Delivery of high flow oxygen through nasal vs. tracheal cannulas: A bench study.

Background: The use of high flow oxygen therapy (HFOT) has significantly escalated during the COVID-19 pandemic. HFOT can be delivered through both dedicated devices and ICU ventilators. HFOT can be administered to a patient via a nasal cannula (NC). In intubated patients, a tracheal cannula (TC) is used instead. In this study, we aim to compare the work of breathing (WOB) using a TC or NC and to explore whether differences exist among HFOT devices. Methods: Seven HFOT devices (three dedicated and four ICU ventilators) were connected to a manikin head (Laerdal Medical) through a NC (Optiflow 3S, large size, Fisher and Paykel Healthcare) or a TC (OPT 970 Optiflow+, Fisher and Paykel Healthcare). Each device was also attached to a manikin head that was connected to a lung simulator (ASL5000, Ingmar Medical), set at 40 ml/cmH2O compliance, 10 cmH2O/L/s resistance, and sinusoidal inspiratory effort (muscular pressure 10 cmH2O, rate 30 breaths/min). HFOT was delivered at 40 L/min and at 21% inspired oxygen fraction. The total WOB per breath and its resistive and elastic components were automatically analyzed breath by breath over the last 20 breaths by using Campbell's diagram. Results: The WOB and its resistive and elastic components were significantly lower with the TC than with the NC for every device, and systematically lower with the reference device than with others. These differences were, however, very small and may be not clinically relevant. Conclusion: The WOB is lower with the TC than with the NC and with the reference device, compared with the most recent devices.

Delivery of high flow oxygen through nasal vs. tracheal cannulas: A bench study

Background The use of high flow oxygen therapy (HFOT) has significantly escalated during the COVID-19 pandemic. HFOT can be delivered through both dedicated devices and ICU ventilators. HFOT can be administered to a patient via a nasal cannula (NC). In intubated patients, a tracheal cannula (TC) is used instead. In this study, we aim to compare the work of breathing (WOB) using a TC or NC and to explore whether differences exist among HFOT devices. Methods Seven HFOT devices (three dedicated and four ICU ventilators) were connected to a manikin head (Laerdal Medical) through a NC (Optiflow 3S, large size, Fisher and Paykel Healthcare) or a TC (OPT 970 Optiflow+, Fisher and Paykel Healthcare). Each device was also attached to a manikin head that was connected to a lung simulator (ASL5000, Ingmar Medical), set at 40 ml/cmH2O compliance, 10 cmH2O/L/s resistance, and sinusoidal inspiratory effort (muscular pressure 10 cmH2O, rate 30 breaths/min). HFOT was delivered at 40 L/min and at 21% inspired oxygen fraction. The total WOB per breath and its resistive and elastic components were automatically analyzed breath by breath over the last 20 breaths by using Campbell's diagram. Results The WOB and its resistive and elastic components were significantly lower with the TC than with the NC for every device, and systematically lower with the reference device than with others. These differences were, however, very small and may be not clinically relevant. Conclusion The WOB is lower with the TC than with the NC and with the reference device, compared with the most recent devices.

Respiratory multiplex PCR and procalcitonin to reduce antibiotic exposure in severe SARS-CoV-2 pneumonia: a multicentre randomized controlled trial.

OBJECTIVES: We aimed at assessing the efficacy and safety on antibiotic exposure of a strategy combining a respiratory multiplex PCR (mPCR) with enlarged panel and daily procalcitonin (PCT) measurements, as compared with a conventional strategy, in adult patients who were critically ill with laboratory-confirmed SARS-CoV-2 pneumonia. METHODS: This multicentre, parallel-group, open-label, randomized controlled trial enrolled patients admitted to 13 intensive care units (ICUs) in France. Patients were assigned (1:1) to the control strategy, in which antibiotic streamlining remained at the discretion of the physicians, or interventional strategy, consisting of using mPCR and daily PCT measurements within the first 7 days of randomization to streamline initial antibiotic therapy, with antibiotic continuation encouraged when PCT was >1 ng/mL and discouraged if < 1 ng/mL or decreased by 80% from baseline. All patients underwent conventional microbiological tests and cultures. The primary end point was antibiotic-free days at day 28. RESULTS: Between April 20th and November 23rd 2020, 194 patients were randomized, of whom 191 were retained in the intention-to-treat analysis. Respiratory bacterial co-infection was detected in 48.4% (45/93) and 21.4% (21/98) in the interventional and control group, respectively. The number of antibiotic-free days was 12.0 (0.0; 25.0) and 14.0 (0.0; 24.0) days, respectively (difference, -2.0, (95% CI, -10.6 to 6.6), p=0.89). Superinfection rates were high (51.6% and 48.5%, respectively). Mortality rates and ICU lengths of stay did not differ between groups. DISCUSSION: In severe SARS-CoV-2 pneumonia, the mPCR/PCT algorithm strategy did not affect 28-day antibiotics exposure nor the major clinical outcomes, as compared with routine practice.

