Moderate-severe Acute Respiratory Distress Syndrome Research Articles

Prone positioning does not improve outcomes of intubated patients with pneumocystis pneumonia and moderate–severe acute respiratory distress syndrome: a single-center, retrospective, observational, cohort study

BackgroundPneumocystis pneumonia is an uncommon precipitant of acute respiratory distress syndrome and is associated with high mortality. Prone positioning ventilation has been proven to reduce mortality in patients with moderate–severe acute respiratory distress syndrome. We investigated the effect of prone positioning on oxygenation and mortality in intubated patients with pneumocystis pneumonia comorbid with moderate–severe acute respiratory distress syndrome.MethodsIn this single-center, retrospective, observational, cohort study, eligible patients were enrolled at West China Hospital of Sichuan University from January 1, 2017, to December 31, 2021. Data on demographics, clinical features, ventilation parameters, arterial blood gas, and outcomes were collected. Patients were assigned to the prone cohort or supine cohort according to whether they received prone positioning ventilation. The main outcome was 28-day mortality.FindingsA total of 79 patients were included in the study. Sixty-three patients were enrolled in the prone cohort, and 16 patients were enrolled in the supine cohort. The 28-day mortality was 61.9% in the prone cohort and 68.8% in the supine cohort (P = 0.26), and 90-day mortality was 66.7% in the prone cohort and 68.8% in the supine cohort (P = 0.55). Patients in the supine cohort had fewer invasive mechanical ventilation days and more ventilator-free days. The incidence of complications was higher in the prone cohort than in the supine cohort.ConclusionsIn patients with pneumocystis pneumonia and moderate–severe acute respiratory distress syndrome, prone positioning did not decrease 28-day or 90-day mortality.Trial registration ClinicalTrials.gov number, ChiCTR2200063889. Registered on 20 September 2022, https://www.chictr.org.cn/showproj.html?proj=174886.

A phase 1/2 clinical trial of invariant natural killer T cell therapy in moderate-severe acute respiratory distress syndrome

Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials.

Feasibility of Setting the Tidal Volume Based on End-Expiratory Lung Volume: A Pilot Clinical Study.

To assess the feasibility of setting the tidal volume (TV) as 25% of the actual aerated lung volume (rather than on ideal body weight) in patients with Acute Respiratory Distress Syndrome (ARDS). Physiologic prospective single-center pilot study. Medical ICU specialized in the care of patients with ARDS. Patients with moderate-severe ARDS deeply sedated or paralyzed, undergoing controlled mechanical ventilation with a ventilator able to measure the end-expiratory lung volume (EELV) with a washin, washout technique. Three-phase study (baseline, strain-selected TV setting, ventilation with strain-selected TV for 24 hr). The TV was calculated as 25% of the measured EELV minus the static strain due to the applied positive end-expiratory pressure. Gas exchanges and respiratory mechanics were measured and compared in each phase. In addition, during the TV setting phase, driving pressure (DP) and lung strain (TV/EELV) were measured at different TVs to assess the correlation between the two measurements. The maintenance of the set strain-selected TV for 24 hours was safe and feasible in 76% of the patients enrolled. Three patients dropped out from the study because of the need to set a respiratory rate higher than 35 breaths per minute to avoid respiratory acidosis. The DP of the respiratory system was a satisfactory surrogate for strain in this population. In our population of 17 patients with moderate to severe ARDS, setting TV based on the actual lung size was feasible. DP was a reliable surrogate of strain in these patients, and DP less than or equal to 8 cm H2O corresponded to a strain less than 0.25.

Prone Positioning and Molecular Biomarkers in COVID and Non-COVID ARDS: A Narrative Review.

