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Background Ventilator-associated pneumonia (VAP) is common in patients with severe SARS-CoV-2 pneumonia. The aim of this ancillary analysis of the coVAPid multicenter observational retrospective study is to assess the relationship between adjuvant corticosteroid use and the incidence of VAP. Methods Planned ancillary analysis of a multicenter retrospective European cohort in 36 ICUs. Adult patients receiving invasive mechanical ventilation for more than 48 h for SARS-CoV-2 pneumonia were consecutively included between February and May 2020. VAP diagnosis required strict definition with clinical, radiological and quantitative microbiological confirmation. We assessed the association of VAP with corticosteroid treatment using univariate and multivariate cause-specific Cox’s proportional hazard models with adjustment on pre-specified confounders. Results Among the 545 included patients, 191 (35%) received corticosteroids. The proportional hazard assumption for the effect of corticosteroids on the incidence of VAP could not be accepted, indicating that this effect varied during ICU stay. We found a non-significant lower risk of VAP for corticosteroid-treated patients during the first days in the ICU and an increased risk for longer ICU stay. By modeling the effect of corticosteroids with time-dependent coefficients, the association between corticosteroids and the incidence of VAP was not significant (overall effect p = 0.082), with time-dependent hazard ratios (95% confidence interval) of 0.47 (0.17–1.31) at day 2, 0.95 (0.63–1.42) at day 7, 1.48 (1.01–2.16) at day 14 and 1.94 (1.09–3.46) at day 21. Conclusions No significant association was found between adjuvant corticosteroid treatment and the incidence of VAP, although a time-varying effect of corticosteroids was identified along the 28-day follow-up.

Background Post-operative pulmonary complications (PPC) can develop in up to 13% of patients undergoing neurosurgical procedures and may adversely affect clinical outcome. The use of intraoperative lung protective ventilation (LPV) strategies, usually including the use of a low Vt, low PEEP and low plateau pressure, seem to reduce the risk of PPC and are strongly recommended in almost all surgical procedures. Nonetheless, feasibility of LPV strategies in neurosurgical patients are still debated because the use of low Vt during LPV might result in hypercapnia with detrimental effects on cerebrovascular physiology. Aim of our study was to determine whether LPV strategies would be feasible compared with a control group in adult patients undergoing cranial or spinal surgery. Methods This single-centre, pilot randomized clinical trial was conducted at the University Hospital “Maggiore della Carità” (Novara, Italy). Adult patients undergoing major cerebral or spinal neurosurgical interventions with risk index for pulmonary post-operative complications > 2 and not expected to need post-operative intensive care unit (ICU) admission were considered eligible. Patients were randomly assigned to either LPV (Vt = 6 ml/kg of ideal body weight (IBW), respiratory rate initially set at 16 breaths/min, PEEP at 5 cmH2O and application of a recruitment manoeuvre (RM) immediately after intubation and at every disconnection from the ventilator) or control treatment (Vt = 10 ml/kg of IBW, respiratory rate initially set at 6–8 breaths/min, no PEEP and no RM). Primary outcomes of the study were intraoperative adverse events, the level of cerebral tension at dura opening and the intraoperative control of PaCO2. Secondary outcomes were the rate of pulmonary and extrapulmonary complications, the number of unplanned ICU admissions, ICU and hospital lengths of stay and mortality. Results A total of 60 patients, 30 for each group, were randomized. During brain surgery, the number of episodes of intraoperative hypercapnia and grade of cerebral tension were similar between patients randomized to receive control or LPV strategies. No difference in the rate of intraoperative adverse events was found between groups. The rate of postoperative pulmonary and extrapulmonary complications and major clinical outcomes were similar between groups. Conclusions LPV strategies in patients undergoing major neurosurgical intervention are feasible. Larger clinical trials are needed to assess their role in postoperative clinical outcome improvements. Trial registration registered on the Australian New Zealand Clinical Trial Registry (www.anzctr.org.au), registration number ACTRN12615000707561.

Background INTELLiVENT–Adaptive Support Ventilation (ASV) is a fully automated closed-loop mode of ventilation for use in critically ill patients. Evidence for benefit of INTELLiVENT–ASV in comparison to ventilation that is not fully automated with regard to duration of ventilation and quality of breathing is largely lacking. We test the hypothesis that INTELLiVENT–ASV shortens time spent on a ventilator and improves the quality of breathing. Methods The “Effects of Automated Closed–loop VenTilation versus Conventional Ventilation on Duration and Quality of Ventilation” (ACTiVE) study is an international, multicenter, two-group randomized clinical superiority trial. In total, 1200 intensive care unit (ICU) patients with an anticipated duration of ventilation of > 24 h will be randomly assigned to one of the two ventilation strategies. Investigators screen patients aged 18 years or older at start of invasive ventilation in the ICU. Patients either receive automated ventilation by means of INTELLiVENT–ASV, or ventilation that is not automated by means of a conventional ventilation mode. The primary endpoint is the number of days free from ventilation and alive at day 28; secondary endpoints are quality of breathing using granular breath-by-breath analysis of ventilation parameters and variables in a time frame of 24 h early after the start of invasive ventilation, duration of ventilation in survivors, ICU and hospital length of stay (LOS), and mortality rates in the ICU and hospital, and at 28 and 90 days. Discussion ACTiVE is one of the first randomized clinical trials that is adequately powered to compare the effects of automated closed-loop ventilation versus conventional ventilation on duration of ventilation and quality of breathing in invasively ventilated critically ill patients. The results of ACTiVE will support intensivist in their choices regarding the use of automated ventilation. Trial registration ACTiVE is registered in clinicaltrials.gov (study identifier: NCT04593810) on 20 October 2020.