Airway Closure and Expiratory Flow Limitation in Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is mostly characterized by the loss of aerated lung volume associated with an increase in lung tissue and intense and complex lung inflammation. ARDS has long been associated with the histological pattern of diffuse alveolar damage (DAD). However, DAD is not the unique pathological figure in ARDS and it can also be observed in settings other than ARDS. In the coronavirus disease 2019 (COVID-19) related ARDS, the impairment of lung microvasculature has been pointed out. The airways, and of notice the small peripheral airways, may contribute to the loss of aeration observed in ARDS. High-resolution lung imaging techniques found that in specific experimental conditions small airway closure was a reality. Furthermore, low-volume ventilator-induced lung injury, also called as atelectrauma, should involve the airways. Atelectrauma is one of the basic tenet subtending the use of positive end-expiratory pressure (PEEP) set at the ventilator in ARDS. Recent data revisited the role of airways in humans with ARDS and provided findings consistent with the expiratory flow limitation and airway closure in a substantial number of patients with ARDS. We discussed the pattern of airway opening pressure disclosed in the inspiratory volume-pressure curves in COVID-19 and in non-COVID-19 related ARDS. In addition, we discussed the functional interplay between airway opening pressure and expiratory flow limitation displayed in the flow-volume curves. We discussed the individualization of the PEEP setting based on these findings.

A 9-mRNA signature measured from whole blood by a prototype PCR panel predicts 28-day mortality upon admission of critically ill COVID-19 patients.

Immune responses affiliated with COVID-19 severity have been characterized and associated with deleterious outcomes. These approaches were mainly based on research tools not usable in routine clinical practice at the bedside. We observed that a multiplex transcriptomic panel prototype termed Immune Profiling Panel (IPP) could capture the dysregulation of immune responses of ICU COVID-19 patients at admission. Nine transcripts were associated with mortality in univariate analysis and this 9-mRNA signature remained significantly associated with mortality in a multivariate analysis that included age, SOFA and Charlson scores. Using a machine learning model with these 9 mRNA, we could predict the 28-day survival status with an Area Under the Receiver Operating Curve (AUROC) of 0.764. Interestingly, adding patients' age to the model resulted in increased performance to predict the 28-day mortality (AUROC reaching 0.839). This prototype IPP demonstrated that such a tool, upon clinical/analytical validation and clearance by regulatory agencies could be used in clinical routine settings to quickly identify patients with higher risk of death requiring thus early aggressive intensive care.

A Bench Comparison of the Effect of High-Flow Oxygen Devices on Work of Breathing.