Prone positioning (PP) represents a therapeutic intervention with the proven capacity of ameliorating gas exchanges and ventilatory mechanics indicated in acute respiratory distress syndrome (ARDS). When PP is selectively applied to moderate-severe cases of ARDS, it sensitively affects clinical outcomes, including mortality. After the COVID-19 outbreak, clinical application of PP peaked worldwide and was applied in 60% of treated cases, according to large reports. Research on this topic has revealed many physiological underpinnings of PP, focusing on regional ventilation redistribution and the reduction of parenchymal stress and strain. However, there is a lack of evidence on biomarkers behavior in different phases and phenotypes of ARDS. Patients response to PP are, to date, decided on PaO2/FiO2 ratio improvement, whereas scarce data exist on biomarker tracking during PP. The purpose of this review is to explore current evidence on the clinical relevance of biomarkers in the setting of moderate-severe ARDS of different etiologies (i.e., COVID and non-COVID-related ARDS). Moreover, this review focuses on how PP may modulate biomarkers and which biomarkers may have a role in outcome prediction in ARDS patients.

Comparison of Fixed Dosing vs Train of Four Titration of Cisatracurium in COVID-19 ARDS Patients

Background: Early neuromuscular blockade with cisatracurium has been associated with improved outcomes in moderate-severe acute respiratory distress syndrome (ARDS). Previous studies have demonstrated increased drug utilization without benefits in oxygenation using fixed dose cisatracurium compared to train-of-four (TOF) titration. Objective: We sought to compare a novel, lower fixed dose cisatracurium protocol to TOF titration evaluating the impact on PaO2:FiO2 ratio (P/F). Methods: We conducted a single-center retrospective cohort study comparing fixed dose cisatracurium to TOF titration. We included patients aged 18-89 treated for COVID-19 ARDS with a baseline P/F≤200 who received a cisatracurium infusion for ≥12 h. The primary outcome was change in P/F at 48 h from baseline. Secondary outcomes included change in P/F at 24 h and 7 days, need for mechanical ventilation at day 28, and cisatracurium utilization. Results: Analyses included 125 patients (fixed dose = 65, TOF = 60). Severe ARDS was common with a baseline median P/F of 73.7 vs 79.5, P = .133. The change in P/F at 48 h was larger in the TOF cohort in the adjusted analysis (24.9 vs 70.8, P < .005). The rate and total cumulative dose of cisatracurium were higher in the fixed dose cohort (5 vs 3 mcg/kg/min, P < .001; 1034 vs 612 mg, P < .001) despite similar infusion durations (44.1 h vs 48.5 h, P = .642). Conclusions: Patients in the TOF cisatracurium cohort had improved P/F at 48 h compared to the fixed dose cohort, while also using only 60% of the cumulative dose. Future directions should include analysis of the implications of increased cisatracurium exposure on patient outcomes.

Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome

The Cooling to Help Injured Lungs (CHILL) trial is an open label, two group, parallel design multicenter, randomized phase IIB clinical trial assessing the efficacy and safety of targeted temperature management with combined external cooling and neuromuscular blockade to block shivering in patients with early moderate-severe acute respiratory distress syndrome (ARDS). This report provides the background and rationale for the clinical trial and outlines the methods using the Consolidated Standards of Reporting Trials guidelines. Key design challenges include: [1] protocolizing important co-interventions; [2] incorporation of patients with COVID-19 as the cause of ARDS; [3] inability to blind the investigators; and [4] ability to obtain timely informed consent from patients or legally authorized representatives early in the disease process. Results of the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial informed the decision to mandate sedation and neuromuscular blockade only in the group assigned to therapeutic hypothermia and proceed without this mandate in the control group assigned to a usual temperature management protocol. Previous trials conducted in National Heart, Lung, and Blood Institute ARDS Clinical Trials (ARDSNet) and Prevention and Early Treatment of Acute Lung Injury (PETAL) Networks informed ventilator management, ventilation liberation and fluid management protocols. Since ARDS due to COVID-19 is a common cause of ARDS during pandemic surges and shares many features with ARDS from other causes, patients with ARDS due to COVID-19 are included. Finally, a stepwise approach to obtaining informed consent prior to documenting critical hypoxemia was adopted to facilitate enrollment and reduce the number of candidates excluded because eligibility time window expiration.