Background Ventilator-associated pneumonia (VAP) is a severe infection among patients in the neurosurgery intensive care unit (NICU). Methods We retrospectively evaluated risk factors for early-onset ventilator-associated pneumonia (EOVAP) from January 2019 to December 2019 at a NICU. A total of 89 NICU patients who were intubated within 48 h of onset and whose mechanical ventilation time was at least 7 days were enrolled. We evaluated EOVAP that occurred within the first 7 days after the onset of mechanical ventilation. The enrolled patients had no history of chronic lung disease and no clinical manifestations of infection before intubation. Clinical data of patients were recorded, and the incidence of and risk factors for EOVAP were analyzed. Patients were also grouped by age (≥ 65 vs. Results Among 89 mechanically ventilated patients (49 men and 40 women; the mean age ± SD was 60.1 ± 14.3 years), 40 patients (44.9%) developed EOVAP within 7 days and 14 patients (15.7%) had a multidrug resistant bacterial infection. Binary logistic regression analysis indicated that older age (≥ 65 years) (odds ratio [OR]:3.53, 95% confidence interval [CI]:1.27–9.79, P = 0.015) and therapeutic hypothermia (OR:3.68, CI:1.10–12.31, p = 0.034) were independent predictors of EOVAP. Levels of peripheral blood leukocytes, neutrophils and platelets were lower in the therapeutic hypothermia group than those who did not receive hypothermia treatment. Conclusions This study found that older age (≥ 65 years) and therapeutic hypothermia were independently associated with the risk of EOVAP in NICU patients.

Background The role of neuromuscular blocking agents (NMBAs) in coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) is not fully elucidated. Therefore, we aimed to investigate in COVID-19 patients with moderate-to-severe ARDS the impact of early use of NMBAs on 90-day mortality, through propensity score (PS) matching analysis. Methods We analyzed a convenience sample of patients with COVID-19 and moderate-to-severe ARDS, admitted to 244 intensive care units within the COVID-19 Critical Care Consortium, from February 1, 2020, through October 31, 2021. Patients undergoing at least 2 days and up to 3 consecutive days of NMBAs (NMBA treatment), within 48 h from commencement of IMV were compared with subjects who did not receive NMBAs or only upon commencement of IMV (control). The primary objective in the PS-matched cohort was comparison between groups in 90-day in-hospital mortality, assessed through Cox proportional hazard modeling. Secondary objectives were comparisons in the numbers of ventilator-free days (VFD) between day 1 and day 28 and between day 1 and 90 through competing risk regression. Results Data from 1953 patients were included. After propensity score matching, 210 cases from each group were well matched. In the PS-matched cohort, mean (± SD) age was 60.3 ± 13.2 years and 296 (70.5%) were male and the most common comorbidities were hypertension (56.9%), obesity (41.1%), and diabetes (30.0%). The unadjusted hazard ratio (HR) for death at 90 days in the NMBA treatment vs control group was 1.12 (95% CI 0.79, 1.59, p = 0.534). After adjustment for smoking habit and critical therapeutic covariates, the HR was 1.07 (95% CI 0.72, 1.61, p = 0.729). At 28 days, VFD were 16 (IQR 0–25) and 25 (IQR 7–26) in the NMBA treatment and control groups, respectively (sub-hazard ratio 0.82, 95% CI 0.67, 1.00, p = 0.055). At 90 days, VFD were 77 (IQR 0–87) and 87 (IQR 0–88) (sub-hazard ratio 0.86 (95% CI 0.69, 1.07; p = 0.177). Conclusions In patients with COVID-19 and moderate-to-severe ARDS, short course of NMBA treatment, applied early, did not significantly improve 90-day mortality and VFD. In the absence of definitive data from clinical trials, NMBAs should be indicated cautiously in this setting.

Background We evaluated the efficacy of high protein intake and early exercise versus standard nutrition care and routine physiotherapy on the outcome of critically ill patients. Methods We randomized mechanically ventilated patients expected to stay in the intensive care unit (ICU) for 4 days. We used indirect calorimetry to determine energy expenditure and guide caloric provision to the patients randomized to the high protein and early exercise (HPE) group and the control group. Protein intakes were 1.48 g/kg/day and 1.19 g/kg/day medians respectively; while the former was submitted to two daily sessions of cycle ergometry exercise, the latter received routine physiotherapy. We evaluated the primary outcome physical component summary (PCS) score at 3 and 6 months) and the secondary outcomes (handgrip strength at ICU discharge and ICU and hospital mortality). Results We analyzed 181 patients in the HPE (87) and control (94) group. There was no significant difference between groups in relation to calories received. However, the amount of protein received by the HPE group was significantly higher than that received by the control group (p p = 0.01) and 6 months (p = 0.01). The mortality was expressively higher in the control group. We found an independent association between age and 3-month PCS and that between age and group and 6-month PCS. Conclusion This study showed that a high-protein intake and resistance exercise improved the physical quality of life and survival of critically ill patients. Trial registration Research Ethics Committee of Hospital São Domingos: Approval number 1.487.683, April 09, 2018. The study protocol was registered in ClinicalTrials.gov (NCT03469882, March 19,2018).

