Publications by authors named "Frederique Paulus"

59 Publications

Effect of INTELLiVENT-ASV versus Conventional Ventilation on Ventilation Intensity in Patients with COVID-19 ARDS-An Observational Study.

J Clin Med 2021 Nov 19;10(22). Epub 2021 Nov 19.

Department of Intensive Care, Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands.

Driving pressure (ΔP) and mechanical power (MP) are associated with outcomes in critically ill patients, irrespective of the presence of Acute Respiratory Distress Syndrome (ARDS). INTELLiVENT-ASV, a fully automated ventilatory mode, controls the settings that affect ΔP and MP. This study compared the intensity of ventilation (ΔP and MP) with INTELLiVENT-ASV versus conventional ventilation in a cohort of COVID-19 ARDS patients in two intensive care units in the Netherlands. The coprimary endpoints were ΔP and MP before and after converting from conventional ventilation to INTELLiVENT-ASV. Compared to conventional ventilation, INTELLiVENT-ASV delivered ventilation with a lower ΔP and less MP. With conventional ventilation, ΔP was 13 cmHO, and MP was 21.5 and 24.8 J/min, whereas with INTELLiVENT-ASV, ΔP was 11 and 10 cmHO (mean difference -2 cm H2O (95 %CI -2.5 to -1.2 cm HO), < 0.001) and MP was 18.8 and 17.5 J/min (mean difference -7.3 J/Min (95% CI -8.8 to -5.8 J/min), < 0.001). Conversion from conventional ventilation to INTELLiVENT-ASV resulted in a lower intensity of ventilation. These findings may favor the use of INTELLiVENT-ASV in COVID-19 ARDS patients, but future studies remain needed to see if the reduction in the intensity of ventilation translates into clinical benefits.
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http://dx.doi.org/10.3390/jcm10225409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622732PMC
November 2021

Incidence and Practice of Early Prone Positioning in Invasively Ventilated COVID-19 Patients-Insights from the PRoVENT-COVID Observational Study.

J Clin Med 2021 Oct 19;10(20). Epub 2021 Oct 19.

Department of Intensive Care, Amsterdam UMC, Location 'AMC', 1105 AZ Amsterdam, The Netherlands.

We describe the incidence and practice of prone positioning and determined the association of use of prone positioning with outcomes in invasively ventilated patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) in a national, multicenter observational study, performed at 22 intensive care units in the Netherlands. Patients were categorized into 4 groups, based on indication for and actual use of prone positioning. The primary outcome was 28-day mortality. Secondary endpoints were 90-day mortality, and ICU and hospital length of stay. In 734 patients, prone positioning was indicated in 60%-the incidence of prone positioning was higher in patients with an indication than in patients without an indication for prone positioning (77 vs. 48%, = 0.001). Patients were left in the prone position for median 15.0 (10.5-21.0) hours per full calendar day-the duration was longer in patients with an indication than in patients without an indication for prone positioning (16.0 (11.0-23.0) vs. 14.0 (10.0-19.0) hours, < 0.001). Ventilator settings and ventilation parameters were not different between the four groups, except for FiO which was higher in patients having an indication for and actually receiving prone positioning. Our data showed no difference in mortality at day 28 between the 4 groups (HR no indication, no prone vs. no indication, prone vs. indication, no prone vs. indication, prone: 1.05 (0.76-1.45) vs. 0.88 (0.62-1.26) vs. 1.15 (0.80-1.54) vs. 0.96 (0.73-1.26) ( = 0.08)). Factors associated with the use of prone positioning were ARDS severity and FiO. The findings of this study are that prone positioning is often used in COVID-19 patients, even in patients that have no indication for this intervention. Sessions of prone positioning lasted long. Use of prone positioning may affect outcomes.
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http://dx.doi.org/10.3390/jcm10204783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541588PMC
October 2021

Longitudinal respiratory subphenotypes in patients with COVID-19-related acute respiratory distress syndrome: results from three observational cohorts.

Lancet Respir Med 2021 Oct 12. Epub 2021 Oct 12.

Department of Intensive Care and Laboratory of Experimental Intensive Care and Anaesthesiology (L·E·I·C·A), Amsterdam UMC, Amsterdam, Netherlands.

Introduction: Patients with COVID-19-related acute respiratory distress syndrome (ARDS) have been postulated to present with distinct respiratory subphenotypes. However, most phenotyping schema have been limited by sample size, disregard for temporal dynamics, and insufficient validation. We aimed to identify respiratory subphenotypes of COVID-19-related ARDS using unbiased data-driven approaches.

Methods: PRoVENT-COVID was an investigator-initiated, national, multicentre, prospective, observational cohort study at 22 intensive care units (ICUs) in the Netherlands. Consecutive patients who had received invasive mechanical ventilation for COVID-19 (aged 18 years or older) served as the derivation cohort, and similar patients from two ICUs in the USA served as the replication cohorts. COVID-19 was confirmed by positive RT-PCR. We used latent class analysis to identify subphenotypes using clinically available respiratory data cross-sectionally at baseline, and longitudinally using 8-hourly data from the first 4 days of invasive ventilation. We used group-based trajectory modelling to evaluate trajectories of individual variables and to facilitate potential clinical translation. The PRoVENT-COVID study is registered with ClinicalTrials.gov, NCT04346342.

Findings: Between March 1, 2020, and May 15, 2020, 1007 patients were admitted to participating ICUs in the Netherlands, and included in the derivation cohort. Data for 288 patients were included in replication cohort 1 and 326 in replication cohort 2. Cross-sectional latent class analysis did not identify any underlying subphenotypes. Longitudinal latent class analysis identified two distinct subphenotypes. Subphenotype 2 was characterised by higher mechanical power, minute ventilation, and ventilatory ratio over the first 4 days of invasive mechanical ventilation than subphenotype 1, but PaO/FiO, pH, and compliance of the respiratory system did not differ between the two subphenotypes. 185 (28%) of 671 patients with subphenotype 1 and 109 (32%) of 336 patients with subphenotype 2 had died at day 28 (p=0·10). However, patients with subphenotype 2 had fewer ventilator-free days at day 28 (median 0, IQR 0-15 vs 5, 0-17; p=0·016) and more frequent venous thrombotic events (109 [32%] of 336 patients vs 176 [26%] of 671 patients; p=0·048) compared with subphenotype 1. Group-based trajectory modelling revealed trajectories of ventilatory ratio and mechanical power with similar dynamics to those observed in latent class analysis-derived trajectory subphenotypes. The two trajectories were: a stable value for ventilatory ratio or mechanical power over the first 4 days of invasive mechanical ventilation (trajectory A) or an upward trajectory (trajectory B). However, upward trajectories were better independent prognosticators for 28-day mortality (OR 1·64, 95% CI 1·17-2·29 for ventilatory ratio; 1·82, 1·24-2·66 for mechanical power). The association between upward ventilatory ratio trajectories (trajectory B) and 28-day mortality was confirmed in the replication cohorts (OR 4·65, 95% CI 1·87-11·6 for ventilatory ratio in replication cohort 1; 1·89, 1·05-3·37 for ventilatory ratio in replication cohort 2).