Mortality Predictors of Pre-variant SARS-CoV-2 Infected ARDS Patients Receiving Favipiravir and Tocilizumab

Objective: In this study, we investigated the risk factors affecting mortality of critically ill COVID-19-related acute respiratory distress syndrome (ARDS) patients who were followed up in the intensive care unit (ICU) and received tocilizumab and favipiravir treatments together before vaccination. Materials and Methods: The data of patients who were followed up and treated between 1, July 2020 and 5, October 2020 were retrospectively analyzed. Demographic data of the patients (age, gender), acute physiology and chronic health evaluation score II (APACHE II), sequential organ failure assessment (SOFA) score, RT-PCR of oro-nasopharyngeal swabs, the severity of ARDS on the day of tocilizumab admission, time from RT-PCR positivity to tocilizumab administration, respiratory support treatments, all other medical treatments, and ICU outcomes were recorded. Risk factors affecting mortality were evaluated with multiple regression analysis. Results: A total of 60 patients with a median age of 69.8 (24-87) years, 25 females and 35 males were included in the study. The mean APACHE II score was 18.9 ± 8.0, and the SOFA score was 4.5 ± 2.0. Fifty-two (86.7%) patients had positive oro-nasopharyngeal swabs for SARS-CoV-2 by RT-PCR; (13,3%) patients had positive IgM/Ig G rapid antibody tests for SARS-CoV-2. Tocilizumab was given on an average of 2.5th days (± 2.0 days). On the day of tocilizumab administration, 1 (1.7%) patient had mild ARDS, 30 (50.0%) had moderate ARDS, and 29 (48.3%) had severe ARDS. The PaO2/FIO2 ratio of the study group on the day of tocilizumab administration was 96.7 ± 36.6 mmHg. Thirty-four (56.7%) patients were intubated during follow-up. Forty (66.7%) patients died, while 20 (33.3%) patients were transferred to the ward. The mean length of stay in the ICU was 11.4 ± 5.5 days. Advanced age (Hazard ratio (HR) 1.8; 95% confidence interval (CI) 0.88-0.93; p < 0.001), higher APACHE II score (HR 0.81, 95% CI 0.74-0.98; p = 0.001), higher SOFA score on the day of tocilizumab administration (HR 1.47, 95% CI 0.39-0.79; p = 0.001), and lower PaO2/FIO2 ratio (HR 2.54, 95% CI 2.33-3.79; p < 0.001) were determined as independent risk factors for mortality. Conclusion: Patients administered tocilizumab and favipiravir in our ICU were mostly patients with moderate-severe ARDS and had higher inflammatory markers. The reason for the high mortality in this study was attributed to the fact that all of the patients had moderate-severe COVID-19-related ARDS, rather than severe COVID-19.

Utilization of mechanical power and associations with clinical outcomes in brain injured patients: a secondary analysis of the extubation strategies in neuro-intensive care unit patients and associations with outcome (ENIO) trial

BackgroundThere is insufficient evidence to guide ventilatory targets in acute brain injury (ABI). Recent studies have shown associations between mechanical power (MP) and mortality in critical care populations. We aimed to describe MP in ventilated patients with ABI, and evaluate associations between MP and clinical outcomes.MethodsIn this preplanned, secondary analysis of a prospective, multi-center, observational cohort study (ENIO, NCT03400904), we included adult patients with ABI (Glasgow Coma Scale ≤ 12 before intubation) who required mechanical ventilation (MV) ≥ 24 h. Using multivariable log binomial regressions, we separately assessed associations between MP on hospital day (HD)1, HD3, HD7 and clinical outcomes: hospital mortality, need for reintubation, tracheostomy placement, and development of acute respiratory distress syndrome (ARDS).ResultsWe included 1217 patients (mean age 51.2 years [SD 18.1], 66% male, mean body mass index [BMI] 26.3 [SD 5.18]) hospitalized at 62 intensive care units in 18 countries. Hospital mortality was 11% (n = 139), 44% (n = 536) were extubated by HD7 of which 20% (107/536) required reintubation, 28% (n = 340) underwent tracheostomy placement, and 9% (n = 114) developed ARDS. The median MP on HD1, HD3, and HD7 was 11.9 J/min [IQR 9.2–15.1], 13 J/min [IQR 10–17], and 14 J/min [IQR 11–20], respectively. MP was overall higher in patients with ARDS, especially those with higher ARDS severity. After controlling for same-day pressure of arterial oxygen/fraction of inspired oxygen (P/F ratio), BMI, and neurological severity, MP at HD1, HD3, and HD7 was independently associated with hospital mortality, reintubation and tracheostomy placement. The adjusted relative risk (aRR) was greater at higher MP, and strongest for: mortality on HD1 (compared to the HD1 median MP 11.9 J/min, aRR at 17 J/min was 1.22, 95% CI 1.14–1.30) and HD3 (1.38, 95% CI 1.23–1.53), reintubation on HD1 (1.64; 95% CI 1.57–1.72), and tracheostomy on HD7 (1.53; 95%CI 1.18–1.99). MP was associated with the development of moderate-severe ARDS on HD1 (2.07; 95% CI 1.56–2.78) and HD3 (1.76; 95% CI 1.41–2.22).ConclusionsExposure to high MP during the first week of MV is associated with poor clinical outcomes in ABI, independent of P/F ratio and neurological severity. Potential benefits of optimizing ventilator settings to limit MP warrant further investigation.