BackgroundTo investigate the effect of extubation in the operating room (OR) on mechanical ventilation-related adverse outcomes in patients who undergo liver transplantation.MethodsPatients who underwent liver transplantation between January 2016 and December 2019 were included. According to the timing of extubation, patients were divided into OR extubation group and intensive care unit (ICU) extubation group. The propensity score was used to match OR extubation group and ICU extubation group at a 1:2 ratio by demographical and clinical covariates. The primary outcome was a composite of mechanical ventilation-related adverse outcomes, including 30-day all-cause mortality, in-hospital acute kidney injury (stage 2 or 3), and in-hospital moderate to severe pulmonary complications. Secondary outcomes included in-hospital moderate to severe infectious complications, unplanned reintubation rates, ICU and postoperative hospital lengths of stay, and total hospital cost.ResultsA total of 438 patients were enrolled. After propensity score matching, 94 patients were in OR extubation group and 148 patients were in ICU extubation group. Incidence of the composite mechanical ventilation-related adverse outcomes was significantly lower in OR extubation group than ICU extubation group, even after adjusting for confounding factors (19.1%vs.31.8%; Odds Ratio, 0.509; 95% Confidence Index [CI], 0.274-0.946;P=0.031). The duration of ICU stay was much shorter in OR extubation group than ICU extubation group (median 4, Interquartile range [IQR] (3 ~ 6)vs.median 6, IQR (4 ~ 8);Pvs.median 4.1, IQR (3.8 ~ 5.1) 10000 US dollars;P=0.021). However, there were no statistically significant differences in moderate to severe infectious complications, unplanned reintubation rates, and the length of postoperative hospital stay between groups.ConclusionsAmong patients who underwent liver transplantation, extubation in the OR compared with extubation in the ICU, significantly reduced the primary composite outcome of 30-day all-cause mortality, in-hospital acute kidney injury (stage 2 or 3), or in-hospital moderate to severe pulmonary complications.Trial registrationThe trial was registered atwww.clinicaltrials.govwith registration number NCT04261816. Retrospectively registered on 1st February 2020.

Background Rapid shallow breathing index (RSBI) is the most commonly used parameter for predicting weaning outcome. Measurement of RSBI by Wright spirometer (RSBIstandard) is the standard method in routine clinical practice. Data specific to the accuracy and reliability of the RSBI value displayed by the ventilator (RSBIvent) are scarce. Accordingly, this study aimed to evaluate the association between the average value of RSBIvent at different time points and RSBIstandard, and to assess the accuracy and reliability of these two RSBI measurement techniques. Methods This prospective cohort study included mechanically ventilated patients who were ready to wean. At the beginning of spontaneous breathing trial using the flow-by method, RSBI was measured by two different techniques at the same time, including: (1) Wright spirometer (breathing frequency/average tidal volume in 1 min) (RSBIstandard), and (2) the values displayed on the ventilator at 0, 15, 30, 45, and 60 s (RSBIvent). Results Forty-seven patients were enrolled. The RSBIvent value was significantly higher than the RSBIstandard value for every comparison. According to Spearman’s correlation coefficient (r) and intraclass correlation coefficient (ICC), the average value of RSBI from 5 time points (0, 15, 30, 45, and 60 s) showed the best correlation with the standard technique (r = 0.76 [P standard and the RSBIvent value averaged among 5 time points (mean difference − 17.1 breaths/min/L). Conclusions We found that the ventilator significantly overestimates the RSBI value compared to the standard technique by Wright spirometer. The average RSBIvent value among 5 time points (0, 15, 30, 45, and 60 s) was found to best correlate with RSBIstandard.

Objectives Defined as the energy applied to the respiratory system by ventilator, mechanical power (MP) of ventilation reflects the risk of ventilation-induced lung injury. This study aims to explore the relationship between dynamic changes in MP and prognosis in critically ill patients. Methods This was a single-centre retrospective cohort study. Patients receiving mechanical ventilation with acute respiratory failure (ARF) and MP > 10 J/min on admission in the ICU were included. MP (J/min) was calculated as 0.098 × minute ventilation (L/min) × [(peak inspiratory pressure + positive end-expiratory pressure)/2] and the MP variation rate (%) as ([baseline MP − 24-h MP]/baseline MP) × 100. Patients were divided into two groups according to whether MP decreased 24 h after admission (MP-improved group defined as 24-h MP variation rate > 0% vs. MP-worsened group defined as 24-h MP variation rate ≤ 0%). Results In total, 14,463 patients were screened between January 2015 and June 2020, and finally, a study cohort of 602 patients was obtained. The MP-improved group had a lower ICU mortality rate than the MP-worsened group (24% vs. 36%; p = 0.005). The 24-h MP variation rate was associated with ICU mortality after adjusting for confounders (odds ratio, 0.906 [95% CI 0.833–0.985]; p = 0.021), while baseline MP (p = 0.909) and 24-h MP (p = 0.059) were not. All MP components improved in the MP-improved group, while minute ventilation and positive end-expiratory pressure contributed to the increase in MP in the MP-worsened group. Conclusions The 24-h MP variation rate was an independent risk factor for ICU mortality among ARF patients with elevated MP. Early decreases in MP may provide prognostic benefits in this population.

Background In Poland, little is known about the most serious cases of influenza that need admittance to the intensive care unit (ICU), as well as the use of extracorporeal respiratory support. Methods This was an electronic survey comprising ICUs in two administrative regions of Poland. The aim of the study was to determine the number of influenza patients with respiratory failure admitted to the ICU in the autumn–winter season of 2018/2019. Furthermore, respiratory support, outcome and other pathogens detected in the airways were investigated. Results Influenza infection was confirmed in 76 patients. The A(H1N1)pdm09 strain was the most common. 34 patients died (44.7%). The median age was 62 years, the median sequential organ failure assessment (SOFA) score was 11 and was higher in patients who died (12 vs. 10, p = 0.017). Mechanical ventilation was used in 75 patients and high flow nasal oxygen therapy in 1 patient. Extracorporeal membrane oxygenation (ECMO) was used in 7 patients (6 survived), and extracorporeal carbon dioxide removal (ECCO2R) in 2 (1 survived). The prone position was used in 16 patients. In addition, other pathogens were detected in the airways on admittance to the ICU. Conclusion A substantial number of influenza infections occurred in the autumn–winter season of 2018/2019 that required costly treatment in the intensive care units. Upon admission to the ICU, influenza patients had a high degree of organ failure as assessed by the SOFA score, and the mortality rate was 44.7%. Advanced extracorporeal respiratory techniques offer real survival opportunities to patients with severe influenza-related ARDS. The presence of coinfection should be considered in patients with influenza and respiratory failure.

