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Rationale It is unknown how to titrate positive end-expiratory pressure (PEEP) in patients with COVID-19-related acute respiratory distress syndrome (ARDS). Guidelines recommend the one-size-fits-all PEEP-FiO 2 table. In this retrospective cohort study, an electrical impedance tomography (EIT)-guided PEEP trial was used to titrate PEEP. Objectives To compare baseline PEEP according to the high PEEP-FiO 2 table and personalized PEEP following an EIT-guided PEEP trial. Methods We performed an EIT-guided decremental PEEP trial in patients with moderate-to-severe COVID-19-related ARDS upon intensive care unit admission. PEEP was set at the lowest PEEP above the intersection of curves representing relative alveolar overdistention and collapse. Baseline PEEP was compared with PEEP set according to EIT. We identified patients in whom the EIT-guided PEEP trial resulted in a decrease or increase in PEEP of ≥ 2 cmH 2 O. Measurements and main results We performed a PEEP trial in 75 patients. In 23 (31%) patients, PEEP was decreased ≥ 2 cmH 2 O, and in 24 (32%) patients, PEEP was increased ≥ 2 cmH 2 O. Patients in whom PEEP was decreased had improved respiratory mechanics and more overdistention in the non-dependent lung region at higher PEEP levels. These patients also had a lower BMI, longer time between onset of symptoms and intubation, and higher incidence of pulmonary embolism. Oxygenation improved in patients in whom PEEP was increased. Conclusions An EIT-guided PEEP trial resulted in a relevant change in PEEP in 63% of patients. These results support the hypothesis that PEEP should be personalized in patients with ARDS.

Background Heterogeneity of acute respiratory distress syndrome (ARDS) could be reduced by identification of biomarker-based phenotypes. The set of ARDS biomarkers to prospectively define these phenotypes remains to be established. Objective To provide an overview of the biomarkers that were multivariately associated with ARDS development or mortality. Data sources We performed a systematic search in Embase, MEDLINE, Web of Science, Cochrane CENTRAL, and Google Scholar from inception until 6 March 2020. Study selection Studies assessing biomarkers for ARDS development in critically ill patients at risk for ARDS and mortality due to ARDS adjusted in multivariate analyses were included. Data extraction and synthesis We included 35 studies for ARDS development (10,667 patients at risk for ARDS) and 53 for ARDS mortality (15,344 patients with ARDS). These studies were too heterogeneous to be used in a meta-analysis, as time until outcome and the variables used in the multivariate analyses varied widely between studies. After qualitative inspection, high plasma levels of angiopoeitin-2 and receptor for advanced glycation end products (RAGE) were associated with an increased risk of ARDS development. None of the biomarkers (plasma angiopoeitin-2, C-reactive protein, interleukin-8, RAGE, surfactant protein D, and Von Willebrand factor) was clearly associated with mortality. Conclusions Biomarker data reporting and variables used in multivariate analyses differed greatly between studies. Angiopoeitin-2 and RAGE in plasma were positively associated with increased risk of ARDS development. None of the biomarkers independently predicted mortality. Therefore, we suggested to structurally investigate a combination of biomarkers and clinical parameters in order to find more homogeneous ARDS phenotypes. PROSPERO identifier PROSPERO, CRD42017078957

Background Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1–4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment. Methods This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MIC ECOFF and ƒT > 4×MIC ECOFF ) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes. Results A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MIC ECOFF and 36.7% achieved 100%ƒT > 4×MIC ECOFF . Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m 2 , and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MIC ECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival. Conclusions Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Trial registration Netherlands Trial Registry (EXPAT trial), NTR 5632 . Registered on 7 December 2015.

Effect of noninvasive respiratory strategies on intubation or mortality among patients with acute hypoxemic respiratory failure and COVID-19: the RECOVERY-RS randomized clinical trial. Yoshida T, Grieco DL, Brochard L, Fujino Y. Patient self-inflicted lung injury and positive end-expiratory pressure for safe spontaneous breathing. Effect of esophageal pressure-guided positive end-expiratory pressure on survival from acute respiratory distress syndrome: a risk-based and mechanistic reanalysis of the EPVent-2 trial.