Interpretation: At baseline, COVID-19-related ARDS has no consistent respiratory subphenotype. Patients diverged from a fairly homogenous to a more heterogeneous population, with trajectories of ventilatory ratio and mechanical power being the most discriminatory. Modelling these parameters alone provided prognostic value for duration of mechanical ventilation and mortality.

Funding: Amsterdam UMC.
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http://dx.doi.org/10.1016/S2213-2600(21)00365-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510633PMC
October 2021

Lung Ultrasound Assessment of Focal and Non-focal Lung Morphology in Patients With Acute Respiratory Distress Syndrome.

Front Physiol 2021 14;12:730857. Epub 2021 Sep 14.

Department of Intensive Care, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, Netherlands.

The identification of phenotypes based on lung morphology can be helpful to better target mechanical ventilation of individual patients with acute respiratory distress syndrome (ARDS). We aimed to assess the accuracy of lung ultrasound (LUS) methods for classification of lung morphology in critically ill ARDS patients under mechanical ventilation. This was a analysis on two prospective studies that performed LUS and chest computed tomography (CT) scanning at the same time. Expert panels from the two participating centers separately developed two LUS methods for classifying lung morphology based on LUS aeration scores from a 12-region exam (Amsterdam and Lombardy method). Moreover, a previously developed LUS method based on anterior LUS scores was tested (Piedmont method). Sensitivity and specificity of all three LUS methods was assessed in the cohort of the other center(s) by using CT as the gold standard for classification of lung morphology. The Amsterdam and Lombardy cohorts consisted of 32 and 19 ARDS patients, respectively. From these patients, 23 (45%) had focal lung morphology while others had non-focal lung morphology. The Amsterdam method could classify focal lung morphology with a sensitivity of 77% and a specificity of 100%, while the Lombardy method had a sensitivity and specificity of 100 and 61%. The Piedmont method had a sensitivity and specificity of 91 and 75% when tested on both cohorts. With both the Amsterdam and Lombardy method, most patients could be classified based on the anterior regions alone. LUS-based methods can accurately classify lung morphology in invasively ventilated ARDS patients compared to gold standard chest CT. The anterior LUS regions showed to be the most discriminant between focal and non-focal lung morphology, although accuracy increased moderately when lateral and posterior LUS regions were integrated in the method.
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http://dx.doi.org/10.3389/fphys.2021.730857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476947PMC
September 2021

Sedation in critically ill patients: will the vaporiser replace the syringe?

Lancet Respir Med 2021 Nov 26;9(11):1205-1207. Epub 2021 Aug 26.

Department of Anaesthesiology, Amsterdam UMC, location AMC, Amsterdam, Netherlands.

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http://dx.doi.org/10.1016/S2213-2600(21)00359-3DOI Listing
November 2021

Association of intensity of ventilation with 28-day mortality in COVID-19 patients with acute respiratory failure: insights from the PRoVENT-COVID study.

Crit Care 2021 08 6;25(1):283. Epub 2021 Aug 6.

Department of Intensive Care, Amsterdam UMC, Location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Background: The intensity of ventilation, reflected by driving pressure (ΔP) and mechanical power (MP), has an association with outcome in invasively ventilated patients with or without acute respiratory distress syndrome (ARDS). It is uncertain if a similar association exists in coronavirus disease 2019 (COVID-19) patients with acute respiratory failure.

Methods: We aimed to investigate the impact of intensity of ventilation on patient outcome. The PRoVENT-COVID study is a national multicenter observational study in COVID-19 patients receiving invasive ventilation. Ventilator parameters were collected a fixed time points on the first calendar day of invasive ventilation. Mean dynamic ΔP and MP were calculated for individual patients at time points without evidence of spontaneous breathing. A Cox proportional hazard model, and a double stratification analysis adjusted for confounders were used to estimate the independent associations of ΔP and MP with outcome. The primary endpoint was 28-day mortality.

Results: In 825 patients included in this analysis, 28-day mortality was 27.5%. ΔP was not independently associated with mortality (HR 1.02 [95% confidence interval 0.88-1.18]; P = 0.750). MP, however, was independently associated with 28-day mortality (HR 1.17 [95% CI 1.01-1.36]; P = 0.031), and increasing quartiles of MP, stratified on comparable levels of ΔP, had higher risks of 28-day mortality (HR 1.15 [95% CI 1.01-1.30]; P = 0.028).

Conclusions: In this cohort of critically ill invasively ventilated COVID-19 patients with acute respiratory failure, we show an independent association of MP, but not ΔP with 28-day mortality. MP could serve as one prognostic biomarker in addition to ΔP in these patients. Efforts aiming at limiting both ΔP and MP could translate in a better outcome. Trial registration Clinicaltrials.gov (study identifier NCT04346342).
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http://dx.doi.org/10.1186/s13054-021-03710-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343355PMC
August 2021

Airway Care Interventions for Invasively Ventilated Critically Ill Adults-A Dutch National Survey.

J Clin Med 2021 Jul 30;10(15). Epub 2021 Jul 30.

Center of Expertise Urban Vitality, Faculty of Health, Amsterdam University of Applied Science, 1105 BD Amsterdam, The Netherlands.

Airway care interventions may prevent accumulation of airway secretions and promote their evacuation, but evidence is scarce. Interventions include heated humidification, nebulization of mucolytics and/or bronchodilators, manual hyperinflation and use of mechanical insufflation-exsufflation (MI-E). Our aim is to identify current airway care practices for invasively ventilated patients in intensive care units (ICU) in the Netherlands. A self-administered web-based survey was sent to a single pre-appointed representative of all ICUs in the Netherlands. Response rate was 85% (72 ICUs). We found substantial heterogeneity in the intensity and combinations of airway care interventions used. Most (81%) ICUs reported using heated humidification as a routine prophylactic intervention. All (100%) responding ICUs used nebulized mucolytics and/or bronchodilators; however, only 43% ICUs reported nebulization as a routine prophylactic intervention. Most (81%) ICUs used manual hyperinflation, although only initiated with a clinical indication like difficult oxygenation. Few (22%) ICUs used MI-E for invasively ventilated patients. Use was always based on the indication of insufficient cough strength or as a continuation of home use. In the Netherlands, use of routine prophylactic airway care interventions is common despite evidence of no benefit. There is an urgent need for evidence of the benefit of these interventions to inform evidence-based guidelines.
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http://dx.doi.org/10.3390/jcm10153381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347919PMC
July 2021

Mortality associated with early changes in ARDS severity in COVID-19 patients - Insights from the PRoVENT-COVID study.

