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Background: Sepsis is a life-threatening syndrome characterized by acute loss of organ function due to infection. Sepsis survivors are at risk for long-term comorbidities, have a reduced Quality of Life (QoL), and are prone to increased long-term mortality. The societal impact of sepsis includes its disease burden and indirect economic costs. However, these societal costs of sepsis are not fully understood. This study assessed sepsis’s disease-related and indirect economic costs in the Netherlands. Methods: Sepsis prevalence, incidence, sepsis-related mortality, hospitalizations, life expectancy, QoL population norms, QoL reduction after sepsis, and healthcare use post-sepsis were obtained from previous literature and Statistics Netherlands. We used these data to estimate annual Quality-adjusted Life Years (QALYs), productivity loss, and increase in healthcare use post-sepsis. A sensitivity analysis was performed to analyze the burden and indirect economic costs of sepsis under alternative assumptions, resulting in a baseline, low, and high estimated burden. The results are presented as a baseline (low–high burden) estimate. Results: The annual disease burden of sepsis is approximately 57,304 (24,398–96,244; low–high burden) QALYs. Of this, mortality accounts for 26,898 (23,166–31,577) QALYs, QoL decrease post-sepsis accounts for 30,406 (1232–64,667) QALYs. The indirect economic burden, attributed to lost productivity and increased healthcare expenditure, is estimated at €416.1 (147.1–610.7) million utilizing the friction cost approach and €3.1 (0.4–5.7) billion using the human capital method. Cumulatively, the combined disease and indirect economic burdens range from €3.8 billion (friction method) to €6.5 billion (human capital method) annually within the Netherlands. Conclusions: Sepsis and its complications pose a substantial disease and indirect economic burden to the Netherlands, with an indirect economic burden due to production loss that is potentially larger

Purpose of reviewTo better understand the established associations between hypocalcaemia and clinical outcomes, we synopsize the mechanisms involved in hypocalcaemia in the critically ill. We also provide an overview of the current evidence on managing hypocalcaemia in critical illness.Recent findingsHypocalcaemia is reported to occur in 55-85% of ICU patients. It appears to be associated with poor outcomes. It appears to be associated with poor outcomes, but it may be a marker rather than a direct cause of disease severity. The recommendations to correct calcium in major bleeding are found on weak evidence and require further exploration by a randomized controlled trial (RCT). Calcium administration in cardiac arrest has shown no benefit and may provoke harm. In addition, no RCT has assessed the risks and benefits of calcium supplementation in critically ill hypocalcemic patients. Several recent studies conclude that it may even harm septic ICU patients. These observations are supported by evidence that septic patients using calcium channel blockers may have better outcomes.SummaryHypocalcaemia is common in critically ill patients. Direct evidence that calcium supplementation improves their outcomes is lacking, and there is even some indication that it may be detrimental. Prospective studies are required to elucidate the risks and benefits, and the pathophysiological mechanisms involved.

Following publication of the original article [1], the authors reported an error in the Competing Interests section. The Competing Interests section currently reads: Competing Interests The authors declare no competing interests. The Competing Interests section should read: Competing Interests Katie N. Robinson works and owns stock in Abbott Nutrition. The Competing Interests section has been updated above and the original article [1] has been corrected.

Personalization of ICU nutrition is essential to future of critical care. Recommendations from American/European guidelines and practice suggestions incorporating recent literature are presented. Low-dose enteral nutrition (EN) or parenteral nutrition (PN) can be started within 48 h of admission. While EN is preferred route of delivery, new data highlight PN can be given safely without increased risk; thus, when early EN is not feasible, provision of isocaloric PN is effective and results in similar outcomes. Indirect calorimetry (IC) measurement of energy expenditure (EE) is recommended by both European/American guidelines after stabilization post-ICU admission. Below-measured EE (~ 70%) targets should be used during early phase and increased to match EE later in stay. Low-dose protein delivery can be used early (~ D1-2) (< 0.8 g/kg/d) and progressed to ≥ 1.2 g/kg/d as patients stabilize, with consideration of avoiding higher protein in unstable patients and in acute kidney injury not on CRRT. Intermittent-feeding schedules hold promise for further research. Clinicians must be aware of delivered energy/protein and what percentage of targets delivered nutrition represents. Computerized nutrition monitoring systems/platforms have become widely available. In patients at risk of micronutrient/vitamin losses (i.e., CRRT), evaluation of micronutrient levels should be considered post-ICU days 5–7 with repletion of deficiencies where indicated. In future, we hope use of muscle monitors such as ultrasound, CT scan, and/or BIA will be utilized to assess nutrition risk and monitor response to nutrition. Use of specialized anabolic nutrients such as HMB, creatine, and leucine to improve strength/muscle mass is promising in other populations and deserves future study. In post-ICU setting, continued use of IC measurement and other muscle measures should be considered to guide nutrition. Research on using rehabilitation interventions such as cardiopulmonary exercise testing (CPET

