therapy may be associated with clinical outcomes in critically ill patients with prolonged intensive care unit (ICU) stay. We wanted to assess nutrition practices in European intensive care units (ICU) and their importance for clinical outcomes. Methods Prospective multinational cohort study in patients staying in ICU ≥ 5 days with outcome recorded until day 90. Macronutrient intake from enteral and parenteral nutrition and non-nutritional sources during the first 15 days after ICU admission was compared with targets recommended by ESPEN guidelines. We modeled associations between three categories of daily calorie and protein intake (low: 20 kcal/kg; > 1.2 g/kg) and the time-varying hazard rates of 90-day mortality or successful weaning from invasive mechanical ventilation (IMV). Results A total of 1172 patients with median [Q1;Q3] APACHE II score of 18.5 [13.0;26.0] were included, and 24% died within 90 days. Median length of ICU stay was 10.0 [7.0;16.0] days, and 74% of patients could be weaned from invasive mechanical ventilation. Patients reached on average 83% [59;107] and 65% [41;91] of ESPEN calorie and protein recommended targets, respectively. Whereas specific reasons for ICU admission (especially respiratory diseases requiring IMV) were associated with higher intakes (estimate 2.43 [95% CI: 1.60;3.25] for calorie intake, 0.14 [0.09;0.20] for protein intake), a lack of nutrition on the preceding day was associated with lower calorie and protein intakes (− 2.74 [− 3.28; − 2.21] and − 0.12 [− 0.15; − 0.09], respectively). Compared to a lower intake, a daily moderate intake was associated with higher probability of successful weaning (for calories: maximum HR 4.59 [95% CI: 1.5;14.09] on day 12; for protein: maximum HR 2.60 [1.09;6.23] on day 12), and with a lower hazard of death (for calories only: minimum HR 0.15, [0.05;0.39] on day 19). There was no evidence that a high calorie or protein intake was associated with further outcome improvements. Conclusions Calorie intake was mainly provided according to the targets recommended by the active ESPEN guideline, but protein intake was lower. In patients staying in ICU ≥ 5 days, early moderate daily calorie and protein intakes were associated with improved clinical outcomes. Trial registration NCT04143503 , registered on October 25, 2019. Graphical abstract

Abstract Background Oscillometric, non-invasive blood pressure measurement (NIBP) is the first choice of blood pressure monitoring in the majority of low and moderate risk surgeries. In patients with morbid obesity, however, it is subject to several limitations. The aim was to compare arterial pressure monitoring by NIBP and a non-invasive finger-cuff technology (Nexfin®) with the gold-standard invasive arterial pressure (IAP). Methods In this secondary analysis of a prospective observational, single centre cohort study, systolic (SAP), diastolic (DAP) and mean arterial pressure (MAP) were measured at 16 defined perioperative time points including posture changes, fluid bolus administration and pneumoperitoneum (PP) in patients undergoing laparoscopic bariatric surgery. Absolute arterial pressures by NIBP, Nexfin® and IAP were compared using correlation and Bland Altman analyses. Interchangeability was defined by a mean difference ≤ 5 mmHg (SD ≤8 mmHg). Percentage error (PE) was calculated as an additional statistical estimate. For hemodynamic trending, concordance rates were analysed according to the Critchley criterion. Results Sixty patients (mean body mass index of 49.2 kg/m2) were enrolled and data from 56 finally analysed. Pooled blood pressure values of all time points showed a significant positive correlation for both NIPB and Nexfin® versus IAP. Pooled PE for NIBP versus IAP was 37% (SAP), 35% (DAP) and 30% (MAP), for Nexfin versus IAP 23% (SAP), 26% (DAP) and 22% (MAP). Correlation of MAP was best and PE lowest before induction of anesthesia for NIBP versus IAP (r = 0.72; PE 24%) and after intraoperative fluid bolus administration for Nexfin® versus IAP (r = 0.88; PE: 17.2%). Concordance of MAP trending was 90% (SAP 85%, DAP 89%) for NIBP and 91% (SAP 90%, DAP 86%) for Nexfin®. MAP trending was best during intraoperative ATP positioning for NIBP (97%) and at induction of anesthesia for Nexfin® (97%). Conclusion As compared with IAP, interchangeability of absolute pressure values could neither be shown for NIBP nor Nexfin®, however, NIBP showed poorer overall correlation and precision. Overall trending ability was generally high with Nexfin® surpassing NIBP. Nexfin® may likely render individualized decision-making in the management of different hemodynamic stresses during laparoscopic bariatric surgery, particularly where NIBP cannot be reliably established. Trial registration The non-interventional, observational study was registered retrospectively at ( NCT03184285 ) on June 12, 2017.