J Crit Care 2021 10 7;65:237-245. Epub 2021 Jul 7.

Department of Intensive Care, Amsterdam UMC, location AMC, Amsterdam, the Netherlands; Department of Critical Care Medicine, Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), Monash University, Melbourne, Australia.

Purpose: We investigated changes in ARDS severity and associations with outcome in COVID-19 ARDS patients.

Methods: We compared outcomes in patients with ARDS classified as 'mild', 'moderate' or 'severe' at calendar day 1, and after reclassification at calendar day 2. The primary endpoint was 28-day mortality. We also identified which ventilatory parameters had an association with presence of severe ARDS at day 2. We repeated the analysis for reclassification at calendar day 4.

Results: Of 895 patients, 8.5%, 60.1% and 31.4% had mild, moderate and severe ARDS at day 1. These proportions were 13.5%, 72.6% and 13.9% at day 2. 28-day mortality was 25.3%, 31.3% and 32.0% in patients with mild, moderate and severe ARDS at day 1 (p = 0.537), compared to 28.6%, 29.2% and 44.3% in patients reclassified at day 2 (p = 0.005). No ventilatory parameter had an independent association with presence of severe ARDS at day 2. Findings were not different reclassifying at day 4.

Conclusions: In this cohort of COVID-19 patients, ARDS severity and mortality between severity classes changed substantially over the first 4 days of ventilation. These findings are important, as reclassification could help identify target patients that may benefit from alternative approaches.
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http://dx.doi.org/10.1016/j.jcrc.2021.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260578PMC
October 2021

Practice of adjunctive treatments in critically ill COVID-19 patients-rational for the multicenter observational PRoAcT-COVID study in The Netherlands.

Ann Transl Med 2021 May;9(9):813

Department of Intensive Care, Amsterdam UMC, location 'AMC', Amsterdam, The Netherlands.

Background: Patients with coronavirus disease 2019 (COVID-19) may need hospitalization for supplemental oxygen, and some need intensive care unit (ICU) admission for escalation of care. Practice of adjunctive and supportive treatments remain uncertain and may vary widely between countries, within countries between hospitals, and possibly even within ICUs. We aim to investigate practice of adjunctive and supportive treatments, and their associations with outcome, in critically ill COVID-19 patients.

Methods: The 'PRactice of Adjunctive Treatments in Intensive Care Unit Patients with Coronavirus Disease 2019' (PRoAcT-COVID) study is a national, observational study to be undertaken in a large set of ICUs in The Netherlands. The PRoAcT-COVID includes consecutive ICU patients, admitted because of COVID-19 to one of the participating ICUs during a 3-month period. Daily follow-up lasts 28 days. The primary endpoint is a combination of adjunctive treatments, including types of oxygen support, ventilation, rescue therapies for hypoxemia refractory to supplementary oxygen or during invasive ventilation, other adjunctive and supportive treatments, and experimental therapies. We will also collect tracheostomy rate, duration of invasive ventilation and ventilator-free days and alive at day 28 (VFD-28), ICU and hospital length of stay, and the mortality rates in the ICU, hospital and at day 90.

Discussion: The PRoAcT-COVID study is an observational study combining high density treatment data with relevant clinical outcomes. Information on treatment practices, and their associations with outcomes in COVID-19 patients in highly and urgently needed. The results of the PRoAcT-COVID study will be rapidly available, and circulated through online presentations, such as webinars and electronic conferences, and publications in peer-reviewed journals-findings will also be presented at a dedicated website. At request, and after agreement of the PRoAcT-COVID steering committee, source data will be made available through local, regional and national anonymized datasets.

Trial Registration: The PRoAcT-COVID study is registered at clinicaltrials.gov (study identifier NCT04719182).
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http://dx.doi.org/10.21037/atm-21-764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246237PMC
May 2021

Association of early positive end-expiratory pressure settings with ventilator-free days in patients with coronavirus disease 2019 acute respiratory distress syndrome: A secondary analysis of the Practice of VENTilation in COVID-19 study.

Eur J Anaesthesiol 2021 12;38(12):1274-1283

From the Department of Intensive Care & Laboratory of Experimental Intensive Care and Anaesthesiology (LEICA), Amsterdam UMC, Location AMC, Amsterdam (CMAV, AMT, MB, LDJB, ASN, MJS, FP), Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (JP), Department of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil (ASN), Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), Monash University (ASN), Data Analytics Research & Evaluation (DARE) Centre, Austin Hospital and University of Melbourne, Melbourne, Victoria, Australia (ASN), Nuffield Department of Medicine, Oxford University, Oxford, UK (MJS), Mahidol-Oxford Tropical Medicine Research Unit (MORU), Mahidol University, Bangkok, Thailand (MJS) and ACHIEVE Centre of Expertise, Faculty of Health, Amsterdam University of Applied Sciences, Amsterdam, The Netherlands (FP).

Background: There is uncertainty about how much positive end-expiratory pressure (PEEP) should be used in patients with acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19).

Objective: To investigate whether a higher PEEP strategy is superior to a lower PEEP strategy regarding the number of ventilator-free days (VFDs).

Design: Multicentre observational study conducted from 1 March to 1 June 2020.

Setting And Patients: Twenty-two ICUs in The Netherlands and 933 invasively ventilated COVID-19 ARDS patients.

Interventions: Patients were categorised retrospectively as having received invasive ventilation with higher (n=259) or lower PEEP (n=674), based on the high and low PEEP/FiO2 tables of the ARDS Network, and using ventilator settings and parameters in the first hour of invasive ventilation, and every 8 h thereafter at fixed time points during the first four calendar days. We also used propensity score matching to control for observed confounding factors that might influence outcomes.

Main Outcomes And Measures: The primary outcome was the number of VFDs. Secondary outcomes included distant organ failures including acute kidney injury (AKI) and use of renal replacement therapy (RRT), and mortality.

Results: In the unmatched cohort, the higher PEEP strategy had no association with the median [IQR] number of VFDs (2.0 [0.0 to 15.0] vs. 0.0 [0.0 to 16.0] days). The median (95% confidence interval) difference was 0.21 (-3.34 to 3.78) days, P = 0.905. In the matched cohort, the higher PEEP group had an association with a lower median number of VFDs (0.0 [0.0 to 14.0] vs. 6.0 [0.0 to 17.0] days) a median difference of -4.65 (-8.92 to -0.39) days, P = 0.032. The higher PEEP strategy had associations with higher incidence of AKI (in the matched cohort) and more use of RRT (in the unmatched and matched cohorts). The higher PEEP strategy had no association with mortality.

Conclusion: In COVID-19 ARDS, use of higher PEEP may be associated with a lower number of VFDs, and may increase the incidence of AKI and need for RRT.

Trial Registration: Practice of VENTilation in COVID-19 is registered at ClinicalTrials.gov, NCT04346342.
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http://dx.doi.org/10.1097/EJA.0000000000001565DOI Listing
December 2021

Battling COVID-19-related mortality: from a fight for ventilators to a cry for oxygen.