Background General practitioners (GPs) often assess patients with acute infections. It is challenging for GPs to recognize patients needing immediate hospital referral for sepsis while avoiding unnecessary referrals. This study aimed to predict adverse sepsis-related outcomes from telephone triage information of patients presenting to out-of-hours GP cooperatives. Methods A retrospective cohort study using linked routine care databases from out-of-hours GP cooperatives, general practices, hospitals and mortality registration. We included adult patients with complaints possibly related to an acute infection, who were assessed (clinic consultation or home visit) by a GP from a GP cooperative between 2017-2019. We used telephone triage information to derive a risk prediction model for sepsis-related adverse outcome (infection-related ICU admission within seven days or infection-related death within 30 days) using logistic regression, random forest, and neural network machine learning techniques. Data from 2017 and 2018 were used for derivation and from 2019 for validation. Results We included 155, 486 patients (median age of 51 years; 59% females) in the analyses. The strongest predictors for sepsis-related adverse outcome were age, type of contact (home visit or clinic consultation), patients considered ABCD unstable during triage, and the entry complaints”general malaise”, “shortness of breath” and “fever”. The multivariable logistic regression model resulted in a C-statistic of 0.89 (95% CI 0.88-0.90) with good calibration. Machine learning models performed similarly to the logistic regression model. A “sepsis alert” based on a predicted probability >1% resulted in a sensitivity of 82% and a positive predictive value of 4.5%. However, most events occurred in patients receiving home visits, and model performance was substantially worse in this subgroup (C-statistic 0.70). Conclusion Several patient characteristics identified during telephone triage of patients presen

Background: Tachypnoea in acutely ill patients can be an early sign of a life-threatening condition such as sepsis. Routine measurement of the respiratory rate by GPs might improve the recognition of sepsis. Aim: To assess the accuracy and feasibility of respiratory rate measurements by GPs. Design & setting: Observational cross-sectional mixed-methods study in the setting of out-of-hours (OOH) home visits at three GP cooperatives in The Netherlands. Method: GPs were observed during the assessment of acutely ill patients, and semi-structured interviews were performed. The GP-assessed respiratory rate was compared with a reference measurement. In the event that the respiratory rate was not counted, GPs were asked to estimate the rate (dichotomised as ≥22 breaths per minute or <22 breaths per minute). Results: Observations of 130 acutely ill patients were included, and 14 GPs were interviewed. In 33 patients (25%), the GP counted the respiratory rate. A mean difference of 0.27 breaths per minute (95% confidence interval [CI] = -5.7 to 6.3) with the reference measurement was found. At a cut-off point of ≥22 breaths per minute, a sensitivity of 86% (95% CI = 57% to 98%) was found when the GP counted the rate, and a sensitivity of 43% (95% CI = 22% to 66%) when GPs estimated respiratory rates. GPs reported both medical and practical reasons for not routinely measuring the respiratory rate. Conclusion: GPs are aware of the importance of assessing the respiratory rate of acutely ill adult patients, and counted measurements are accurate. However, in most patients the respiratory rate was not counted, and the rate was often underestimated when estimated.

IMPORTANCE: Despite high mortality rates of COVID-19-associated pulmonary aspergillosis (CAPA) in the ICU, antifungal prophylaxis remains a subject of debate. We initiated nebulized conventional amphotericin B (c-AmB) as antifungal prophylaxis in COVID-19 patients on invasive mechanical ventilation (IMV). OBJECTIVES: To assess the CAPA incidence in COVID-19 patients on IMV treated with and without nebulized c-AmB as antifungal prophylaxis. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of consecutive COVID-19 patients admitted to our adult 17-bed ICU in a university-affiliated general hospital in Ede, The Netherlands, between January 25, 2021, and July 9, 2021. Patients not requiring IMV or transferred from or to another ICU were excluded. From April 9, 2021, daily nebulized amphotericin B in all patients on IMV was initiated. MAIN OUTCOMES AND MEASURES: Bronchoscopy with bronchoalveolar lavage (BAL) was performed in case of positive cultures for Aspergillus from the respiratory tract and/or unexplained respiratory deterioration. Incidence of probable and proven CAPA was compared between patients treated with and without nebulized antifungal prophylaxis using Pearson chi-square test. RESULTS: A total of 39 intubated COVID-19 patients could be analyzed, of which 16 were treated with antifungal prophylaxis and 23 were not. Twenty-six patients underwent bronchoscopy with BAL. In patients treated with antifungal prophylaxis, the incidence of probable/proven CAPA was significantly lower when compared with no antifungal prophylaxis (27% vs 67%; p = 0.047). Incidence of tracheobronchial lesions and positive Aspergillus cultures and BAL-galactomannan was significantly lower in patients treated with antifungal prophylaxis (9% vs 47%; p = 0.040, 9% vs 53%; p = 0.044, and 20% vs 60%; p = 0.047, respectively). No treatment-related adverse events and no case of proven CAPA were encountered in patients receiving antifungal prophylaxis. CONCLUSIONS AND RELEVANCE: Ne