Abstract Background Proteins are an essential part of medical nutrition therapy in critically ill patients. Guidelines almost universally recommend a high protein intake without robust evidence supporting its use. Methods Using a large international database, we modelled associations between the hazard rate of in-hospital death and live hospital discharge (competing risks) and three categories of protein intake (low: 1.2 g/kg per day) during the first 11 days after ICU admission (acute phase). Time-varying cause-specific hazard ratios (HR) were calculated from piece-wise exponential additive mixed models. We used the estimated model to compare five different hypothetical protein diets (an exclusively low protein diet, a standard protein diet administered early (day 1 to 4) or late (day 5 to 11) after ICU admission, and an early or late high protein diet). Results Of 21,100 critically ill patients in the database, 16,489 fulfilled inclusion criteria for the analysis. By day 60, 11,360 (68.9%) patients had been discharged from hospital, 4,192 patients (25.4%) had died in hospital, and 937 patients (5.7%) were still hospitalized. Median daily low protein intake was 0.49 g/kg [IQR 0.27–0.66], standard intake 0.99 g/kg [IQR 0.89– 1.09], and high intake 1.41 g/kg [IQR 1.29–1.60]. In comparison with an exclusively low protein diet, a late standard protein diet was associated with a lower hazard of in-hospital death: minimum 0.75 (95% CI 0.64, 0.87), and a higher hazard of live hospital discharge: maximum HR 1.98 (95% CI 1.72, 2.28). Results on hospital discharge, however, were qualitatively changed by a sensitivity analysis. There was no evidence that an early standard or a high protein intake during the acute phase was associated with a further improvement of outcome. Conclusions Provision of a standard protein intake during the late acute phase may improve outcome compared to an exclusively low protein diet. In unselected critically ill patients, clinical outcome may not be improved by a high protein intake during the acute phase. Study registration ID number ISRCTN17829198

Abstract Background Parenteral lipid emulsions in critical care are traditionally based on soybean oil (SO) and rich in pro-inflammatory omega-6 fatty acids (FAs). Parenteral nutrition (PN) strategies with the aim of reducing omega-6 FAs may potentially decrease the morbidity and mortality in critically ill patients. Methods A systematic search of MEDLINE, EMBASE, CINAHL and CENTRAL was conducted to identify all randomized controlled trials in critically ill patients published from inception to June 2021, which investigated clinical omega-6 sparing effects. Two independent reviewers extracted bias risk, treatment details, patient characteristics and clinical outcomes. Random effect meta-analysis was performed. Results 1054 studies were identified in our electronic search, 136 trials were assessed for eligibility and 26 trials with 1733 critically ill patients were included. The median methodologic score was 9 out of 14 points (95% confidence interval [CI] 7, 10). Omega-6 FA sparing PN in comparison with traditional lipid emulsions did not decrease overall mortality (20 studies; risk ratio [RR] 0.91; 95% CI 0.76, 1.10; p = 0.34) but hospital length of stay was substantially reduced (6 studies; weighted mean difference [WMD] − 6.88; 95% CI − 11.27, − 2.49; p = 0.002). Among the different lipid emulsions, fish oil (FO) containing PN reduced the length of intensive care (8 studies; WMD − 3.53; 95% CI − 6.16, − 0.90; p = 0.009) and rate of infectious complications (4 studies; RR 0.65; 95% CI 0.44, 0.95; p = 0.03). When FO was administered as a stand-alone medication outside PN, potential mortality benefits were observed compared to standard care. Conclusion Overall, these findings highlight distinctive omega-6 sparing effects attributed to PN. Among the different lipid emulsions, FO in combination with PN or as a stand-alone treatment may have the greatest clinical impact. Trial registration PROSPERO international prospective database of systematic reviews (CRD42021259238). Graphical abstract