Lancet Respir Med 2021 09 2;9(9):939-941. Epub 2021 Jul 2.

Department of Intensive Care, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands.

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http://dx.doi.org/10.1016/S2213-2600(21)00267-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253539PMC
September 2021

Ultrasound versus Computed Tomography Assessment of Focal Lung Aeration in Invasively Ventilated ICU Patients.

Ultrasound Med Biol 2021 09 23;47(9):2589-2597. Epub 2021 Jun 23.

Department of Intensive Care, Amsterdam UMC, location AMC, Amsterdam, The Netherlands.

It is unknown whether and to what extent the penetration depth of lung ultrasound (LUS) influences the accuracy of LUS findings. The current study evaluated and compared the LUS aeration score and two frequently used B-line scores with focal lung aeration assessed by chest computed tomography (CT) at different levels of depth in invasively ventilated intensive care unit (ICU) patients. In this prospective observational study, patients with a clinical indication for chest CT underwent a 12-region LUS examination shortly before CT scanning. LUS images were compared with corresponding regions on the chest CT scan at different subpleural depths. For each LUS image, the LUS aeration score was calculated. LUS images with B-lines were scored as the number of separately spaced B-lines (B-line count score) and the percentage of the screen covered by B-lines divided by 10 (B-line percentage score). The fixed-effect correlation coefficient (β) was presented per 100 Hounsfield units. A total of 40 patients were included, and 372 regions were analyzed. The best association between the LUS aeration score and CT was found at a subpleural depth of 5 cm for all LUS patterns (β = 0.30, p < 0.001), 1 cm for A- and B1-patterns (β = 0.10, p < 0.001), 6 cm for B1- and B2-patterns (β = 0.11, p < 0.001) and 4 cm for B2- and C-patterns (β = 0.07, p = 0.001). The B-line percentage score was associated with CT (β = 0.46, p = 0.001), while the B-line count score was not (β = 0.07, p = 0.305). In conclusion, the subpleural penetration depth of ultrasound increased with decreased aeration reflected by the LUS pattern. The LUS aeration score and the B-line percentage score accurately reflect lung aeration in ICU patients, but should be interpreted while accounting for the subpleural penetration depth of ultrasound.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.05.019DOI Listing
September 2021

Assessment of the Effect of Recruitment Maneuver on Lung Aeration Through Imaging Analysis in Invasively Ventilated Patients: A Systematic Review.

Front Physiol 2021 4;12:666941. Epub 2021 Jun 4.

Department of Intensive Care, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Recruitment maneuvers (RMs) have heterogeneous effects on lung aeration and have adverse side effects. We aimed to identify morphological, anatomical, and functional imaging characteristics that might be used to predict the RMs on lung aeration in invasively ventilated patients. We performed a systemic review. Studies included invasively ventilated patients who received an RM and in whom re-aeration was examined with chest computed tomography (CT), electrical impedance tomography (EIT), and lung ultrasound (LUS) were included. Twenty studies were identified. Different types of RMs were applied. The amount of re-aerated lung tissue after an RM was highly variable between patients in all studies, irrespective of the used imaging technique and the type of patients (ARDS or non-ARDS). Imaging findings suggesting a non-focal morphology (i.e., radiologic findings consistent with attenuations with diffuse or patchy loss of aeration) were associated with higher likelihood of recruitment and lower chance of overdistention than a focal morphology (i.e., radiological findings suggestive of lobar or segmental loss of aeration). This was independent of the used imaging technique but only observed in patients with ARDS. In patients without ARDS, the results were inconclusive. ARDS patients with imaging findings suggestive of non-focal morphology show most re-aeration of previously consolidated lung tissue after RMs. The role of imaging techniques in predicting the effect of RMs on re-aeration in patients without ARDS remains uncertain.
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http://dx.doi.org/10.3389/fphys.2021.666941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212037PMC
June 2021

Assessment of Lung Reaeration at 2 Levels of Positive End-expiratory Pressure in Patients With Early and Late COVID-19-related Acute Respiratory Distress Syndrome.

J Thorac Imaging 2021 Sep;36(5):286-293

Departments of Intensive Care.

Purpose: Patients with novel coronavirus disease (COVID-19) frequently develop acute respiratory distress syndrome (ARDS) and need invasive ventilation. The potential to reaerate consolidated lung tissue in COVID-19-related ARDS is heavily debated. This study assessed the potential to reaerate lung consolidations in patients with COVID-19-related ARDS under invasive ventilation.

Materials And Methods: This was a retrospective analysis of patients with COVID-19-related ARDS who underwent chest computed tomography (CT) at low positive end-expiratory pressure (PEEP) and after a recruitment maneuver at high PEEP of 20 cm H2O. Lung reaeration, volume, and weight were calculated using both CT scans. CT scans were performed after intubation and start of ventilation (early CT), or after several days of intensive care unit admission (late CT).

Results: Twenty-eight patients were analyzed. The median percentages of reaerated and nonaerated lung tissue were 19% [interquartile range, IQR: 10 to 33] and 11% [IQR: 4 to 15] for patients with early and late CT scans, respectively (P=0.049). End-expiratory lung volume showed a median increase of 663 mL [IQR: 483 to 865] and 574 mL [IQR: 292 to 670] after recruitment for patients with early and late CT scans, respectively (P=0.43). The median decrease in lung weight attributed to nonaerated lung tissue was 229 g [IQR: 165 to 376] and 171 g [IQR: 81 to 229] after recruitment for patients with early and late CT scans, respectively (P=0.16).

Conclusions: The majority of patients with COVID-19-related ARDS undergoing invasive ventilation had substantial reaeration of lung consolidations after recruitment and ventilation at high PEEP. Higher PEEP can be considered in patients with reaerated lung consolidations when accompanied by improvement in compliance and gas exchange.
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http://dx.doi.org/10.1097/RTI.0000000000000600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386391PMC
September 2021

Dead space estimates may not be independently associated with 28-day mortality in COVID-19 ARDS.

Crit Care 2021 05 17;25(1):171. Epub 2021 May 17.

Department of Intensive Care & Laboratory of Experimental Intensive Care and Anaesthesiology (L·E·I·C·A), Amsterdam UMC Location AMC, Amsterdam, The Netherlands.

Background: Estimates for dead space ventilation have been shown to be independently associated with an increased risk of mortality in the acute respiratory distress syndrome and small case series of COVID-19-related ARDS.

Methods: Secondary analysis from the PRoVENT-COVID study. The PRoVENT-COVID is a national, multicenter, retrospective observational study done at 22 intensive care units in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The aim was to quantify the dynamics and determine the prognostic value of surrogate markers of wasted ventilation in patients with COVID-19-related ARDS.