Abstract PurposeTo study the effect of interferon-α2 auto-antibodies (IFN-α2 Abs) on clinical and virological outcomes in critically ill COVID-19 patients and the risk of IFN-α2 Abs transfer during convalescent plasma treatment.MethodsSera from healthy controls, cases of COVID-19, and other respiratory illness were tested for IFN-α2 Abs by ELISA and a pseudo virus–based neutralization assay. The effects of disease severity, sex, and age on the risk of having neutralizing IFN-α2 Abs were determined. Longitudinal analyses were performed to determine association between IFN-α2 Abs and survival and viral load and whether serum IFN-α2 Abs appeared after convalescent plasma transfusion.ResultsIFN-α2 neutralizing sera were found only in COVID-19 patients, with proportions increasing with disease severity and age. In the acute stage of COVID-19, all sera from patients with ELISA-detected IFN-α2 Abs (13/164, 7.9%) neutralized levels of IFN-α2 exceeding physiological concentrations found in human plasma and this was associated with delayed viral clearance. Convalescent plasma donors that were anti-IFN-α2 ELISA positive (3/118, 2.5%) did not neutralize the same levels of IFN-α2. Neutralizing serum IFN-α2 Abs were associated with delayed viral clearance from the respiratory tract.ConclusionsIFN-α2 Abs were detected by ELISA and neutralization assay in COVID-19 patients, but not in ICU patients with other respiratory illnesses. The presence of neutralizing IFN-α2 Abs in critically ill COVID-19 is associated with delayed viral clearance. IFN-α2 Abs in COVID-19 convalescent plasma donors were not neutralizing in the conditions tested.

Background Patients with a severe COVID-19 infection often require admission at an intensive care unit (ICU) when they develop acute respiratory distress syndrome (ARDS). Hyperinflammation plays an important role in the development of ARDS in COVID-19. Procalcitonin (PCT) is a biomarker which may be a predictor of hyperinflammation. When patients with COVID-19 are in the emergency department (ED), elevated PCT levels could be associated with severe COVID-19 infections. The goal of this study is to investigate the association between PCT levels and severe COVID-19 infections in the ED. Methods This was a retrospective cohort study including patients with a confirmed COVID-19 infection who visited the ED of Erasmus Medical Center in Rotterdam, the Netherlands, between March and December 2020. The primary outcome was a severe COVID-19 infection, which was defined as patients who required ICU admission, all cause in-hospital mortality and mortality within 30 days after hospital discharge. PCT levels were measured during the ED visit. We used logistic regression to calculate the odds ratio (OR) with 95% confidence interval (95% CI) and corresponding area under the curve (AUC) of PCT on a severe COVID-19 infection, adjusting for bacterial coinfections, age, sex, comorbidities, C-reactive protein (CRP) and D-dimer. Results A total of 332 patients were included in the final analysis of this study, of which 105 patients reached the composite outcome of a severe COVID-19 infection. PCT showed an unadjusted OR of 4.19 (95%CI: 2.52–7.69) on a severe COVID-19 infection with an AUC of 0.82 (95% CI: 0.76–0.87). Corrected for bacterial coinfection, the OR of PCT was 4.05 (95% CI: 2.45–7.41). Adjusted for sex, bacterial coinfection, age any comorbidity, CRP and D-dimer, elevated PCT levels were still significantly associated with a severe COVID-19 infection with an adjusted OR of 2.11 (95% CI: 1.36–3.61). The AUC of this multivariable model was 0.85 (95%CI: 0.81–0.90). Conclusion High PCT levels are associated with high rates of severe COVID-19 infections in patients with a COVID-19 infection in the ED. The routine measurement of PCT in patients with a COVID-19 infection in the ED may assist physicians in the clinical decision making process regarding ICU disposition.