Effect of the duration of prone position in ARDS patients during the SARS-CoV-2 pandemic

ObjectiveTo describe the characteristics of patients with acute respiratory distress syndrome (ARDS) due to bilateral COVID-19 pneumonia on invasive mechanical ventilation (IMV), and to analyze the effect of prone position >24 h (prolonged) (PPP) compared to prone decubitus <24 h (PP). DesignA retrospective observational descriptive study was carried out, with uni- and bivariate analyses. SettingDepartment of Intensive Care Medicine. Hospital General Universitario de Elche (Elche, Alicante, Spain). ParticipantsPatients with SARS-CoV-2 pneumonia (2020−2021) on IMV due to moderate-severe ARDS, ventilated in prone position (PP). InterventionsIMV. PP maneuvers. Main variables of interestSociodemographic characteristics, analgo-sedation, neuromuscular blockade (NMB), PD duration, ICU stay and mortality, days of IMV, non-infectious complications, healthcare associated infections. ResultsFifty-one patients required PP, and of these, 31 (69.78%) required PPP. No differences were observed in terms of patient characteristics (gender, age, comorbidities, initial severity, antiviral and antiinflammatory treatment received). Patients on PPP had poorer tolerance to supine ventilation (61.29% vs 89.47%, p = 0.031), longer hospital stay (41 vs 30 days, p = 0.023), more days of IMV (32 vs 20 days, p = 0.032), longer duration of NMB (10.5 vs 3 days, p = 0.0002), as well as a higher percentage of episodes of orotracheal tube obstruction (48.39% vs 15%, p = 0.014). ConclusionsPPP was associated with greater resource use and complications in patients with moderate-severe ARDS due to COVID-19.

Critical Care Pharmacist Attitudes and Perceptions of Neuromuscular Blocker Infusions in ARDS.

Current critical care pharmacist (CCP) practices and perceptions related to neuromuscular infusion (NMBI) use for acute respiratory distress syndrome (ARDS) maybe different with the COVID-19 pandemic and the publication of 2020 NMBI practice guidelines. To evaluate CCP practices and perceptions regarding NMBI use for patients with moderate-severe ARDS. We developed, tested, and electronically administered a questionnaire (7 parent-, 42 sub-questions) to 409 American College of Clinical Pharmacy (ACCP) Critical Care Practice and Research Network members in 12 geographically diverse states. The questionnaire focused on adults with moderate-severe ARDS (PaO2:FiO2<150) whose causes of dyssynchrony were addressed. Two reminders were sent at 10-day intervals. Respondents [131/409 (32%)] primarily worked in a medical intensive care unit (ICU) 102 (78%). Compared to COVID-negative(-) ARDS patients, COVID positive(+) ARDS patients were twice as likely to receive a NMBI (34 ± 18 vs.16 ± 17%; P < 0.01). Respondents somewhat/strongly agreed a NMBI should be reserved until after trials of deep sedation (112, 86%) or proning (92, 81%) and that NMBI reduced barotrauma (88, 67%), dyssynchrony (87, 66%), and plateau pressure (79, 60%). Few respondents somewhat/strongly agreed that a NMBI should be initiated at ARDS onset (23, 18%) or that NMBI reduced 90-day mortality (12, 10%). Only 2/14 potential NMBI risks [paralysis awareness (101, 82%) and prolonged muscle weakness (84, 68%)] were frequently reported to be of high/very high concern. Multiple NMBI titration targets were assessed as very/extremely important including arterial pH (109, 88%), dyssynchrony (107, 86%), and PaO2: FiO2 ratio (82, 66%). Train-of-four (55, 44%) and BIS monitoring (36, 29%) were deemed less important. Preferred NMBI discontinuation criteria included absence of dysschrony (84, 69%) and use ≥48 hour (72, 59%). Current critical care pharmacists believe NMBI for ARDS patients are best reserved until after trials of deep sedation or proning; unique considerations exist in COVID+ patients. Our results should be considered when ICU NMBI protocols are being developed and bedside decisions regarding NMBI use in ARDS are being formulated.