Background Mechanical Ventilation (MV) is a complex and central treatment process in the care of critically ill patients. It influences acid–base balance and can also cause prognostically relevant biotrauma by generating forces and liberating reactive oxygen species, negatively affecting outcomes. In this work we evaluate the use of a Recurrent Neural Network (RNN) modelling to predict outcomes of mechanically ventilated patients, using standard mechanical ventilation parameters. Methods We performed our analysis on VENTILA dataset, an observational, prospective, international, multi-centre study, performed to investigate the effect of baseline characteristics and management changes over time on the all-cause mortality rate in mechanically ventilated patients in ICU. Our cohort includes 12,596 adult patients older than 18, associated with 12,755 distinct admissions in ICUs across 37 countries and receiving invasive and non-invasive mechanical ventilation. We carry out four different analysis. Initially we select typical mechanical ventilation parameters and evaluate the machine learning model on both, the overall cohort and a subgroup of patients admitted with respiratory disorders. Furthermore, we carry out sensitivity analysis to evaluate whether inclusion of variables related to the function of other organs, improve the predictive performance of the model for both the overall cohort as well as the subgroup of patients with respiratory disorders. Results Predictive performance of RNN-based model was higher with Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) of 0.72 (± 0.01) and Average Precision (AP) of 0.57 (± 0.01) in comparison to RF and LR for the overall patient dataset. Higher predictive performance was recorded in the subgroup of patients admitted with respiratory disorders with AUC of 0.75 (± 0.02) and AP of 0.65 (± 0.03). Inclusion of function of other organs further improved the performance to AUC of 0.79 (± 0.01) and AP 0.68 (± 0.02) for the overall patient dataset and AUC of 0.79 (± 0.01) and AP 0.72 (± 0.02) for the subgroup with respiratory disorders. Conclusion The RNN-based model demonstrated better performance than RF and LR in patients in mechanical ventilation and its subgroup admitted with respiratory disorders. Clinical studies are needed to evaluate whether it impacts decision-making and patient outcomes. Trial registration: NCT02731898 ( https://clinicaltrials.gov/ct2/show/NCT02731898 ), prospectively registered on April 8, 2016.

Background Fluid overload has been associated with increased morbidity and mortality in critically ill patients. The goal of this study was to assess the efficacy and safety of a diuretic strategy to overcome positive fluid balance in patients on invasive mechanical ventilation. Methods Design: Multicenter, single-blind, randomized-controlled study. Patients were randomized into a diuretic (furosemide) or a control group. Patients were eligible in case of fluid overload defined as in-ICU weight increase ≥ 3%, invasive mechanical ventilation (FiO2 ≤ 60% and PEEP ≤ 10 cm H2O on inclusion) and hemodynamic stabilization. The primary outcome was fluid balance, defined as weight variation from reference weight to successful extubation. The main secondary outcome was the safety of diuretic. Results 171 patients were randomized. After 5 exclusions, 166 patients were included in the analysis: 77 in the diuretic and 89 in the control group. Fluid balance was 1.4 [− 2.5 to 4.5] kg in the diuretic and 6.4 [0.5–11.2] kg in the control group (p p p = 0.5). There was a worsening of Acute Kidney Injury in 67 (75.3%) patients of the control group versus 46 (59.7%) patients in the diuretic group (p = 0.03). Conclusions In this multicenter randomized-controlled study, protocolized diuretic therapy reduced fluid accumulation in patients receiving mechanical ventilation and was well tolerated with a favorable safety profile. Trial registration NCT 02345681, Registered January 26 2015, Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT02345681?term=02345681&draw=2&rank=1.