BACKGROUND: Point-of-care testing (POCT) has shown promising results in the primary care setting to improve antibiotic therapy in respiratory tract infections and it might also aid general practitioners (GPs) to decide if patients should be referred to a hospital in cases of suspected sepsis. We aimed to assess whether biomarkers with possible POCT use can improve the recognition of sepsis in adults in the primary care setting. METHODS: We prospectively included adult patients with suspected severe infections during out-of-hours home visits. Relevant clinical signs and symptoms were recorded, as well as the biomarkers C-reactive protein, lactate, procalcitonin, high-sensitive troponin I, N-terminal pro b-type natriuretic peptide, creatinine, urea, and pancreatic stone protein. We used a POCT device for lactate only, and the remaining biomarkers were measured in a laboratory from stored blood samples. The primary outcome was sepsis within 72 h of inclusion. The potential of biomarkers to either rule in or rule out sepsis was tested for individual biomarkers combined with a model consisting of signs and symptoms. Net reclassification indices were also calculated. RESULTS: In total, 336 patients, with a median age of 80 years, were included. One hundred forty-one patients (42%) were diagnosed with sepsis. The C statistic for the model with clinical symptoms and signs was 0.84 (95% CI 0.79-0.88). Both lactate and procalcitonin increased the C statistic to 0.85, but none of the biomarkers significantly changed the net reclassification index. CONCLUSIONS: We do not advocate the routine use of POCT in general practice for any of the tested biomarkers of suspected sepsis.

Food is not medicine. However, nutrition is essential to recover from acutemetabolic stress. Metabolic stress induced by critical illness markedly changesthe metabolism of patients and interacts with nutrition therapy. Therefore,feeding patients during metabolic stress and convalescence cannot easily becompared with the anabolic-catabolic changes observed in health. Optimaltiming and dosing of macronutrients and micronutrients is paramount to do noharm, enhance recovery and achieve the maximum functional performance andquality of life for patients after acute metabolic stress. Personalised, tailorednutrition strategies throughout the patient journey are essential to improveoutcomes.

Background: This review has been developed following a panel discussion with an international group of experts in the care of patients with obesity in the critical care setting and focuses on current best practices in malnutrition screening and assessment, estimation of energy needs for patients with obesity, the risks and management of sarcopenic obesity, the value of tailored nutrition recommendations, and the emerging role of immunonutrition. Patients admitted to the intensive care unit (ICU) increasingly present with overweight and obesity that require individualized nutrition considerations due to underlying comorbidities, immunological factors such as inflammation, and changes in energy expenditure and other aspects of metabolism. While research continues to accumulate, important knowledge gaps persist in recognizing and managing the complex nutritional needs in ICU patients with obesity. Available malnutrition screening and assessment tools are limited in patients with obesity due to a lack of validation and heterogeneous factors impacting nutrition status in this population. Estimations of energy and protein demands are also complex in patients with obesity and may include estimations based upon ideal, actual, or adjusted body weight. Evidence is still sparse on the role of immunonutrition in patients with obesity, but the presence of inflammation that impacts immune function may suggest a role for these nutrients in hemodynamically stable ICU patients. Educational efforts are needed for all clinicians who care for complex cases of critically ill patients with obesity, with a focus on strategies for optimal nutrition and the consideration of issues such as weight stigma and bias impacting the delivery of care. Conclusions: Current nutritional strategies for these patients should be undertaken with a focus on individualized care that considers the whole person, including the possibility of preexisting comorbidities, altered metabolism, and chronic stigma, whi