Efecto de la duración del decúbito prono en pacientes con SDRA durante la pandemia por SARS-CoV-2

ObjectiveTo describe the characteristics of patients with acute respiratory distress syndrome due to bilateral COVID-19 pneumonia on invasive mechanical ventilation (IMV) and analyze the effect of prolonged prone decubitus>24h (PPD) compared to prone decubitus<24h (PD). DesignRetrospective observational descriptive study. Uni and bivariate analysis. SettingDepartment of Intensive Care Medicine. General University Hospital of Elche. ParticipantsPatients with SARS-CoV-2 pneumonia (2020–2021) in VMI for moderate-severe acute respiratory distress syndrome, ventilated in PD. InterventionsIMV. PD maneuvers. Main variables of interestSociodemographic; analgo-sedation; neuromuscular blockade; PD (duration), ICU stay and mortality, days of IMV; non-infectious complications; health care-associated infections. ResultsFifty-one patients required PD and of these 31 (69.78%) required PPD. No differences were found in patient characteristics (sex, age, comorbidities, initial severity, antiviral and anti-inflammatory treatment received). Patients on PPD had lower tolerance to supine ventilation (61.29 vs. 89.47%, p=0.031), longer hospital stay (41 vs. 30 days, p=0.023), more days of IMV (32 vs. 20 days, p=0.032), longer duration of neuromuscular blockade (10.5 vs. 3 days, p=0.0002), as well as a higher percentage of episodes of orotracheal tube obstruction (48.39 vs. 15%, p=0.014). ConclusionsPPD was associated with higher resource use and complications in patients with moderate-severe acute respiratory distress syndrome by COVID-19.

Electric impedance tomography-guided PEEP titration reduces mechanical power in ARDS: a randomized crossover pilot trial

BackgroundIn patients with acute respiratory distress syndrome undergoing mechanical ventilation, positive end-expiratory pressure (PEEP) can lead to recruitment or overdistension. Current strategies utilized for PEEP titration do not permit the distinction. Electric impedance tomography (EIT) detects and quantifies the presence of both collapse and overdistension. We investigated whether using EIT-guided PEEP titration leads to decreased mechanical power compared to high-PEEP/FiO2 tables.MethodsA single-center, randomized crossover pilot trial comparing EIT-guided PEEP selection versus PEEP selection using the High-PEEP/FiO2 table in patients with moderate–severe acute respiratory distress syndrome. The primary outcome was the change in mechanical power after each PEEP selection strategy. Secondary outcomes included changes in the 4 × driving pressure + respiratory rate (4 ΔP, + RR index) index, driving pressure, plateau pressure, PaO2/FiO2 ratio, and static compliance.ResultsEIT was consistently associated with a decrease in mechanical power compared to PEEP/FiO2 tables (mean difference − 4.36 J/min, 95% CI − 6.7, − 1.95, p = 0.002) and led to lower values in the 4ΔP + RR index (− 11.42 J/min, 95% CI − 19.01, − 3.82, p = 0.007) mainly driven by a decrease in the elastic–dynamic power (− 1.61 J/min, − 2.99, − 0.22, p = 0.027). The elastic–static and resistive powers were unchanged. Similarly, EIT led to a statistically significant change in set PEEP (− 2 cmH2O, p = 0.046), driving pressure, (− 2.92 cmH2O, p = 0.003), peak pressure (− 6.25 cmH2O, p = 0.003), plateau pressure (− 4.53 cmH2O, p = 0.006), and static respiratory system compliance (+ 7.93 ml/cmH2O, p = 0.008).ConclusionsIn patients with moderate–severe acute respiratory distress syndrome, EIT-guided PEEP titration reduces mechanical power mainly through a reduction in elastic–dynamic power.Trial registration This trial was prospectively registered on Clinicaltrials.gov (NCT 03793842) on January 4th, 2019.