Results: A total of 927 consecutive patients admitted with COVID-19-related ARDS were included in this study. Estimations of wasted ventilation such as the estimated dead space fraction (by Harris-Benedict and direct method) and ventilatory ratio were significantly higher in non-survivors than survivors at baseline and during the following days of mechanical ventilation (p < 0.001). The end-tidal-to-arterial PCO ratio was lower in non-survivors than in survivors (p < 0.001). As ARDS severity increased, mortality increased with successive tertiles of dead space fraction by Harris-Benedict and by direct estimation, and with an increase in the VR. The same trend was observed with decreased levels in the tertiles for the end-tidal-to-arterial PCO ratio. After adjustment for a base risk model that included chronic comorbidities and ventilation- and oxygenation-parameters, none of the dead space estimates measured at the start of ventilation or the following days were significantly associated with 28-day mortality.

Conclusions: There is significant impairment of ventilation in the early course of COVID-19-related ARDS but quantification of this impairment does not add prognostic information when added to a baseline risk model.

Trial Registration: ISRCTN04346342. Registered 15 April 2020. Retrospectively registered.
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http://dx.doi.org/10.1186/s13054-021-03570-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127435PMC
May 2021

Ventilation management in acute respiratory failure related to COVID-19 versus ARDS from another origin - a descriptive narrative review.

Expert Rev Respir Med 2021 08 13;15(8):1013-1023. Epub 2021 Apr 13.

Department of Intensive Care, Amsterdam University Medical Centers, location 'AMC', Amsterdam, The Netherlands.

Introduction: It is uncertain whether ventilation in patients with acute respiratory failure related to coronavirus disease 2019 (COVID-19) differs from that in patients with acute respiratory distress syndrome (ARDS) from another origin.

Areas Covered: We undertook two literature searches in PubMed to identify observational studies reporting on ventilation management--one in patients with acute respiratory failure related to COVID-19, and one in patients with ARDS from another origin. The searches identified 14 studies in patients with acute respiratory failure related to COVID-19, and 8 studies in patients with ARDS from another origin.

Expert Opinion: In patients with acute respiratory failure related to COVID-19, ventilation management seems to be similar to that of patients with ARDS from another origin. The future lies in studies focused on personalized treatment of ARDS of all origins, including COVID-19.
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http://dx.doi.org/10.1080/17476348.2021.1913060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054495PMC
August 2021

Associations of Body Mass Index with Ventilation Management and Clinical Outcomes in Invasively Ventilated Patients with ARDS Related to COVID-19-Insights from the PRoVENT-COVID Study.

J Clin Med 2021 03 11;10(6). Epub 2021 Mar 11.

Department of Intensive Care, Amsterdam UMC, Location AMC, 1105 AZ Amsterdam, The Netherlands.

We describe the practice of ventilation and mortality rates in invasively ventilated normal-weight (18.5 ≤ BMI ≤ 24.9 kg/m), overweight (25.0 ≤ BMI ≤ 29.9 kg/m), and obese (BMI > 30 kg/m) COVID-19 ARDS patients in a national, multicenter observational study, performed at 22 intensive care units in the Netherlands. The primary outcome was a combination of ventilation variables and parameters over the first four calendar days of ventilation, including tidal volume, positive end-expiratory pressure (PEEP), respiratory system compliance, and driving pressure in normal-weight, overweight, and obese patients. Secondary outcomes included the use of adjunctive treatments for refractory hypoxaemia and mortality rates. Between 1 March 2020 and 1 June 2020, 1122 patients were included in the study: 244 (21.3%) normal-weight patients, 531 (47.3%) overweight patients, and 324 (28.8%) obese patients. Most patients received a tidal volume < 8 mL/kg PBW; only on the first day was the tidal volume higher in obese patients. PEEP and driving pressure were higher, and compliance of the respiratory system was lower in obese patients on all four days. Adjunctive therapies for refractory hypoxemia were used equally in the three BMI groups. Adjusted mortality rates were not different between BMI categories. The findings of this study suggest that lung-protective ventilation with a lower tidal volume and prone positioning is similarly feasible in normal-weight, overweight, and obese patients with ARDS related to COVID-19. A patient's BMI should not be used in decisions to forgo or proceed with invasive ventilation.
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http://dx.doi.org/10.3390/jcm10061176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000207PMC
March 2021

Awake Proning as an Adjunctive Therapy for Refractory Hypoxemia in Non-Intubated Patients with COVID-19 Acute Respiratory Failure: Guidance from an International Group of Healthcare Workers.

Am J Trop Med Hyg 2021 Mar 11. Epub 2021 Mar 11.

1Department of Intensive Care, Amsterdam University Medical Centers, Location 'AMC', Amsterdam, The Netherlands.

Non-intubated patients with acute respiratory failure due to COVID-19 could benefit from awake proning. Awake proning is an attractive intervention in settings with limited resources, as it comes with no additional costs. However, awake proning remains poorly used probably because of unfamiliarity and uncertainties regarding potential benefits and practical application. To summarize evidence for benefit and to develop a set of pragmatic recommendations for awake proning in patients with COVID-19 pneumonia, focusing on settings where resources are limited, international healthcare professionals from high and low- and middle-income countries (LMICs) with known expertise in awake proning were invited to contribute expert advice. A growing number of observational studies describe the effects of awake proning in patients with COVID-19 pneumonia in whom hypoxemia is refractory to simple measures of supplementary oxygen. Awake proning improves oxygenation in most patients, usually within minutes, and reduces dyspnea and work of breathing. The effects are maintained for up to 1 hour after turning back to supine, and mostly disappear after 6-12 hours. In available studies, awake proning was not associated with a reduction in the rate of intubation for invasive ventilation. Awake proning comes with little complications if properly implemented and monitored. Pragmatic recommendations including indications and contraindications were formulated and adjusted for resource-limited settings. Awake proning, an adjunctive treatment for hypoxemia refractory to supplemental oxygen, seems safe in non-intubated patients with COVID-19 acute respiratory failure. We provide pragmatic recommendations including indications and contraindications for the use of awake proning in LMICs.
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http://dx.doi.org/10.4269/ajtmh.20-1445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103477PMC
March 2021

Effects of Lung Ultrasonography-Guided Management on Cumulative Fluid Balance and Other Clinical Outcomes: A Systematic Review.

Ultrasound Med Biol 2021 05 23;47(5):1163-1171. Epub 2021 Feb 23.

Department of Intensive Care, Amsterdam University Medical Centers, location VUmc, Amsterdam, The Netherlands; Amsterdam Leiden IC Focused Echography, Amsterdam, The Netherlands.