BACKGROUND: Oxygen therapy via high-flow nasal cannula (HFNC) has been extensively used during the COVID-19 pandemic. The number of devices has also increased. We conducted this study to answer the following questions: Do HFNC devices differ from the original device for work of breathing (WOB) and generated PEEP? METHODS: Seven devices were tested on ASL 5000 lung model. Compliance was set to 40 mL/cm H2O and resistance to 10 cm H2O/L/s. The devices were connected to a manikin head via a nasal cannula with FIO2 set at 0.21. The measurements were performed at baseline (manikin head free of nasal cannula) and then with the cannula and the device attached with oxygen flow set at 20, 40, and 60 L/min. WOB and PEEP were assessed at 3 simulated inspiratory efforts (-5, -10, -15 cm H2O muscular pressure) and at 2 breathing frequencies (20 and 30 breaths/min). Data were expressed as median (first-third quartiles) and compared with nonparametric tests to the Optiflow device taken as reference. RESULTS: Baseline WOB and PEEP were comparable between devices. Over all the conditions tested, WOB was 4.2 (1.0-9.4) J/min with the reference device, and the relative variations from it were 0, -3 (2-4), 1 (0-1), -2 (1-2), -1 (1-2), and -1 (1-2)% with Airvo 2, G5, HM80, T60, V500, and V60 Plus devices, respectively, (P < .05 Kruskal-Wallis test). PEEP was 0.9 (0.3-1.5) cm H2O with Optiflow, and the relative differences were -28 (22-33), -41 (38-46), -30 (26-36), -31 (28-34), -37 (32-42), and -24 (21-34)% with Airvo 2, G5, HM80, T60, V500, and V60 Plus devices, respectively, (P < .05 Kruskal-Wallis test). CONCLUSIONS: WOB was marginally higher and PEEP marginally lower with devices as compared to the reference device.

Prone Positioning and Neuromuscular Blocking Agents as Adjunctive Therapies in Mechanically Ventilated Patients with Acute Respiratory Distress Syndrome.

Neuromuscular blocking agents (NMBAs) and prone position (PP) are two major adjunctive therapies that can improve outcome in moderate-to-severe acute respiratory distress syndrome. NMBA should be used once lung-protective mechanical ventilation has been set, for 48 hours or less and as a continuous intravenous infusion. PP should be used as early as possible for long sessions; in COVID-19 its use has exploded. In nonintubated patients, PP might reduce the rate of intubation but not mortality. The goal of this article is to perform a narrative review on the pathophysiological rationale, the clinical effects, and the clinical use and recommendations of both NMBA and PP.

Recombinant human interleukin-7 reverses T cell exhaustion ex vivo in critically ill COVID-19 patients

BackgroundLymphopenia is a hallmark of severe coronavirus disease 19 (COVID-19). Similar alterations have been described in bacterial sepsis and therapeutic strategies targeting T cell function such as recombinant human interleukin 7 (rhIL-7) have been proposed in this clinical context. As COVID-19 is a viral sepsis, the objectives of this study were to characterize T lymphocyte response over time in severe COVID-19 patients and to assess the effect of ex vivo administration of rhIL-7.ResultsPeripheral blood mononuclear cells from COVID-19 patients hospitalized in intensive care unit (ICU) were collected at admission and after 20 days. Transcriptomic profile was evaluated through NanoString technology. Inhibitory immune checkpoints expressions were determined by flow cytometry. T lymphocyte proliferation and IFN-γ production were evaluated after ex vivo stimulation in the presence or not of rhIL-7. COVID-19 ICU patients were markedly lymphopenic at admission. Mononuclear cells presented with inhibited transcriptomic profile prevalently with impaired T cell activation pathways. CD4 + and CD8 + T cells presented with over-expression of co-inhibitory molecules PD-1, PD-L1, CTLA-4 and TIM-3. CD4 + and CD8 + T cell proliferation and IFN-γ production were markedly altered in samples collected at ICU admission. These alterations, characteristic of a T cell exhaustion state, were more pronounced at ICU admission and alleviated over time. Treatment with rhIL-7 ex vivo significantly improved both T cell proliferation and IFN-γ production in cells from COVID-19 patients.ConclusionsSevere COVID-19 patients present with features of profound T cell exhaustion upon ICU admission which can be reversed ex vivo by rhIL-7. These results reinforce our understanding of severe COVID-19 pathophysiology and opens novel therapeutic avenues to treat such critically ill patients based of immunomodulation approaches. Defining the appropriate timing for initiating such immune-adjuvant therapy in clinical setting and the pertinent markers for a careful selection of patients are now warranted to confirm the ex vivo results described so far.Trial registration ClinicalTrials.gov identifier: NCT04392401 Registered 18 May 2020, http:// clinicaltrials.gov/ct2/show/NCT04392401.

Prone Position in COVID-19 and -COVID-19 Acute Respiratory Distress Syndrome: An International Multicenter Observational Comparative Study.