Prone position failure in moderate-severe acute respiratory distress syndrome: and now?

Prone position failure in moderate-severe acute respiratory distress syndrome: and now?

Physicians' attitudes and perceptions of neuromuscular blocker infusions in ARDS

PurposeThe perceptions and practices of ICU physicians regarding initiating neuromuscular blocker infusions (NMBI) in acute respiratory distress syndrome (ARDS) may not be evidence-based amidst the surge of severe ARDS during the SARS-CoV-2 pandemic and new practice guidelines. We identified ICU physicians' perspectives and practices regarding NMBI use in adults with moderate-severe ARDS. Materials and methodsAfter extensive development and testing, an electronic survey was distributed to 342 ICU physicians from three geographically-diverse U.S. health systems(n = 12 hospitals). ResultsThe 173/342 (50.5%) respondents (75% medical) somewhat/strongly agreed a NMBI should be reserved until: after a trial of deep sedation (142, 82%) or proning (59, 34%) and be dose-titrated based on train-of-four monitoring (107, 62%). Of 14 potential NMBI risks, 2 were frequently reported to be of high/very high concern: prolonged muscle weakness with steroid use (135, 79%) and paralysis awareness due to inadequate sedation (114, 67%). Absence of dyssychrony (93, 56%) and use ≥48 h (87, 53%) were preferred NMBI stopping criteria. COVID-19 + ARDS patients were twice as likely to receive a NMBI (56 ± 37 vs. 28 ± 19%, p < 0.01). ConclusionsMost intensivists agreed NMBI in ARDS should be reserved until after a deep sedation trial. Stopping criteria remain poorly defined. Unique considerations exist regarding the role of paralysis in COVID-19+ ARDS.

Venovenous extracorporeal CO2 removal to support ultraprotective ventilation in moderate-severe acute respiratory distress syndrome: A systematic review and meta-analysis of the literature.

A strategy that limits tidal volumes and inspiratory pressures, improves outcomes in patients with the acute respiratory distress syndrome (ARDS). Extracorporeal carbon dioxide removal (ECCO2R) may facilitate ultra-protective ventilation. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of venovenous ECCO2R in supporting ultra-protective ventilation in moderate-to-severe ARDS. MEDLINE and EMBASE were interrogated for studies (2000-2021) reporting venovenous ECCO2R use in patients with moderate-to-severe ARDS. Studies reporting ≥10 adult patients in English language journals were included. Ventilatory parameters after 24h of initiating ECCO2R, device characteristics, and safety outcomes were collected. The primary outcome measure was the change in driving pressure at 24h of ECCO2R therapy in relation to baseline. Secondary outcomes included change in tidal volume, gas exchange, and safety data. Ten studies reporting 421 patients (PaO2:FiO2 141.03mmHg) were included. Extracorporeal blood flow rates ranged from 0.35-1.5L/min. Random effects modelling indicated a 3.56cmH2O reduction (95%-CI: 3.22-3.91) in driving pressure from baseline (p < .001) and a 1.89mL/kg (95%-CI: 1.75-2.02, p < .001) reduction in tidal volume. Oxygenation, respiratory rate and PEEP remained unchanged. No significant interactions between driving pressure reduction and baseline driving pressure, partial pressure of arterial carbon dioxide or PaO2:FiO2 ratio were identified in metaregression analysis. Bleeding and haemolysis were the commonest complications of therapy. Venovenous ECCO2R permitted significant reductions in ∆P in patients with moderate-to-severe ARDS. Heterogeneity amongst studies and devices, a paucity of randomised controlled trials, and variable safety reporting calls for standardisation of outcome reporting. Prospective evaluation of optimal device operation and anticoagulation in high quality studies is required before further recommendations can be made.