Lung ultrasonography is accurate in detecting pulmonary edema and overcomes most limitations of traditional diagnostic modalities. Whether use of lung ultrasonography-guided management has an effect on cumulative fluid balances and other clinical outcomes remains unclear. In this systematic review, we included 12 studies using ultrasonography guided-management with a total of 2290 patients. Four in-patient studies found a reduced cumulative fluid balance (ranging from -0.3 L to -2.4 L), whereas three out-patient studies found reduction in dialysis dry weight (ranging from -2.6 kg to -0.2 kg) compared with conventionally managed patients. None of the studies found adverse effects related to hypoperfusion. The use of lung ultrasonography-guided management was not associated with other clinical outcomes. This systematic review shows that lung ultrasonography-guided management, exclusively or in concert with other diagnostic modalities, is associated with a reduced cumulative fluid balance. Studies thus far have not shown a consistent effect on clinical outcomes.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.01.024DOI Listing
May 2021

Instrumental dead space in ventilator management - Authors' reply.

Lancet Respir Med 2021 03 29;9(3):e23. Epub 2021 Jan 29.

Department of Intensive Care, Amsterdam University Medical Center, location Academic Medical Center, 1105 AZ Amsterdam, Netherlands; Department of Critical Care Medicine, Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1016/S2213-2600(21)00015-1DOI Listing
March 2021

Epidemiological Characteristics, Ventilator Management, and Clinical Outcome in Patients Receiving Invasive Ventilation in Intensive Care Units from 10 Asian Middle-Income Countries (PRoVENT-iMiC): An International, Multicenter, Prospective Study.

Am J Trop Med Hyg 2021 01 11. Epub 2021 Jan 11.

Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

Epidemiology, ventilator management, and outcome in patients receiving invasive ventilation in intensive care units (ICUs) in middle-income countries are largely unknown. PRactice of VENTilation in Middle-income Countries is an international multicenter 4-week observational study of invasively ventilated adult patients in 54 ICUs from 10 Asian countries conducted in 2017/18. Study outcomes included major ventilator settings (including tidal volume [ ] and positive end-expiratory pressure [PEEP]); the proportion of patients at risk for acute respiratory distress syndrome (ARDS), according to the lung injury prediction score (LIPS), or with ARDS; the incidence of pulmonary complications; and ICU mortality. In 1,315 patients included, median was similar in patients with LIPS < 4 and patients with LIPS ≥ 4, but lower in patients with ARDS (7.90 [6.8-8.9], 8.0 [6.8-9.2], and 7.0 [5.8-8.4] mL/kg Predicted body weight; = 0.0001). Median PEEP was similar in patients with LIPS < 4 and LIPS ≥ 4, but higher in patients with ARDS (five [5-7], five [5-8], and 10 [5-12] cmHO; < 0.0001). The proportions of patients with LIPS ≥ 4 or with ARDS were 68% (95% CI: 66-71) and 7% (95% CI: 6-8), respectively. Pulmonary complications increased stepwise from patients with LIPS < 4 to patients with LIPS ≥ 4 and patients with ARDS (19%, 21%, and 38% respectively; = 0.0002), with a similar trend in ICU mortality (17%, 34%, and 45% respectively; < 0.0001). The capacity of the LIPS to predict development of ARDS was poor (ROC AUC of 0.62, 95% CI: 0.54-0.70). In Asian middle-income countries, where two-thirds of ventilated patients are at risk for ARDS according to the LIPS and pulmonary complications are frequent, setting of is globally in line with current recommendations.
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http://dx.doi.org/10.4269/ajtmh.20-1177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941813PMC
January 2021

The predictive validity for mortality of the driving pressure and the mechanical power of ventilation.

Intensive Care Med Exp 2020 Dec 18;8(Suppl 1):60. Epub 2020 Dec 18.

Department of Intensive Care, University of Amsterdam, Amsterdam University Medical Centers, Location "Academic Medical Center", Meibergdreeg 9, 1105 AZ, Amsterdam, The Netherlands.

Background: Outcome prediction in critically ill patients under invasive ventilation remains extremely challenging. The driving pressure (ΔP) and the mechanical power of ventilation (MP) are associated with patient-centered outcomes like mortality and duration of ventilation. The objective of this study was to assess the predictive validity for mortality of the ΔP and the MP at 24 h after start of invasive ventilation.

Methods: This is a post hoc analysis of an observational study in intensive care unit patients, restricted to critically ill patients receiving invasive ventilation for at least 24 h. The two exposures of interest were the modified ΔP and the MP at 24 h after start of invasive ventilation. The primary outcome was 90-day mortality; secondary outcomes were ICU and hospital mortality. The predictive validity was measured as incremental 90-day mortality beyond that predicted by the Acute Physiology, Age and Chronic Health Evaluation (APACHE) IV score and the Simplified Acute Physiology Score (SAPS) II.

Results: The analysis included 839 patients with a 90-day mortality of 42%. The median modified ΔP at 24 h was 15 [interquartile range 12 to 19] cm HO; the median MP at 24 h was 206 [interquartile range 145 to 298] 10 J/min/kg predicted body weight (PBW). Both parameters were associated with 90-day mortality (odds ratio (OR) for 1 cm HO increase in the modified ΔP, 1.05 [95% confidence interval (CI) 1.03 to 1.08]; P < 0.001; OR for 100 10 J/min/kg PBW increase in the MP, 1.20 [95% CI 1.09 to 1.33]; P < 0.001). Area under the ROC for 90-day mortality of the modified ΔP and the MP were 0.70 [95% CI 0.66 to 0.74] and 0.69 [95% CI 0.65 to 0.73], which was neither different from that of the APACHE IV score nor that of the SAPS II.

Conclusions: In adult patients under invasive ventilation, the modified ΔP and the MP at 24 h are associated with 90 day mortality. Neither the modified ΔP nor the MP at 24 h has predictive validity beyond the APACHE IV score and the SAPS II.
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http://dx.doi.org/10.1186/s40635-020-00346-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746416PMC
December 2020

Effect of routine vs on-demand nebulization of acetylcysteine with salbutamol on accumulation of airway secretions in endotracheal tubes: substudy of a randomized clinical trial.

Intensive Care Med Exp 2020 Dec 18;8(Suppl 1):71. Epub 2020 Dec 18.

Department of Intensive Care, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, The Netherlands.

Background: Accumulated airway secretions in the endotracheal tube increase work of breathing and may favor airway colonization eventually leading to pneumonia. The aim of this preplanned substudy of the 'Preventive Nebulization of Mucolytic Agents and Bronchodilating Drugs in Intubated and Ventilated Intensive Care Unit Patients trial' (NEBULAE) was to compare the effect of routine vs on-demand nebulization of acetylcysteine with salbutamol on accumulation of secretions in endotracheal tubes in critically ill patients.