Abstract Background Ultrasound education is propagated already during medical school due to its diagnostic importance. Courses are usually supervised by experienced faculty staff (FS) with patient bedside examinations or students among each other but often overbooked due to limited FS availability. To overcome this barrier, use of teaching videos may be advantageous. Likewise, peer teaching concepts solely with trained student tutors have shown to be feasible and effective. The aim was to evaluate 1) objective learning outcomes of a combined video-based, student-tutor (ViST) as compared to a FS-led course without media support, 2) acceptance and subjective learning success of the videos. Methods Two ultrasound teaching videos for basic and advanced abdominal ultrasound (AU) and transthoracic echocardiography (TTE) were produced and six students trained as tutors. Fourth-year medical students (N = 96) were randomized to either the ViST- or FS course (6 students per tutor). Learning objectives were defined equally for both courses. Acquired practical basic and advanced ultrasound skills were tested in an objective structured clinical examination (OSCE) using modified validated scoring sheets with a maximum total score of 40 points. Acceptance and subjective learning success of both videos were evaluated by questionnaires based on Kirkpatrick’s evaluation model with scale-rated closed and open questions. Results 79 of 96 medical students completed the OSCE and 77 could be finally analyzed. There was no significant difference in the mean total point score of 31.3 in the ViST (N = 42) and 32.7 in the FS course (N = 35, P = 0.31) or in any of the examined basic or advanced ultrasound skill subtasks. Of the 42 ViST participants, 29 completed the AU and 27 the TTE video questionnaire. Acceptance and subjective learning success of both videos was rated positively in 14–52% and 48–88% of the rated responses to each category, respectively. Attendance of either the student or faculty tutor was deemed necessary in addition to the videos. Conclusions A ViST versus FS teaching concept was able to effectively teach undergraduate students in AU and TTE, albeit acceptance of the teaching videos alone was limited. However, the ViST concept has the potential to increase course availability and FS resource allocation.

Abstract Background In morbidly obese patients undergoing laparoscopic bariatric surgery, the combination of obesity-related comorbidities, pneumoperitoneum and extreme posture changes constitutes a high risk of perioperative hemodynamic complications. Thus, an advanced hemodynamic monitoring including continuous cardiac index (CI) assessment is desirable. While invasive catheterization may bear technical difficulties, transesophageal echocardiography is contraindicated due to the surgical procedure. Evidence on the clinical reliability of alternative semi- or non-invasive cardiac monitoring devices is limited. The aim was to compare the non-invasive vascular unloading to a semi-invasive pulse contour analysis reference technique for continuous CI measurements in bariatric surgical patients. Methods This prospective observational study included adult patients scheduled for elective, laparoscopic bariatric surgery after obtained institutional ethics approval and written informed consent. CI measurements were performed using the vascular unloading technique (Nexfin®) and semi-invasive reference method (FloTrac™). At 10 defined measurement time points, the influence of clinically indicated body posture changes, passive leg raising, fluid bolus administration and pneumoperitoneum was evaluated pre- and intraoperatively. Correlation, Bland-Altman and concordance analyses were performed. Results Sixty patients (mean BMI 49.2 kg/m2) were enrolled into the study and data from 54 patients could be entered in the final analysis. Baseline CI was 3.2 ± 0.9 and 3.3 ± 0.8 l/min/m2, respectively. Pooled absolute CI values showed a positive correlation (rs = 0.76, P 92%). Conclusion Non-invasive as compared to semi-invasive CI measurements did not reach criteria of interchangeability for monitoring absolute and trending values of CI in morbidly obese patients undergoing bariatric surgery. Trial registration The study was registered retrospectively on June 12, 2017 with the registration number NCT03184272 .