Monitoring respiratory mechanics by oscillometry in COVID-19 patients receiving non-invasive respiratory support.

BackgroundNon-invasive ventilation (NIV) has been increasingly used in COVID-19 patients. The limited physiological monitoring and the unavailability of respiratory mechanic measures, usually obtainable during invasive ventilation, is a limitation of NIV for ARDS and COVID-19 patients management.ObjectivesThis pilot study was aimed to evaluate the feasibility of non-invasively monitoring respiratory mechanics by oscillometry in COVID-19 patients with moderate-severe acute respiratory distress syndrome (ARDS) receiving NIV.Method15 COVID-19 patients affected by moderate-severe ARDS at the RICU (Respiratory Intensive Care Unit) of the University hospital of Cattinara, Trieste, Italy were recruited. Patients underwent oscillometry tests during short periods of spontaneous breathing between NIV sessions.ResultsOscillometry proved to be feasible, reproducible and well-tolerated by patients. At admission, 8 of the 15 patients showed oscillometry parameters within the normal range which further slightly improved before discharge. At discharge, four patients had still abnormal respiratory mechanics, not exclusively linked to pre-existing respiratory comorbidities. Lung mechanics parameters were not correlated with oxygenation.ConclusionsOur results suggest that lung mechanics provide complementary information for improving patients phenotyping and personalisation of treatments during NIV in COVID 19 patients, especially in the presence of respiratory comorbidities where deterioration of lung mechanics may be less coupled with changes in oxygenation and more difficult to identify. Oscillometry may provide a valuable tool for monitoring lung mechanics in COVID 19 patients receiving NIV.

The INVENT COVID trial: a structured protocol for a randomized controlled trial investigating the efficacy and safety of intravenous imatinib mesylate (Impentri\xae) in subjects with acute respiratory distress syndrome induced by COVID-19

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has led to a disruptive increase in the number of intensive care unit (ICU) admissions with acute respiratory distress syndrome (ARDS). ARDS is a severe, life-threatening medical condition characterized by widespread inflammation and vascular leak in the lungs. Although there is no proven therapy to reduce pulmonary vascular leak in ARDS, recent studies demonstrated that the tyrosine kinase inhibitor imatinib reinforces the endothelial barrier and prevents vascular leak in inflammatory conditions, while leaving the immune response intact.MethodsThis is a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial of intravenous (IV) imatinib mesylate in 90 mechanically ventilated subjects with COVID-19-induced ARDS. Subjects are 18 years or older, admitted to the ICU for mechanical ventilation, meeting the Berlin criteria for moderate-severe ARDS with a positive polymerase chain reaction test for SARS-CoV2. Participants will be randomized in a 1:1 ratio to either imatinib (as mesylate) 200 mg bis in die (b.i.d.) or placebo IV infusion for 7 days, or until ICU discharge or death. The primary study outcome is the change in Extravascular Lung Water Index (EVLWi) between day 1 and day 4. Secondary outcome parameters include changes in oxygenation and ventilation parameters, duration of invasive mechanical ventilation, number of ventilator-free days during the 28-day study period, length of ICU stay, and mortality during 28 days after randomization. Additional secondary parameters include safety, tolerability, and pharmacokinetics.DiscussionThe current study aims to investigate the efficacy and safety of IV imatinib in mechanically ventilated subjects with COVID-19-related ARDS. We hypothesize that imatinib decreases pulmonary edema, as measured by extravascular lung water using a PiCCO catheter. The reduction in pulmonary edema may reverse hypoxemic respiratory failure and hasten recovery. As pulmonary edema is an important contributor to ARDS, we further hypothesize that imatinib reduces disease severity, reflected by a reduction in 28-day mortality, duration of mechanical ventilation, and ICU length of stay.Trial statusProtocol version and date: V3.1, 16 April 2021. Recruitment started on 09 March 2021. Estimated recruitment period of approximately 40 weeks.Trial registrationClinicalTrials.govNCT04794088. Registered on 11 March 2021.

Current situation in ARDS in the light of recent studies: Classification, epidemiology and pharmacotherapeutics.