OBJECTIVES: Prone position is used in acute respiratory distress syndrome and in coronavirus disease 2019 acute respiratory distress syndrome. However, it is unclear how responders may be identified and whether an oxygenation response improves outcome. The objective of this study was to quantify the response to prone position, describe the differences between coronavirus disease 2019 acute respiratory distress syndrome and acute respiratory distress syndrome, and explore variables associated with survival. DESIGN: Retrospective, observational, multicenter, international cohort study. SETTING: Seven ICUs in Italy, United Kingdom, and France. PATIENTS: Three hundred seventy-six adults (220 coronavirus disease 2019 acute respiratory distress syndrome and 156 acute respiratory distress syndrome). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Preproning, a greater proportion of coronavirus disease 2019 acute respiratory distress syndrome patients had severe disease (53% vs 40%), worse Pao2/Fio2 (13.0 kPa [interquartile range, 10.5-15.5 kPa] vs 14.1 kPa [interquartile range, 10.5-18.6 kPa]; p = 0.017) but greater compliance (38 mL/cm H2O [interquartile range, 27-53 mL/cm H2O] vs 31 mL/cm H2O [interquartile range, 21-37 mL/cm H2O]; p < 0.001). Patients with coronavirus disease 2019 acute respiratory distress syndrome had a longer median time from intubation to prone position (2.0 d [interquartile range, 0.7-5.0 d] vs 1.0 d [interquartile range, 0.5-2.9 d]; p = 0.03). The proportion of responders, defined by an increase in Pao2/Fio2 greater than or equal to 2.67 kPa (20 mm Hg), upon proning, was similar between acute respiratory distress syndrome and coronavirus disease 2019 acute respiratory distress syndrome (79% vs 76%; p = 0.5). Responders had earlier prone position (1.4 d [interquartile range, 0.7-4.2 d] vs 2.5 d [interquartile range, 0.8-6.2 d]; p = 0.06)]. Prone position less than 24 hours from intubation achieved greater improvement in oxygenation (11 kPa [interquartile range, 4-21 kPa] vs 7 kPa [interquartile range, 2-13 kPa]; p = 0.002). The variables independently associated with the "responder" category were Pao2/Fio2 preproning (odds ratio, 0.89 kPa-1 [95% CI, 0.85-0.93 kPa-1]; p < 0.001) and interval between intubation and proning (odds ratio, 0.94 d-1 [95% CI, 0.89-0.99 d-1]; p = 0.019). The overall mortality was 45%, with no significant difference observed between acute respiratory distress syndrome and coronavirus disease 2019 acute respiratory distress syndrome. Variables independently associated with mortality included age (odds ratio, 1.03 yr-1 [95% CI, 1.01-1.05 yr-1]; p < 0.001); interval between hospital admission and proning (odds ratio, 1.04 d-1 [95% CI, 1.002-1.084 d-1]; p = 0.047); and change in Pao2/Fio2 on proning (odds ratio, 0.97 kPa-1 [95% CI, 0.95-0.99 kPa-1]; p = 0.002). CONCLUSIONS: Prone position, particularly when delivered early, achieved a significant oxygenation response in ~80% of coronavirus disease 2019 acute respiratory distress syndrome, similar to acute respiratory distress syndrome. This response was independently associated with improved survival.

T cell response against SARS-CoV-2 persists after one year in patients surviving severe COVID-19.

BACKGROUND: In critically ill COVID-19 patients, the initial response to SARS-CoV-2 infection is characterized by major immune dysfunctions. The capacity of these severe patients to mount a robust and persistent SARS-CoV-2 specific T cell response despite the presence of severe immune alterations during the ICU stay is unknown. METHODS: Critically ill COVID-19 patients were sampled five times during the ICU stay and 9 and 13 months afterwards. Immune monitoring included counts of lymphocyte subpopulations, HLA-DR expression on monocytes, plasma IL-6 and IL-10 concentrations, anti-SARS-CoV-2 IgG levels and T cell proliferation in response to three SARS-CoV-2 antigens. FINDINGS: Despite the presence of major lymphopenia and decreased monocyte HLA-DR expression during the ICU stay, convalescent critically ill COVID-19 patients consistently generated adaptive and humoral immune responses against SARS-CoV-2 maintained for more than one year after hospital discharge. Patients with long hospital stays presented with stronger anti-SARS-CoV-2 specific T cell response but no difference in anti-SARS-CoV2 IgG levels. INTERPRETATION: Convalescent critically ill COVID-19 patients consistently generated a memory immune response against SARS-CoV-2 maintained for more than one year after hospital discharge. In recovered individuals, the intensity of SARS-CoV-2 specific T cell response was dependent on length of hospital stay. FUNDING: This observational study was supported by funds from the Hospices Civils de Lyon, Fondation HCL, Claude Bernard Lyon 1 University and Région Auvergne Rhône-Alpes and by partial funding by REACTing (Research and ACTion targeting emerging infectious diseases) INSERM, France and a donation from Fondation AnBer (http://fondationanber.fr/).