Abstract Background Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies. Methods This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds. Results Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness. Conclusions Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.

Abstract Metabolic alterations in the critically ill have been studied for more than a century, but the heterogeneity of the critically ill patient population, the varying duration and severity of the acute phase of illness, and the many confounding factors have hindered progress in the field. These factors may explain why management of metabolic alterations and related conditions in critically ill patients has for many years been guided by recommendations based essentially on expert opinion. Over the last decade, a number of randomized controlled trials have been conducted, providing us with important population-level evidence that refutes several longstanding paradigms. However, between-patient variation means there is still substantial uncertainty when translating population-level evidence to individuals. A cornerstone of metabolic care is nutrition, for which there is a multifold of published guidelines that agree on many issues but disagree on others. Using a series of nine questions, we provide a review of the latest data in this field and a background to promote efforts to address the need for international consistency in recommendations related to the metabolic care of the critically ill patient. Our purpose is not to replace existing guidelines, but to comment on differences and add perspective.

Abstract Background This study assessed the ability of mid-regional proadrenomedullin (MR-proADM) in comparison to conventional biomarkers (procalcitonin (PCT), lactate, C-reactive protein) and clinical scores to identify disease severity in patients with sepsis. Methods This is a secondary analysis of a randomised controlled trial in patients with severe sepsis or septic shock across 33 German intensive care units. The association between biomarkers and clinical scores with mortality was assessed by Cox regression analysis, area under the receiver operating characteristic and Kaplan-Meier curves. Patients were stratified into three severity groups (low, intermediate, high) for all biomarkers and scores based on cutoffs with either a 90% sensitivity or specificity. Results 1089 patients with a 28-day mortality rate of 26.9% were analysed. According to the Sepsis-3 definition, 41.2% and 58.8% fulfilled the criteria for sepsis and septic shock, with respective mortality rates of 20.0% and 32.1%. MR-proADM had the strongest association with mortality across all Sepsis-1 and Sepsis-3 subgroups and could facilitate a more accurate classification of low (e.g. MR-proADM vs. SOFA: N = 265 vs. 232; 9.8% vs. 13.8% mortality) and high (e.g. MR-proADM vs. SOFA: N = 161 vs. 155; 55.9% vs. 41.3% mortality) disease severity. Patients with decreasing PCT concentrations of either ≥ 20% (baseline to day 1) or ≥ 50% (baseline to day 4) but continuously high MR-proADM concentrations had a significantly increased mortality risk (HR (95% CI): 19.1 (8.0–45.9) and 43.1 (10.1–184.0)). Conclusions MR-proADM identifies disease severity and treatment response more accurately than established biomarkers and scores, adding additional information to facilitate rapid clinical decision-making and improve personalised sepsis treatment.

Abstract Nutrition support is a necessary therapy for critically ill cardiac surgery patients. However, conclusive evidence for this population, consisting of well-conducted clinical trials is lacking. To clarify optimal strategies to improve outcomes, an international multidisciplinary group of 25 experts from different clinical specialties from Germany, Canada, Greece, USA and Russia discussed potential approaches to identify patients who may benefit from nutrition support, when best to initiate nutrition support, and the potential use of pharmaco-nutrition to modulate the inflammatory response to cardiopulmonary bypass. Despite conspicuous knowledge and evidence gaps, a rational nutritional support therapy is presented to benefit patients undergoing cardiac surgery.