Background Several prediction models of survival after in-hospital cardiac arrest (IHCA) have been published, but no overview of model performance and external validation exists. We performed a systematic review of the available prognostic models for outcome prediction of attempted resuscitation for IHCA using pre-arrest factors to enhance clinical decision-making through improved outcome prediction. Methods This systematic review followed the CHARMS and PRISMA guidelines. Medline, Embase, Web of Science were searched up to October 2021. Studies developing, updating or validating a prediction model with pre-arrest factors for any potential clinical outcome of attempted resuscitation for IHCA were included. Studies were appraised critically according to the PROBAST checklist. A random-effects meta-analysis was performed to pool AUROC values of externally validated models. Results Out of 2678 initial articles screened, 33 studies were included in this systematic review: 16 model development studies, 5 model updating studies and 12 model validation studies. The most frequently included pre-arrest factors included age, functional status, (metastatic) malignancy, heart disease, cerebrovascular events, respiratory, renal or hepatic insufficiency, hypotension and sepsis. Only six of the developed models have been independently validated in external populations. The GO-FAR score showed the best performance with a pooled AUROC of 0.78 (95% CI 0.69–0.85), versus 0.59 (95%CI 0.50–0.68) for the PAM and 0.62 (95% CI 0.49–0.74) for the PAR. Conclusions Several prognostic models for clinical outcome after attempted resuscitation for IHCA have been published. Most have a moderate risk of bias and have not been validated externally. The GO-FAR score showed the most acceptable performance. Future research should focus on updating existing models for use in clinical settings, specifically pre-arrest counselling. Systematic review registration PROSPERO CRD42021269235. Registered 21 July 2021.

Background In-hospital cardiac arrest (IHCA) is a major adverse event with a high mortality rate if not treated appropriately. Extracorporeal cardiopulmonary resuscitation (ECPR), as adjunct to conventional cardiopulmonary resuscitation (CCPR), is a promising technique for IHCA treatment. Evidence pertaining to neurological outcomes after ECPR is still scarce. Methods We performed a comprehensive systematic search of all studies up to December 20, 2019. Our primary outcome was neurological outcome after ECPR at any moment after hospital discharge, defined by the Cerebral Performance Category (CPC) score. A score of 1 or 2 was defined as favourable outcome. Our secondary outcome was post-discharge mortality. A fixed-effects meta-analysis was performed. Results Our search yielded 1215 results, of which 19 studies were included in this systematic review. The average survival rate was 30% (95% CI 28–33%, I 2  = 0%, p  = 0.24). In the surviving patients, the pooled percentage of favourable neurological outcome was 84% (95% CI 80–88%, I 2  = 24%, p  = 0.90). Conclusion ECPR as treatment for in-hospital cardiac arrest is associated with a large proportion of patients with good neurological outcome. The large proportion of favourable outcome could potentially be explained by the selection of patients for treatment using ECPR. Moreover, survival is higher than described in the conventional CPR literature. As indications for ECPR might extend to older or more fragile patient populations in the future, research should focus on increasing survival, while maintaining optimal neurological outcome.

Background Prolonged weaning from mechanical ventilation is associated with poor clinical outcome. Therefore, choosing the right moment for weaning and extubation is essential. Electrical Impedance Tomography (EIT) is a promising innovative lung monitoring technique, but its role in supporting weaning decisions is yet uncertain. We aimed to evaluate physiological trends during a T-piece spontaneous breathing trail (SBT) as measured with EIT and the relation between EIT parameters and SBT success or failure. Methods This is an observational study in which twenty-four adult patients receiving mechanical ventilation performed an SBT. EIT monitoring was performed around the SBT. Multiple EIT parameters including the end-expiratory lung impedance (EELI), delta Tidal Impedance (ΔZ), Global Inhomogeneity index (GI), Rapid Shallow Breathing Index (RSBI EIT ), Respiratory Rate (RR EIT ) and Minute Ventilation (MV EIT ) were computed on a breath-by-breath basis from stable tidal breathing periods. Results EELI values dropped after the start of the SBT ( p  < 0.001) and did not recover to baseline after restarting mechanical ventilation. The ΔZ dropped ( p  < 0.001) but restored to baseline within seconds after restarting mechanical ventilation. Five patients failed the SBT, the GI ( p  = 0.01) and transcutaneous CO 2 ( p  < 0.001) values significantly increased during the SBT in patients who failed the SBT compared to patients with a successful SBT. Conclusion EIT has the potential to assess changes in ventilation distribution and quantify the inhomogeneity of the lungs during the SBT. High lung inhomogeneity was found during SBT failure. Insight into physiological trends for the individual patient can be obtained with EIT during weaning from mechanical ventilation, but its role in predicting weaning failure requires further study.

Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation. In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerised randomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00471640. Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4–5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6·5 days (IQR 5·0–9·0) in the dexamethasone group compared with 7·5 days (5·3–11·5) in the placebo group (95% CI of difference in medians 0–2 days; p=0·0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p<0·0001). Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in non-immunocompromised patients with community-acquired pneumonia. None.