Objectives SARS-Cov-2 virus preferentially binds to the Angiotensin Converting Enzyme 2 (ACE2) on alveolar epithelial type II cells, initiating an inflammatory response and tissue damage which may impair surfactant synthesis contributing to alveolar collapse, worsening hypoxia and leading to respiratory failure. The objective of this study is to evaluate the feasibility, safety and efficacy of nebulised surfactant in COVID-19 adult patients requiring mechanical ventilation for respiratory failure. Trial design This study is a dose-escalating randomized open-label clinical trial of 20 COVID-19 patients. Participants This study is conducted in two centres: University Hospital Southampton and University College London Hospitals. Eligible participants are aged ≥18, hospitalised with COVID-19 (confirmed by PCR), who require endotracheal intubation and are enrolled within 24 hours of mechanical ventilation. For patients unable to consent, assent is obtained from a personal legal representative (PerLR) or professional legal representative (ProfLR) prior to enrolment. The following are exclusion criteria: imminent expected death within 24 hours; specific contraindications to surfactant administration (e.g. known allergy, pneumothorax, pulmonary hemorrhage); known or suspected pregnancy; stage 4 chronic kidney disease or requiring dialysis (i.e., eGFR < 30); liver failure (Child-Pugh Class C); anticipated transfer to another hospital, which is not a study site, within 72 hours; current or recent (within 1 month) participation in another study that, in the opinion of the investigator, would prevent enrollment for safety reasons; and declined consent or assent. Intervention and comparator Intervention: The study is based on an investigational drug/device combination product. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactant formulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilled syringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13% phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5% cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lyso-phosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, an investigational device based on the Aerogen® Solo vibrating mesh nebulizer. The timing and escalation dosing plans for the surfactant are as follows. Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and 30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention. Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240 mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls. 2 controls with no placebo intervention. The trial steering committee, advised by the data monitoring committee, will review trial progression and dose escalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached) based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinued on the basis of lack of efficacy. The trial may be stopped early on the basis of safety or feasibility concerns. Comparator: No placebo intervention. All participants will receive usual standard of care in accordance with the local policies for mechanically ventilated patients and all other treatments will be left to the discretion of the attending physician. Main outcomes The co-primary outcome is the improvement in oxygenation (PaO2/FiO2 ratio) and pulmonary ventilation (Ventilation Index (VI), where VI = [RR x (PIP − PEEP) × PaCO2]/1000) at 48 hours after study initiation. The secondary outcomes include frequency and severity of adverse events (AEs), Adverse Device Effects (ADEs), Serious Adverse Events (SAEs) and Serious Adverse Device Events (SADEs), change in pulmonary compliance, change in positive end-expiratory pressure (PEEP) requirement of ventilatory support at 24 and 48 hours after study initiation, clinical improvement defined by time to one improvement point on the ordinal scale described in the WHO master protocol (2020) recorded while hospitalised, days of mechanical ventilation, mechanical ventilator free days (VFD) at day 21, length of intensive care unit stay, number of days hospitalised and mortality at day 28. Exploratory end points will include quantification of SARS-CoV-2 viral load from tracheal aspirates using PCR, surfactant dynamics (synthesis and turnover) and function (surface tension reduction) from deep tracheal aspirate samples (DTAS), surfactant phospholipid concentrations in plasma and DTAS, inflammatory markers (cellular and cytokine) in plasma and DTAS, and blood oxidative stress markers. Randomisation After informed assent, patients fulfilling inclusion criteria will be randomised to 3:2 for the treatment and control arms using an internet-based block randomization service (ALEA tool for clinical trials, FormsVision BV) in combination with electronic data collection. Randomisation will be done by the recruiting centre with a unique subject identifier specific to that centre. Blinding (masking) This is an open-labelled unblinded study. Numbers to be randomised (sample size) The total sample size is 20 COVID-19 mechanically ventilated patients (12 intervention; 8 control). Trial Status Current protocol version is V2 dated 5th of June 2020. The recruitment is currently ongoing and started on the 14th of October 2020. The anticipated study completion date is November 2021. Trial registration ClinicalTrials.gov: NCT04362059 (Registered 24 April 2020), EUDAMED number: CIV-GB-20-06-033328, EudraCT number: 2020-001886-35 (Registered 11 May 2020) Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Background: The COVID-19 pandemic reached Europe in early 2020. Convalescent plasma is used without a consistent evidence of efficacy. Our hypothesis is that passive immunization with plasma collected from patients having contracted COVID-19 and developed specific neutralizing antibodies may alleviate symptoms and reduce mortality in patients treated with mechanical ventilation for severe respiratory failure during the evolution of SARS-CoV-2 pneumonia. Methods: We plan to include 500 adult patients, hospitalized in 16 Belgian intensive care units between September 2020 and 2022, diagnosed with SARS-CoV-2 pneumonia, under mechanical ventilation for less than 5 days and a clinical frailty scale less than 6. The study treatment will be compared to standard of care and allocated by randomization in a 1 to 1 ratio without blinding. The main endpoint will be mortality at day 28. We will perform an intention to treat analysis. The number of patients to include is based on an expected mortality rate at day 28 of 40 percent and an expected relative reduction with study intervention of 30 percent with α risk of 5 percent and β risk of 20 percent. Discussion: This study will assess the efficacy of plasma in the population of mechanically ventilated patients. A stratification on the delay from mechanical ventilation and inclusion will allow to approach the optimal time use. Selecting convalescent plasmas with a high titer of neutralizing antibodies against SARS-CoV-2 will allow a homogeneous study treatment. The inclusion in the study is based on the consent of the patient or his/her legal representative, and the approval of the Investigational Review Board of the University hospital of Liège, Belgium. A data safety monitoring board (DSMB) has been implemented. Interim analyses have been planned at 100, 2002, 300 and 400 inclusions in order to decide whether the trail should be discontinued prematurely for ethical issues. We plan to publish our results in a peer-reviewed journal and to present them at national and international conferences. Funding and registration: The trial is funded by the Belgian Health Care Knowledge Center KCE, SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction Pressure support ventilation (PSV) should allow spontaneous breathing with a “normal” neuro-ventilatory drive. Low neuro-ventilatory drive puts the patient at risk of diaphragmatic atrophy while high neuro-ventilatory drive may causes dyspnea and patient self-inflicted lung injury. We continuously assessed for 12 h the electrical activity of the diaphragm (EAdi), a close surrogate of neuro-ventilatory drive, during PSV. Our aim was to document the EAdi trend and the occurrence of periods of “Low” and/or “High” neuro-ventilatory drive during clinical application of PSV. Method In 16 critically ill patients ventilated in the PSV mode for clinical reasons, inspiratory peak EAdi peak (EAdiPEAK), pressure time product of the trans-diaphragmatic pressure per breath and per minute (PTPDI/b and PTPDI/min, respectively), breathing pattern and major asynchronies were continuously monitored for 12 h (from 8 a.m. to 8 p.m.). We identified breaths with “Normal” (EAdiPEAK 5–15 μV), “Low” (EAdiPEAK PEAK > 15 μV) neuro-ventilatory drive. Results Within all the analyzed breaths (177.117), the neuro-ventilatory drive, as expressed by the EAdiPEAK, was “Low” in 50.116 breath (28%), “Normal” in 88.419 breaths (50%) and “High” in 38.582 breaths (22%). The average times spent in “Low”, “Normal” and “High” class were 1.37, 3.67 and 0.55 h, respectively (p Conclusions We observed wide variations in EAdi amplitude and unevenly distributed “Low” and “High” neuro ventilatory drive periods during 12 h of PSV in critically ill patients. Further studies are needed to assess the possible clinical implications of our physiological findings.