Results: In this single-center substudy of a national multicenter trial, patients were randomized to a strategy of routine nebulizations of acetylcysteine with salbutamol every 6 h until end of invasive ventilation, or to a strategy with on-demand nebulizations of acetylcysteine or salbutamol applied on strict clinical indications only. The primary endpoint, the maximum reduction in cross-sectional area (CSA) of the endotracheal tube was assessed with high-resolution computed tomography. Endotracheal tubes were collected from 72 patients, 36 from patients randomized to the routine nebulization strategy and 36 of patients randomized to the on-demand nebulization strategy. The maximum cross-sectional area (CSA) of the endotracheal tube was median 12 [6 to 15]% in tubes obtained from patients in the routine nebulization group, not different from median 9 [6 to 14]% in tubes obtained from patients in the on-demand nebulization group (P = 0.33).

Conclusion: In adult critically ill patients under invasive ventilation, routine nebulization of mucolytics and bronchodilators did not affect accumulation of airway secretions in the endotracheal tube. Trial registration Clinicaltrials.gov Identifier: NCT02159196.
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http://dx.doi.org/10.1186/s40635-020-00351-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746420PMC
December 2020

Effect of a Lower vs Higher Positive End-Expiratory Pressure Strategy on Ventilator-Free Days in ICU Patients Without ARDS: A Randomized Clinical Trial.

JAMA 2020 12;324(24):2509-2520

Department of Intensive Care and Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC, Location AMC, Amsterdam, the Netherlands.

Importance: It is uncertain whether invasive ventilation can use lower positive end-expiratory pressure (PEEP) in critically ill patients without acute respiratory distress syndrome (ARDS).

Objective: To determine whether a lower PEEP strategy is noninferior to a higher PEEP strategy regarding duration of mechanical ventilation at 28 days.

Design, Setting, And Participants: Noninferiority randomized clinical trial conducted from October 26, 2017, through December 17, 2019, in 8 intensive care units (ICUs) in the Netherlands among 980 patients without ARDS expected not to be extubated within 24 hours after start of ventilation. Final follow-up was conducted in March 2020.

Interventions: Participants were randomized to receive invasive ventilation using either lower PEEP, consisting of the lowest PEEP level between 0 and 5 cm H2O (n = 476), or higher PEEP, consisting of a PEEP level of 8 cm H2O (n = 493).

Main Outcomes And Measures: The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for the difference in ventilator-free days at day 28 of -10%. Secondary outcomes included ICU and hospital lengths of stay; ICU, hospital, and 28- and 90-day mortality; development of ARDS, pneumonia, pneumothorax, severe atelectasis, severe hypoxemia, or need for rescue therapies for hypoxemia; and days with use of vasopressors or sedation.

Results: Among 980 patients who were randomized, 969 (99%) completed the trial (median age, 66 [interquartile range {IQR}, 56-74] years; 246 [36%] women). At day 28, 476 patients in the lower PEEP group had a median of 18 ventilator-free days (IQR, 0-27 days) and 493 patients in the higher PEEP group had a median of 17 ventilator-free days (IQR, 0-27 days) (mean ratio, 1.04; 95% CI, 0.95-∞; P = .007 for noninferiority), and the lower boundary of the 95% CI was within the noninferiority margin. Occurrence of severe hypoxemia was 20.6% vs 17.6% (risk ratio, 1.17; 95% CI, 0.90-1.51; P = .99) and need for rescue strategy was 19.7% vs 14.6% (risk ratio, 1.35; 95% CI, 1.02-1.79; adjusted P = .54) in patients in the lower and higher PEEP groups, respectively. Mortality at 28 days was 38.4% vs 42.0% (hazard ratio, 0.89; 95% CI, 0.73-1.09; P = .99) in patients in the lower and higher PEEP groups, respectively. There were no statistically significant differences in other secondary outcomes.

Conclusions And Relevance: Among patients in the ICU without ARDS who were expected not to be extubated within 24 hours, a lower PEEP strategy was noninferior to a higher PEEP strategy with regard to the number of ventilator-free days at day 28. These findings support the use of lower PEEP in patients without ARDS.

Trial Registration: ClinicalTrials.gov Identifier: NCT03167580.
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http://dx.doi.org/10.1001/jama.2020.23517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726701PMC
December 2020

The use of mechanical insufflation-exsufflation in invasively ventilated critically ill adults: a scoping review protocol.

Syst Rev 2020 12 8;9(1):287. Epub 2020 Dec 8.

Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, London, UK.

Background: Critically ill patients receiving invasive ventilation are at risk of sputum retention. Mechanical insufflation-exsufflation (MI-E) is a technique used to mobilise sputum and optimise airway clearance. Recently, interest has increased in the use of mechanical insufflation-exsufflation for invasively ventilated critically ill adults, but evidence for the feasibility, safety and efficacy of this treatment is sparse. The aim of this scoping review is to map current and emerging evidence on the feasibility, safety and efficacy of MI-E for invasively ventilated adult patients with the aim of highlighting knowledge gaps and identifying areas for future research. Specific research questions aim to identify information informing indications and contraindications to the use of MI-E in the invasively ventilated adult, MI-E settings used, outcome measures reported within studies, adverse effects reported and perceived barriers and facilitators to using MI-E reported.

Methods: We will search electronic databases MEDLINE, EMBASE, CINAHL using the OVID platform, PROSPERO, The Cochrane Library, ISI Web of Science and the International Clinical Trials Registry Platform. Two authors will independently screen citations, extract data and evaluate risk of bias using the Mixed Methods Appraisal Tool. Studies included will present original data and describe MI-E in invasively ventilated adult patients from 1990 onwards. Our exclusion criteria are studies in a paediatric population, editorial pieces or letters and animal or bench studies. Search results will be presented in a PRISMA study flow diagram. Descriptive statistics will be used to summarise quantitative data. For qualitative data relating to barriers and facilitators, we will use content analysis and the Theoretical Domains Framework (TDF) as a conceptual framework. Additional tables and relevant figures will present data addressing our research questions.

Discussion: Our findings will enable us to map current and emerging evidence on the feasibility, safety and efficacy of MI-E for invasively ventilated critically ill adult patients. These data will provide description of how the technique is currently used, support healthcare professionals in their clinical decision making and highlight areas for future research in this important clinical area.

Systematic Review Registration: Open Science Framework submitted on 9 July 2020.  https://osf.io/mpksq/ .
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http://dx.doi.org/10.1186/s13643-020-01547-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724723PMC
December 2020

PRactice of VENTilation in Patients with Novel Coronavirus Disease (PRoVENT-COVID): rationale and protocol for a national multicenter observational study in The Netherlands.

Ann Transl Med 2020 Oct;8(19):1251

Department of Intensive Care, Amsterdam UMC location AMC, The Netherlands.

Background: The coronavirus disease 2019 (COVID-19) pandemic is rapidly expanding across the world, with more than 100,000 new cases each day as of end-June 2020. Healthcare workers are struggling to provide the best care for COVID-19 patients. Approaches for invasive ventilation vary widely between and within countries and new insights are acquired rapidly. We aim to investigate invasive ventilation practices and outcome in COVID-19 patients in the Netherlands.