In the last 50 years, there have been great research and developments in the definition and pathophysiology of acute respiratory distress syndrome (ARDS), the most progressive form of acute hypoxemic respiratory failure. Although there are various discussions and recommendations, the definition of ARDS is still based on the Berlin 2012 diagnostic criteria. Despite various studies in recent years, there is still no effective pharmacotherapeutic agent for the treatment of ARDS. Lung protective mechanical ventilation (low tidal volume, low plateau pressure, low driving pressure) in all ARDS patients, prone position, neuromuscular blockade (cisatracurium) in moderate-severe ARDS patients, and hydrocortisone therapy in sepsis-associated ARDS patients are treatments that contribute to survival. In this review, current changes in the definition and epidemiology of ARDS, recent pharmacotherapeutic research and mesenchymal stem cell therapies will be discussed in the light of newly introduced ARDS phenotypes.

Surfactant protein D is a biomarker of influenza-related pediatric lung injury.

Biomarkers that can risk-stratify children with influenza virus lower respiratory infection may identify patients for targeted intervention. Early elevation of alveolar-related proteins in the bloodstream in these patients could indicate more severe lung damage portending worse outcomes. We used a mouse model of human influenza infection and evaluated relationships between lung pathophysiology and surfactant protein D (SP-D), SP-A, and Club cell protein 16 (CC16). We then measured SP-A, SP-D, and CC16 levels in plasma samples from 94 children with influenza-associated acute respiratory failure (PICFLU cohort), excluding children with underlying conditions explaining disease severity. We tested for associations between levels of circulating proteins and disease severity including the diagnosis of acute respiratory distress syndrome (ARDS), mechanical ventilator, intensive care unit and hospital days, and hospital mortality. Circulating SP-D showed a greater increase than SP-A and CC16 in mice with increased alveolar-vascular permeability following influenza infection. In the PICFLU cohort, SP-D was associated with moderate-severe ARDS diagnosis (p = 0.01) and with mechanical ventilator (r = 0.45, p = 0.002), ICU (r = 0.44, p = 0.002), and hospital days (r = 0.37, p = 0.001) in influenza-infected children without bacterial coinfection. Levels of SP-D were lower in children with secondary bacterial pneumonia (p = 0.01) and not associated with outcomes. CC16 and SP-A levels did not differ with bacterial coinfection and were not consistently associated with severe outcomes. SP-D has potential as an early circulating biomarker reflecting a degree of lung damage caused directly by influenza virus infection in children. Secondary bacterial pneumonia alters SP-D biomarker performance.

Timing of ARDS Resolution (TARU): A Pragmatic Clinical Assessment of ARDS Resolution in the ICU.

PurposeLack of a pragmatic outcome measures for acute respiratory distress syndrome (ARDS) resolution is a barrier to meaningful interventional trials of novel treatments. We evaluated a pragmatic, electronic health record (EHR)-based approach toward the clinical assessment of a novel outcome measure: ICU ARDS resolution.MethodsWe conducted a retrospective observational cohort study evaluating adult patients with moderate–severe ARDS admitted to the medical intensive care unit (ICU) at Mayo Clinic in Rochester, MN, from January 2001 through December 2010. We compared the association of ICU ARDS resolution vs non-resolution with mortality. ICU ARDS resolution was defined as improvement in P/F > 200 for at least 48 h or (if arterial blood gas unavailable) SpO2:FiO2 (S/F) > 235, or discharge prior to 48 h from first P/F > 200 without subsequent decline in P/F, as documented in EHR.ResultsOf the 254 patients included, ICU ARDS resolution was achieved in 179 (70%). Hospital mortality was lower in patients who met ICU ARDS resolution criteria as compared to those who did not (23% vs. 41%, p < 0.01). After adjusting for age, gender, and illness severity, the patients who met ICU ARDS resolution criteria had lower odds of hospital mortality [odds ratio 0.47, 95% CI 0.25–0.86; p = 0.015].ConclusionThe electronic health record-based pragmatic measure of ICU ARDS resolution is associated with patient outcomes and may serve as an intermediate outcome assessing novel mechanistic treatments.