Background Several randomized controlled trials (RCTs) have compared the treatment of acute lung injury (ALI) with omega-3 fatty, yet the results remained inconsistent. Therefore, we attempted this meta-analysis to analyze the role of omega-3 fatty in the treatment of ALI patients. Methods We searched PubMed databases from inception date to October 31, 2019, for RCTs that compared the treatment of ALI with or without omega-3 fatty. Two authors independently screened the studies and extracted data from the published articles. Summary mean differences (MD) with 95% confidence intervals (CI) were calculated for each outcome by fixed- or random-effects model. Results Six RCTs with a total of 277 patients were identified, of whom 142 patients with omega-3 fatty acid treatment and 135 patients without omega-3 fatty treatment. Omega-3 fatty treatments significantly improve the PaO2 (MD = 13.82, 95% CI 8.55–19.09), PaO2/FiO2 (MD = 33.47, 95% CI 24.22–42.72), total protein (MD = 2.02, 95% CI 0.43–3.62) in ALI patients, and omega-3 fatty acid treatments reduced the duration of mechanical ventilation (MD = − 1.72, 95% CI − 2.84 to − 0.60) and intensive care unit stay (MD = − 1.29, 95% CI − 2.14 to − 0.43) in ALI patients. Conclusions Omega-3 fatty can effectively improve the respiratory function and promote the recovery of ALI patients. Future studies focused on the long-term efficacy and safety of omega-3 fatty use for ALI are needed.

Background Reinforcement learning (RL) provides a promising technique to solve complex sequential decision making problems in healthcare domains. Recent years have seen a great progress of applying RL in addressing decision-making problems in Intensive Care Units (ICUs). However, since the goal of traditional RL algorithms is to maximize a long-term reward function, exploration in the learning process may have a fatal impact on the patient. As such, a short-term goal should also be considered to keep the patient stable during the treating process. Methods We use a Supervised-Actor-Critic (SAC) RL algorithm to address this problem by combining the long-term goal-oriented characteristics of RL with the short-term goal of supervised learning. We evaluate the differences between SAC and traditional Actor-Critic (AC) algorithms in addressing the decision making problems of ventilation and sedative dosing in ICUs. Results Results show that SAC is much more efficient than the traditional AC algorithm in terms of convergence rate and data utilization. Conclusions The SAC algorithm not only aims to cure patients in the long term, but also reduces the degree of deviation from the strategy applied by clinical doctors and thus improves the therapeutic effect.

Objective In septic patients, multiple retrospective studies show an association between large volumes of fluids administered in the first 24 h and mortality, suggesting a benefit to fluid restrictive strategies. However, these studies do not directly estimate the causal effects of fluid-restrictive strategies, nor do their analyses properly adjust for time-varying confounding by indication. In this study, we used causal inference techniques to estimate mortality outcomes that would result from imposing a range of arbitrary limits (“caps”) on fluid volume administration during the first 24 h of intensive care unit (ICU) care. Design Retrospective cohort study Setting ICUs at the Beth Israel Deaconess Medical Center, 2008–2012 Patients One thousand six hundred thirty-nine septic patients (defined by Sepsis-3 criteria) 18 years and older, admitted to the ICU from the emergency department (ED), who received less than 4 L fluids administered prior to ICU admission Measurements and main results Data were obtained from the Medical Information Mart for Intensive Care III (MIMIC-III). We employed a dynamic Marginal Structural Model fit by inverse probability of treatment weighting to obtain confounding adjusted estimates of mortality rates that would have been observed had fluid resuscitation volume caps between 4 L–12 L been imposed on the population. The 30-day mortality in our cohort was 17%. We estimated that caps between 6 and 10 L on 24 h fluid volume would have reduced 30-day mortality by − 0.6 to − 1.0%, with the greatest reduction at 8 L (− 1.0% mortality, 95% CI [− 1.6%, − 0.3%]). Conclusions We found that 30-day mortality would have likely decreased relative to observed mortality under current practice if these patients had been subject to “caps” on the total volume of fluid administered between 6 and 10 L, with the greatest reduction in mortality rate at 8 L.

Background Mechanically ventilated patients in the intensive care unit (ICU) experience profound communication impairment, placing them at risk for poor physical and psychological outcomes. Patient communication strategies such as augmentative and alternative communication (AAC) and voice restorative devices are recommended to facilitate communication. These strategies, however, are inconsistently adopted in ICU practice signaling utilization barriers. Our objective is to map and synthesize the current evidence-base for stakeholder-reported barriers and facilitators to patient communication strategy utilization for adults with an advanced airway in the ICU. Methods and analysis We will use Arskey and O’Malley’s recommended methods to conduct a scoping review using a rapid review framework to streamline the process. A single reviewer will conduct a search and an initial screen of titles and abstracts from five electronic databases (MEDLINE, EMBASE, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature [CINAHL], and PsychInfo) from 1990 to present to identify English language peer-reviewed studies. Subsequently, two reviewers will independently screen a shorter list of studies for inclusion. We will also search the reference lists of eligible studies. Two reviewers will independently extract study characteristics, communication strategy, and stakeholder reported barriers and facilitators. We will code and categorize the extracted barriers and facilitators according to the Theoretical Domains Framework (TDF), an integrative framework of behavior change. Discussion To our knowledge, this will be the first scoping review to map and synthesize reported barriers and facilitators to communication strategy utilization in the adult ICU using a theoretical framework. The results of this scoping review will help to identify trends and gaps in the current evidence-base and support recommendations for improving patient-centered practice, policy, and research related to successfully establishing ICU patient communication.