Background: The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of sepsis in adults. Methods: Our multidisciplinary guideline committee generated ten population, intervention, comparison, and outcome (PICO) questions relevant for adult patients with sepsis. For each question, a literature search was performed to obtain the best available evidence and assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The quality of evidence for clinically relevant outcomes was graded from high to very low. In structured consensus meetings, the committee formulated recommendations as strong or weak. When evidence could not be obtained, recommendations were provided based on expert opinion and experience (good practice statements). Results: Fifty-five recommendations on the antibacterial therapy of sepsis were generated. Recommendations on empiric antibacterial therapy choices were differentiated for sepsis according to the source of infection, the potential causative pathogen and its resistance pattern. One important revision was the distinction between low, increased and high risk of infection with Enterobacterales resistant to third generation cephalosporins (3GRC-E) to guide the choice of empirical therapy. Other new topics included empirical antibacterial therapy in patients with a reported penicillin allergy and the role of pharmacokinetics and pharmacodynamics to guide dosing in sepsis. We also established recommendations on timing and duration of antibacterial treatment. Conclusions: Our multidisciplinary committee formulated evidence-based recommendations for the empiric antibacterial therapy of adults with sepsis in The Netherlands.

BACKGROUND: Patients discharged from the Intensive Care Unit (ICU) frequently suffer from ICU-acquired weakness because of immobilization and massive inflammation-induced muscle mass loss. Consequently, rehospitalization, reduced quality of life (QoL), increased disabilities, and higher post-ICU mortality is observed. Exercise rehabilitation and optimal nutrition, particularly protein intake, are pivotal to regaining muscle mass and function. Studies have shown that protein requirements in the post-ICU phase are often unmet. Furthermore, protein supplementation in other patient groups has shown beneficial effects. However, a study on protein supplementation during the post-ICU period is lacking. This study aims to investigate the effect of a six-week intervention of daily porcine protein supplementation versus an isocaloric control (maltodextrin) on functional outcomes in the post-ICU period in patients with moderately severe ICU-acquired weakness. METHODS: 72 post-ICU patients with moderately severe ICU-acquired weakness of Hospital Gelderse Vallei will be randomly assigned to either the intervention or the control group (36 per arm). The intervention group receives a porcine protein supplement twice a day. The control group receives a maltodextrin supplement twice a day. The intervention starts on the first day in the general ward and lasts 42 days (6 weeks). The primary outcome is the between-group difference in physical function at hospital discharge (t;=2), the end of the intervention (t;=3, day 42), and the 3-month follow-up (t;=4) expressed as a composite score consisting of handgrip strength, muscle strength leg, muscle strength arm and exercise capacity. Secondary outcomes encompass physical function, QoL, Activity of daily living (ADL), and plasma amino acids concentrations. Lastly, ICU readmission after ICU discharge, hospital readmission after hospital discharge, and overall survival status will be considered. Linear mixed models will be used to test the

Case Presentation: A 67-year-old obese man (BMI 38.0) with type 2 diabetes mellitus (DM), chronic atrial fibrillation, and chronic lymphocytic leukemia stage II, stable for 8 years after chemotherapy, and a history of smoking presented to the ED with progressive dyspnea and fever due to SARS-CoV-2 infection. He was admitted to a general ward and treated with dexamethasone (6 mg IV once daily) and oxygen. On day 3 of hospital admission, he became progressively hypoxemic and was admitted to the ICU for invasive mechanical ventilation. Dexamethasone treatment was continued, and a single dose of tocilizumab (800 mg) was administered. On day 9 of ICU admission, voriconazole treatment was initiated after tracheal white plaques at bronchoscopy, suggestive of invasive Aspergillus tracheobronchitis, were noticed. However, his medical situation dramatically deteriorated.