Methods: PRoVENT-COVID ('study of PRactice of VENTilation in COVID-19') is an investigator-initiated national, multicenter observational study to be undertaken in intensive care units (ICUs) in The Netherlands. Consecutive COVID-19 patients aged 18 years or older, who are receiving invasive ventilation in the participating ICUs, are to be enrolled during a 10-week period, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cmHO) during the first 3 days of ventilation. Secondary outcomes include other ventilatory variables, use of rescue therapies for refractory hypoxemia such as prone positioning and extracorporeal membrane oxygenation, use of sedatives, vasopressors and inotropes; daily cumulative fluid balances; acute kidney injury; ventilator-free days and alive at day 28 (VFD-28), duration of ICU and hospital stay, and ICU, hospital and 90-day mortality.

Discussion: PRoVENT-COVID will be the largest observational study to date, with high density ventilatory data and major outcomes. There is urgent need for a better understanding of ventilation practices, and the effects of ventilator settings on outcomes in COVID-19 patients. The results of PRoVENT-COVID will be rapidly disseminated through electronic presentations, such as webinars and electronic conferences, and publications in international peer-reviewed journals. Access to source data will be made available through local, regional and national anonymized datasets on request, and after agreement of the PRoVENT-COVID steering committee.

Trial Registration: PRoVENT-COVID is registered at clinicaltrials.gov (identifier NCT04346342).
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http://dx.doi.org/10.21037/atm-20-5107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607125PMC
October 2020

Ventilation management and clinical outcomes in invasively ventilated patients with COVID-19 (PRoVENT-COVID): a national, multicentre, observational cohort study.

Lancet Respir Med 2021 02 23;9(2):139-148. Epub 2020 Oct 23.

Department of Intensive Care, Amsterdam University Medical Centers location Academic Medical Center, Amsterdam, Netherlands; ACHIEVE, Centre of Applied Research, Amsterdam University of Applied Sciences, Faculty of Health, Amsterdam, Netherlands.

Background: Little is known about the practice of ventilation management in patients with COVID-19. We aimed to describe the practice of ventilation management and to establish outcomes in invasively ventilated patients with COVID-19 in a single country during the first month of the outbreak.

Methods: PRoVENT-COVID is a national, multicentre, retrospective observational study done at 18 intensive care units (ICUs) in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The primary outcome was a combination of ventilator variables and parameters over the first 4 calendar days of ventilation: tidal volume, positive end-expiratory pressure (PEEP), respiratory system compliance, and driving pressure. Secondary outcomes included the use of adjunctive treatments for refractory hypoxaemia and ICU complications. Patient-centred outcomes were ventilator-free days at day 28, duration of ventilation, duration of ICU and hospital stay, and mortality. PRoVENT-COVID is registered at ClinicalTrials.gov (NCT04346342).

Findings: Between March 1 and April 1, 2020, 553 patients were included in the study. Median tidal volume was 6·3 mL/kg predicted bodyweight (IQR 5·7-7·1), PEEP was 14·0 cm HO (IQR 11·0-15·0), and driving pressure was 14·0 cm HO (11·2-16·0). Median respiratory system compliance was 31·9 mL/cm HO (26·0-39·9). Of the adjunctive treatments for refractory hypoxaemia, prone positioning was most often used in the first 4 days of ventilation (283 [53%] of 530 patients). The median number of ventilator-free days at day 28 was 0 (IQR 0-15); 186 (35%) of 530 patients had died by day 28. Predictors of 28-day mortality were gender, age, tidal volume, respiratory system compliance, arterial pH, and heart rate on the first day of invasive ventilation.

Interpretation: In patients with COVID-19 who were invasively ventilated during the first month of the outbreak in the Netherlands, lung-protective ventilation with low tidal volume and low driving pressure was broadly applied and prone positioning was often used. The applied PEEP varied widely, despite an invariably low respiratory system compliance. The findings of this national study provide a basis for new hypotheses and sample size calculations for future trials of invasive ventilation for COVID-19. These data could also help in the interpretation of findings from other studies of ventilation practice and outcomes in invasively ventilated patients with COVID-19.

Funding: Amsterdam University Medical Centers, location Academic Medical Center.
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http://dx.doi.org/10.1016/S2213-2600(20)30459-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584441PMC
February 2021

Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial.

Lancet Rheumatol 2020 Dec 28;2(12):e764-e773. Epub 2020 Sep 28.

Department of Neurology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.

Background: Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19.

Methods: We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO/FiO) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO/FiO in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420).

Findings: Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO/FiO assessments (irrespective of position). At day 5 after randomisation, the mean PaO/FiO (irrespective of position) was 158 mm Hg (SD 63; range 84-265) in the IFX-1 group and 189 mm Hg (89; 71-329) in the control group. Analyses of the least squares mean relative change in PaO/FiO at day 5 showed no differences between treatment groups (17% change in the IFX-1 group 41% in the control group; difference -24% [95% CI -58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0-31) for the IFX-1 group and 27% (4-49) for the control group (adjusted hazard ratio for death 0·65 [95% CI 0·10-4·14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group.

Interpretation: In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint.

Funding: InflaRx.
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http://dx.doi.org/10.1016/S2665-9913(20)30341-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521913PMC
December 2020

Mucoactive agents for acute respiratory failure in the critically ill: a systematic review and meta-analysis.

Thorax 2020 08 8;75(8):623-631. Epub 2020 Jun 8.

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.

Purpose: Acute respiratory failure (ARF) is a common cause of admission to intensive care units (ICUs). Mucoactive agents are medications that promote mucus clearance and are frequently administered in patients with ARF, despite a lack of evidence to underpin clinical decision making. The aim of this systematic review was to determine if the use of mucoactive agents in patients with ARF improves clinical outcomes.

Methods: We searched electronic and grey literature (January 2020). Two reviewers independently screened, selected, extracted data and quality assessed studies. We included trials of adults receiving ventilatory support for ARF and involving at least one mucoactive agent compared with placebo or standard care. Outcomes included duration of mechanical ventilation. Meta-analysis was undertaken using random-effects modelling and certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation.

Results: Thirteen randomised controlled trials were included (1712 patients), investigating four different mucoactive agents. Mucoactive agents showed no effect on duration of mechanical ventilation (seven trials, mean difference (MD) -1.34, 95% CI -2.97 to 0.29, I=82%, very low certainty) or mortality, hospital stay and ventilator-free days. There was an effect on reducing ICU length of stay in the mucoactive agent groups (10 trials, MD -3.22, 95% CI -5.49 to -0.96, I=89%, very low certainty).

Conclusion: Our findings do not support the use of mucoactive agents in critically ill patients with ARF. The existing evidence is of low quality. High-quality randomised controlled trials are needed to determine the role of specific mucoactive agents in critically ill patients with ARF.

Prospero Registration Number: CRD42018095408.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402561PMC
August 2020
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