Obesity is associated with the development of acute respiratory distress syndrome (ARDS) in at-risk patients. Low plasma levels of adiponectin, a circulating hormone-like molecule, have been implicated as a possible mechanism for this association. The objective of this study was to determine the association of plasma adiponectin level at ICU admission with ARDS and 30-day mortality in patients with severe sepsis and septic shock.This is a prospective cohort study of patients admitted to the medical ICU at the Hospital of the University of Pennsylvania. Plasma adiponectin was measured at the time of ICU admission. ARDS was defined by Berlin criteria. Multivariable logistic regression was used to determine the association of plasma adiponectin with the development of ARDS and mortality at 30 days.The study included 164 patients. The incidence of ARDS within 5 days of admission was 45%. The median initial plasma adiponectin level was 7.62 mcg/ml (IQR: 3.87, 14.90) in those without ARDS compared to 8.93 mcg/ml (IQR: 4.60, 18.85) in those developing ARDS. The adjusted odds ratio for ARDS associated with each 5 mcg increase in adiponectin was 1.12 (95% CI 1.01, 1.25), p-value 0.025). A total of 82 patients (51%) of the cohort died within 30 days of ICU admission. There was a statistically significant association between adiponectin and mortality in the unadjusted model (OR 1.11, 95% CI 1.00, 1.23, p-value 0.04) that was no longer significant after adjusting for potential confounders.In this study, low levels of adiponectin were not associated with an increased risk of ARDS in patients with severe sepsis and septic shock. This argues against low levels of adiponectin as a mechanism explaining the association of obesity with ARDS. At present, it is unclear whether circulating adiponectin is involved in the pathogenesis of ARDS or simply represents an epiphenomenon of other unknown functions of adipose tissue or metabolic alterations in sepsis.

Patients admitted to the intensive care unit (ICU) often require invasive mechanical ventilation. Ventilator-associated lower respiratory tract infections (VA-LRTI), either ventilator-associated tracheobronchitis (VAT) or ventilator-associated pneumonia (VAP), are the most common complication among this patient cohort. VAT and VAP are currently diagnosed and treated as separate entities, viewed as binary disease elements despite an inherent subjectivity in distinguishing them clinically. This paper describes a new approach to pulmonary infections in critically ill patients. Our conjecture is that the host-pathogen interaction during mechanical ventilation determines a local compartmentalized or systemic de-compartmentalized response, based on host immunity and inflammation, and the pathogenic potential of the infecting organism. This compartmentalized or de-compartmentalized response establishes disease severity along a continuum of colonization, VAT or VAP. This change in approach is underpinned by the dissemination hypothesis, which acknowledges the role of immune and inflammatory systems in determining host response to pathogenic organisms in the lower respiratory tract. Those with intact immune and inflammatory pathways may limit infection to a compartmentalized VAT, while immunosuppressed mechanically ventilated patients are at greater risk of a de-compartmentalized VAP. Taking this model from the realm of theory to the bedside will require a greater understanding of inflammatory and immune pathways, and the development of novel disease-specific biomarkers and diagnostic techniques. Advances will lead to early initiation of optimal bespoke antimicrobial therapy, where the intensity and duration of therapy are tailored to clinical, immune and biomarker response. This approach will benefit towards a personalized treatment.

Background Hospital-acquired and ventilator-associated pneumonia (HAP/VAP) are often selected for randomized clinical trials (RCTs) aiming at new drug approval. Guidelines for the design of such RCTs have been repeatedly updated by regulatory agencies. We hypothesized that large variability in the enrolled populations, the endpoints assessed and the HAP/VAP definition criteria may impact the results of these studies, and addressed this through a systematic review of HAP/VAP RCTs. Methods A search (Pubmed-Embase-ICAAC-ECCMID) of all RCTs published between 1994 and 2016 comparing antimicrobial treatment for HAP/VAP in the intensive care unit was conducted. The populations enrolled, inclusion/exclusion criteria, statistical design and endpoints assessed were recorded. All unpublished RCTs recorded on the ClinicalTrials.gov registry were also screened. Results From the 93 abstracts reviewed, 39 potentially relevant studies were inspected, leading to 27 studies being included. As expected, illness severity or the proportion with VAP (27–100%) differed greatly among the enrolled populations. The HAP/VAP definition used various clinical and biological criteria, and only 55% of studies required a microbiological sample. The mandatory duration of prior hospital stay was variable; the mechanical ventilation duration was an inclusion criterion in only 41% of VAP studies. Nine studies had non-inferiority design, but nine studies (33%) did not have a pre-specified statistical hypothesis. Clinical cure was the primary endpoint in 24 studies, but was recorded in several populations or as the co-primary endpoint in 13 studies. The definition of clinical cure and the timing of its assessment greatly differed. This variability slightly improved over time but remained significant in the 13 registered but currently unpublished RCTs that we screened. Conclusion Our study provides a description of populations and endpoints of RCTs evaluating antimicrobials for treatment of HAP/VAP in the ICU. There was significant heterogeneity in enrollment criteria, endpoints and statistical design, which may influence the ability of studies to demonstrate differences between studied drugs. Electronic supplementary material The online version of this article (doi:10.1186/s13054-017-1755-5) contains supplementary material, which is available to authorized users.