Background: A large proportion of hospitalised COVID-19 patients are overweight. There is no consensus in the literature on how lean body mass (LBM) can best be estimated to adequately guide nutritional protein recommendations in hospitalised patients who are not at an ideal weight. We aim to explore which method best agrees with lean body mass as measured by bioelectric impedance (LBMBIA) in this population. Methods: LBM was calculated by five commonly used methods for 150 hospitalised COVID-19 patients previously included in the BIAC-19 study; total body weight, regression to a BMI of 22.5, regression to BMI 27.5 when BMI>30, and the equations described by Gallagher and the ESPEN ICU guideline. Error–standard plots were used to assess agreement and bias compared to LBMBIA. The actual protein provided to ICU patients during their stay was compared to targets set using LBMBIA and LBM calculated by other methods. Results: All methods to calculate LBM suffered from overestimation, underestimation, fixed- and proportional bias and wide limits of agreement compared to LBMBIA. Bias was inconsistent across sex and BMI subgroups. Twenty-eight ICU patients received a mean of 51.19 (95%-BCa CI 37.1;64.1) grams of protein daily, accumulating to a mean of 61.6% (95%-BCa CI 43.2;80.8) of TargetBIA during their ICU stay. The percentage received of the target as calculated by the LBMGallagher method for males was the only one to not differ significantly from the percentage received of TargetBIA (mean difference 1.4% (95%-BCa CI -1.3;4.6) p = 1.0). Conclusions: We could not identify a mathematical method for calculating LBM that had an acceptable agreement with LBM as derived from BIA for males and females across all BMI subgroups in our hospitalised COVID-19 population. Consequently, discrepancies when assessing the adequacy of protein provision in ICU patients were found. We strongly advise using baseline LBMBIA to guide protein dosing if possible. In the absence of BIA, using a

Background & aims: Gaining insight into readily obtainable baseline characteristics that allow prediction of adverse outcome in COVID-19 aids both treatment and healthcare planning. Bioelectric impedance (BIA) Phase Angle (PhA) is correlated with outcome in a multitude of diseases and may be of added value in predicting adverse outcome of COVID-19. We aimed to associate baseline body composition parameters with 90-day adverse outcome of COVID-19 including ICU-admission and to explore the added predictive value of baseline PhA. Methods: We performed a prospective observational study, conducting BIA amongst COVID-19 patients within 24 hours of hospital admission, with a follow-up of 90 days. Data were compared between ward-only and ICU-patients. Regression models were used to assess the associations between baseline characteristics, body composition and 90-day adverse outcome, including a composite outcome score of morbidity, ICU-admission, and mortality. An ROC-curve was used to explore the added predictive value of PhA to other clinical parameters at baseline for the prediction of adverse outcome. Results: One-hundred-and-fifty patients were included. Mean age was 68 (66–70) years, 67% were male. Forty-one (27%) patients were admitted to ICU and 77 (51%) met the criteria of the composite outcome score. In multiple regression, PhA was independently, inversely correlated with risk of ICU-admission (OR.531, p =.021), complications (OR.579, p =.031), hospital length of stay (OR.875, p =.037) and the composite outcome score (OR.502, p =.012). An ROC-curve showed that the incorporation of PhA in a composite risk-score improved the discriminative power for the composite outcome from poor to fair, compared to individual predictors (AUC 0.79 (95% CI 0.71–0.87)). Conclusion: BIA measurements including Phase Angle are independently correlated with an adverse outcome of COVID-19. Interpretation of Phase Angle can be a valuable addition to risk assessment of adverse outcome of C

Background: High-dose intravenous vitamin C directly scavenges and decreases the production of harmful reactive oxygen species (ROS) generated during ischemia/reperfusion after a cardiac arrest. The aim of this study is to investigate whether short-term treatment with a supplementary or very high-dose intravenous vitamin C reduces organ failure in post-cardiac arrest patients. Methods: This is a double-blind, multi-center, randomized placebo-controlled trial conducted in 7 intensive care units (ICUs) in The Netherlands. A total of 270 patients with cardiac arrest and return of spontaneous circulation will be randomly assigned to three groups of 90 patients (1:1:1 ratio, stratified by site and age). Patients will intravenously receive a placebo, a supplementation dose of 3 g of vitamin C or a pharmacological dose of 10 g of vitamin C per day for 96 h. The primary endpoint is organ failure at 96 h as measured by the Resuscitation-Sequential Organ Failure Assessment (R-SOFA) score at 96 h minus the baseline score (delta R-SOFA). Secondary endpoints are a neurological outcome, mortality, length of ICU and hospital stay, myocardial injury, vasopressor support, lung injury score, ventilator-free days, renal function, ICU-acquired weakness, delirium, oxidative stress parameters, and plasma vitamin C concentrations. Discussion: Vitamin C supplementation is safe and preclinical studies have shown beneficial effects of high-dose IV vitamin C in cardiac arrest models. This is the first RCT to assess the clinical effect of intravenous vitamin C on organ dysfunction in critically ill patients after cardiac arrest. Trial registration: ClinicalTrials.gov NCT03509662. Registered on April 26, 2018. https://clinicaltrials.gov/ct2/show/NCT03509662European Clinical Trials Database (EudraCT): 2017-004318-25. Registered on June 8, 2018. https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004318-25/NL