Feasibility of non-invasive respiratory drive and breathing pattern evaluation using CPAP in COVID-19 patients.

PURPOSE: Increased respiratory drive and respiratory effort are major features of acute hypoxemic respiratory failure (AHRF) and might help to predict the need for intubation. We aimed to explore the feasibility of a non-invasive respiratory drive evaluation and describe how these parameters may help to predict the need for intubation. MATERIALS AND METHODS: We conducted a prospective observational study. All consecutive patients with COVID-19-related AHRF requiring high-flow nasal cannula (HFNC) were screened for inclusion. Physiologic data (including: occlusion pressure (P0.1), tidal volume (Vt), inspiratory time (Ti), peak and mean inspiratory flow (Vt/Ti)) were collected during a short continuous positive airway pressure (CPAP) session. Measurements were repeated once, 12-24 h later. RESULTS: Measurements were completed in 31 patients after the screening of 45 patients (70%). P0.1 was high (4.4 [2.7-5.1]), but it was not significantly higher in patients who were intubated. The Vt (p = .006), Vt/Ti (p = .019), minute ventilation (p = .006), and Ti/Ttot (p = .003) were higher among intubated patients compared to non-intubated patients. Intubated patients had a significant increase in their diaphragm thickening fraction, Vt, and Vt/Ti over time. CONCLUSIONS: Non-invasive assessment of respiratory drive was feasible in patients with AHRF and showed an increased P0.1, although it was not predictive of intubation.

Airway Closure and Expiratory Flow Limitation in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is mostly characterized by the loss of aerated lung volume associated with an increase in lung tissue and intense and complex lung inflammation. ARDS has long been associated with the histological pattern of diffuse alveolar damage (DAD). However, DAD is not the unique pathological figure in ARDS and it can also be observed in settings other than ARDS. In the coronavirus disease 2019 (COVID-19) related ARDS, the impairment of lung microvasculature has been pointed out. The airways, and of notice the small peripheral airways, may contribute to the loss of aeration observed in ARDS. High-resolution lung imaging techniques found that in specific experimental conditions small airway closure was a reality. Furthermore, low-volume ventilator-induced lung injury, also called as atelectrauma, should involve the airways. Atelectrauma is one of the basic tenet subtending the use of positive end-expiratory pressure (PEEP) set at the ventilator in ARDS. Recent data revisited the role of airways in humans with ARDS and provided findings consistent with the expiratory flow limitation and airway closure in a substantial number of patients with ARDS. We discussed the pattern of airway opening pressure disclosed in the inspiratory volume-pressure curves in COVID-19 and in non-COVID-19 related ARDS. In addition, we discussed the functional interplay between airway opening pressure and expiratory flow limitation displayed in the flow-volume curves. We discussed the individualization of the PEEP setting based on these findings.

Seroconversion in septic ICU patients presenting with COVID-19: necessary but not sufficient.

BACKGROUND: As COVID-19 pandemic and vaccination effects progress, research now focuses on adaptive immunological response to SARS-CoV-2. Few studies specifically investigated intensive care unit (ICU) patients, and little is known about kinetics of humoral response in such critically ill patients. In this context, the main objective of the present work was to perform a longitudinal analysis of the humoral response in critically ill COVID-19 patients with prolonged ICU stays in regard with initial inflammatory response, disease severity and mortality. METHODS: Over a 3 week period, circulating immunoglobulins (Ig) against SARS-CoV-2 along with several immunological and clinical parameters were measured in 64 ICU COVID-19 patients. RESULTS: Critically ill COVID-19 patients mounted a dynamic and sustained antibody response of both IgM and IgG as soon as the first day of ICU hospitalization. This serological response was not associated with any of the classical immunological parameters measured at ICU admission or with initial severity clinical scores. IgM and IgG levels and seroconversion trajectories were not associated with unfavourable outcome. CONCLUSION: Despite rapid seroconversion and elevated humoral response, COVID-19 patients are still characterized by elevated mortality. Additional studies, including cytotoxic T cell functions, are mandatory to understand the immunological mechanisms contributing to long stay of COVID-19 patients in ICU.