Background Assessment of fluid responsiveness is problematic in intensive care unit (ICU) patients, in particular for those undergoing modes of partial support, such as pressure support ventilation (PSV). We propose a new test, based on application of a ventilator-generated sigh, to predict fluid responsiveness in ICU patients undergoing PSV. Methods This was a prospective bi-centric interventional study conducted in two general ICUs. In 40 critically ill patients with a stable ventilatory PSV pattern and requiring volume expansion (VE), we assessed the variations in arterial systolic pressure (SAP), pulse pressure (PP) and stroke volume index (SVI) consequent to random application of 4-s sighs at three different inspiratory pressures. A radial arterial signal was directed to the MOSTCARE™ pulse contour hemodynamic monitoring system for hemodynamic measurements. Data obtained during sigh tests were recorded beat by beat, while all the hemodynamic parameters were averaged over 30 s for the remaining period of the study protocol. VE consisted of 500 mL of crystalloids over 10 min. A patient was considered a responder if a VE-induced increase in cardiac index (CI) ≥ 15% was observed. Results The slopes for SAP, SVI and PP of were all significantly different between responders and non-responders (p

Background Intrapartum-related death is the third leading cause of under-5 mortality. Effective ventilation during neonatal resuscitation has the potential to reduce 40% of these deaths. Face-mask ventilation performed by midwives is globally the most common method of resuscitating neonates. It requires considerable operator skills and continuous training because of its complexity. The i-gel® is a cuffless supraglottic airway which is easy to insert and provides an efficient seal that prevents air leakage; it has the potential to enhance performance in neonatal resuscitation. A pilot study in Uganda demonstrated that midwives could safely resuscitate newborns with the i-gel® after a short training session. The aim of the present trial is to investigate whether the use of a cuffless supraglottic airway device compared with face-mask ventilation during neonatal resuscitation can reduce mortality and morbidity in asphyxiated neonates. Methods A randomized phase III open-label superiority controlled clinical trial will be conducted at Mulago Hospital, Kampala, Uganda, in asphyxiated neonates in the delivery units. Prior to the intervention, health staff performing resuscitation will receive training in accordance with the Helping Babies Breathe curriculum with a special module for training on supraglottic airway insertion. A total of 1150 to 1240 babies (depending on cluster size) that need positive pressure ventilation and that have an expected gestational age of more than 34 weeks and an expected birth weight of more than 2000 g will be ventilated by daily unmasked randomization with a supraglottic airway device (i-gel®) (intervention group) or with a face mask (control group). The primary outcome will be a composite outcome of 7-day mortality and admission to neonatal intensive care unit (NICU) with neonatal encephalopathy. Discussion Although indications for the beneficial effect of a supraglottic airway device in the context of neonatal resuscitation exist, so far no large studies powered to assess mortality and morbidity have been carried out. We hypothesize that effective ventilation will be easier to achieve with a supraglottic airway device than with a face mask, decreasing early neonatal mortality and brain injury from neonatal encephalopathy. The findings of this trial will be important for low and middle-resource settings where the majority of intrapartum-related events occur. Trial registration ClinicalTrials.gov. Identifier: NCT03133572. Registered April 28, 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3455-8) contains supplementary material, which is available to authorized users.

Background The study objective was to assess the influence of neutropenia on outcome of critically ill cancer patients by meta-analysis of individual data. Secondary objectives were to assess the influence of neutropenia on outcome of critically ill patients in prespecified subgroups (according to underlying tumor, period of admission, need for mechanical ventilation and use of granulocyte colony stimulating factor (G-CSF)). Methods Data sources were PubMed and the Cochrane database. Study selection included articles focusing on critically ill cancer patients published in English and studies in humans from May 2005 to May 2015. For study selection, the study eligibility was assessed by two investigators. Individual data from selected studies were obtained from corresponding authors. Results Overall, 114 studies were identified and authors of 30 studies (26.3% of selected studies) agreed to participate in this study. Of the 7515 included patients, three were excluded due to a missing major variable (neutropenia or mortality) leading to analysis of 7512 patients, including 1702 neutropenic patients (22.6%). After adjustment for confounders, and taking study effect into account, neutropenia was independently associated with mortality (OR 1.41; 95% CI 1.23–1.62; P = 0.03). When analyzed separately, neither admission period, underlying malignancy nor need for mechanical ventilation modified the prognostic influence of neutropenia on outcome. However, among patients for whom data on G-CSF administration were available (n = 1949; 25.9%), neutropenia was no longer associated with outcome in patients receiving G-CSF (OR 1.03; 95% CI 0.70–1.51; P = 0.90). Conclusion Among 7512 critically ill cancer patients included in this systematic review, neutropenia was independently associated with poor outcome despite a meaningful survival. Neutropenia was no longer significantly associated with outcome in patients treated by G-CSF, which may suggest a beneficial effect of G-CSF in neutropenic critically ill cancer patients. Systematic review registration PROSPERO CRD42015026347. Date of registration: Sept 18 2015 Electronic supplementary material The online version of this article (10.1186/s13054-018-2076-z) contains supplementary material, which is available to authorized users.

Background Ventilator-associated pneumonia (VAP) is a common nosocomial infection in intensive care units (ICUs). The objective of this study was to describe the epidemiology and microbiology of VAP in Polish ICUs from 2013 to 2015, as well as to understand how these depended on the diagnostic methods used to identify VAP pathogens and the clinical strategy for VAP treatment. Methods This observational study was carried out in seven Polish adult ICUs. VAP surveillance was based on the European Healthcare-associated Infections Surveillance Network recommendations and was defined as pneumonia occurring more than 48 h after receiving mechanical ventilation, with symptom onset 3 days or more after the hospital stay. Depending on the microbiological diagnostic method, VAP cases were classified as PNEU-1 (positive quantitative culture from minimally contaminated lower respiratory tract specimen such as broncho-alveolar lavage, protected brush or distal protected aspirate) or other VAP cases. Results The incidence of VAP was 8.0% and the incidence density: 12.3/1000 ventilator days. Microbiological diagnosis was made using PNEU-1 in 80 cases (39%); over the study duration, the proportion of cases diagnosed with PNEU-1 increased from 14 to 60% (p

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.

In this review, we seek to highlight how critical illness and critical care affect longer-term outcomes, to underline the contribution of ICU delirium to cognitive dysfunction several months after ICU discharge, to give new insights into ICU acquired weakness, to emphasize the importance of value-based healthcare, and to delineate the elements of family-centered care. This consensus of 29 also provides a perspective and a research agenda about post-ICU recovery., SCOPUS: re.j, info:eu-repo/semantics/published