Forensic autopsy-confirmed COVID-19-induced out-of-hospital cardiac arrest.

BACKGROUND: In the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, data from autopsy in subjects who died at home during lockdown are scarce. We here report the first forensic autopsy series of coronavirus disease 2019 (COVID-19)-related out-of-hospital cardiac arrest (OHCA). METHODS: Between March and April 2020, four COVID-19-related OHCA were autopsied at the Institute of Legal Medicine of the metropolitan area of Lyon (France) according safe recommended procedures. RESULTS: Four Caucasian individuals (3 men/1 woman; age: 56.8±2.1 years, body mass index: 29.5±7.4 kg/m2), presenting symptomatic COVID-19 were autopsied. Autopsies of 3 individuals reported natural death by acute respiratory failure implicating SARS-CoV-2 with typical COVID-19 pulmonary aspect of gross findings and pulmonary microscopy findings, i.e., diffusely congestive edematous lungs with peripheral thrombi and diffuse alveolar damage (DAD) at different stages of inflammatory reaction. For one individual, autopsy concluded of violent death due to suicidal acute alcohol intoxication in a patient that could no longer endure COVID-19 lockdown. No significant lesions were found in the heart. CONCLUSIONS: We report here OHCAs of non-cardiac cause directly implicating COVID-19 at various stages of SARS-CoV-2-related DAD. Thus, autopsy remain of interest during this epidemic, both legally and medically to better understand the pathogenic processes of this emerging infectious disease.

Electrocardiogram monitoring in the prone position in coronavirus disease 2019 acute respiratory distress syndrome.

AIMS: Prone positioning is increasingly used for treating coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). In these high-risk patients for cardiovascular events who may spend more than 16 h a day in the prone position, an adequate monitoring of electrocardiogram (ECG) is mandatory. However, effects of prone positioning on the ECG are unknown as is the validity of the ECG recorded with electrodes placed dorsally. We aimed to compare ECG data obtained in the prone position from five electrodes positioned conventionally and dorsally, and to assess the effects of the change of position (from supine to prone) on the ECGs in patients with COVID-19 ARDS. METHODS AND RESULTS: In patients with COVID-19 ARDS for whom the prone position was indicated, seven-lead ECG (frontal plane leads and V6) performed in the supine and the prone position with electrodes positioned conventionally and dorsally were compared. A total of 22 patients [20 (91%) males] were included. Among them, 10 (45%) patients had structural or ischaemic heart disease. After prone positioning, PR duration significantly increased and QRS duration significantly decreased whereas QT interval did not significantly change. In the prone position, there were excellent correlations between QRS axis, PR, RR, QRS, and QT intervals durations measured with electrodes placed on the torso and dorsally (with no change in the position of V6). CONCLUSION: Prone positioning induced significant change in the ECG. In the prone position, ECG can be reliably monitored with four electrodes translated from conventional position to the back and with a precordial electrode left in V6 position.

Effects of dexamethasone on immune dysfunction and ventilator-associated pneumonia in COVID-19 acute respiratory distress syndrome: an observational study.

Dexamethasone improves survival of patients with COVID-19 acute respiratory distress syndrome, but might shorten the delay between the start of invasive mechanical ventilation and the occurrence of ventilator-associated pneumonia, suggesting possible worsening of COVID-19-induced immune dysfunction with this treatment. In a prospective observational study, we found that mechanically ventilated patients with COVID-19 treated with dexamethasone presented earlier ventilator-associated pneumonia, had significantly lower monocyte Human Leukocyte Antigen-DR expression and number of circulating CD4 + cells after ICU admission, than those not treated with corticoids.