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1.
Trials ; 22(1): 172, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1622253

ABSTRACT

OBJECTIVES: The primary objective of this study is to test the hypothesis that administration of dexamethasone 20 mg is superior to a 6 mg dose in adult patients with moderate or severe ARDS due to confirmed COVID-19. The secondary objective is to investigate the efficacy and safety of dexamethasone 20 mg versus dexamethasone 6 mg. The exploratory objective of this study is to assess long-term consequences on mortality and quality of life at 180 and 360 days. TRIAL DESIGN: REMED is a prospective, phase II, open-label, randomised controlled trial testing superiority of dexamethasone 20 mg vs 6 mg. The trial aims to be pragmatic, i.e. designed to evaluate the effectiveness of the intervention in conditions that are close to real-life routine clinical practice. PARTICIPANTS: The study is multi-centre and will be conducted in the intensive care units (ICUs) of ten university hospitals in the Czech Republic. INCLUSION CRITERIA: Subjects will be eligible for the trial if they meet all of the following criteria: 1. Adult (≥18 years of age) at time of enrolment; 2. Present COVID-19 (infection confirmed by RT-PCR or antigen testing); 3. Intubation/mechanical ventilation or ongoing high-flow nasal cannula (HFNC) oxygen therapy; 4. Moderate or severe ARDS according to Berlin criteria: • Moderate - PaO2/FiO2 100-200 mmHg; • Severe - PaO2/FiO2 < 100 mmHg; 5. Admission to ICU in the last 24 hours. EXCLUSION CRITERIA: Subjects will not be eligible for the trial if they meet any of the following criteria: 1. Known allergy/hypersensitivity to dexamethasone or excipients of the investigational medicinal product (e.g. parabens, benzyl alcohol); 2. Fulfilled criteria for ARDS for ≥14 days at enrolment; 3. Pregnancy or breastfeeding; 4. Unwillingness to comply with contraception measurements from enrolment until at least 1 week after the last dose of dexamethasone (sexual abstinence is considered an adequate contraception method); 5. End-of-life decision or patient is expected to die within next 24 hours; 6. Decision not to intubate or ceilings of care in place; 7. Immunosuppression and/or immunosuppressive drugs in medical history: a) Systemic immunosuppressive drugs or chemotherapy in the past 30 days; b) Systemic corticosteroid use before hospitalization; c) Any dose of dexamethasone during the present hospital stay for COVID-19 for ≥5 days before enrolment; d) Systemic corticosteroids during present hospital stay for conditions other than COVID-19 (e.g. septic shock); 8. Current haematological or generalized solid malignancy; 9. Any contraindication for corticosteroid administration, e.g. • intractable hyperglycaemia; • active gastrointestinal bleeding; • adrenal gland disorders; • presence of superinfection diagnosed with locally established clinical and laboratory criteria without adequate antimicrobial treatment; 10. Cardiac arrest before ICU admission; 11. Participation in another interventional trial in the last 30 days. INTERVENTION AND COMPARATOR: Dexamethasone solution for injection/infusion is the investigational medicinal product as well as the comparator. The trial will assess two doses, 20 mg (investigational) vs 6 mg (comparator). Patients in the intervention group will receive dexamethasone 20 mg intravenously once daily on day 1-5, followed by dexamethasone 10 mg intravenously once daily on day 6-10. Patients in the control group will receive dexamethasone 6 mg day 1-10. All authorized medicinal products containing dexamethasone in the form of solution for i.v. injection/infusion can be used. MAIN OUTCOMES: Primary endpoint: Number of ventilator-free days (VFDs) at 28 days after randomisation, defined as being alive and free from mechanical ventilation. SECONDARY ENDPOINTS: a) Mortality from any cause at 60 days after randomisation; b) Dynamics of inflammatory marker (C-Reactive Protein, CRP) change from Day 1 to Day 14; c) WHO Clinical Progression Scale at Day 14; d) Adverse events related to corticosteroids (new infections, new thrombotic complications) until Day 28 or hospital discharge; e) Independence at 90 days after randomisation assessed by Barthel Index. The long-term outcomes of this study are to assess long-term consequences on mortality and quality of life at 180 and 360 days through telephone structured interviews using the Barthel Index. RANDOMISATION: Randomisation will be carried out within the electronic case report form (eCRF) by the stratified permuted block randomisation method. Allocation sequences will be prepared by a statistician independent of the study team. Allocation to the treatment arm of an individual patient will not be available to the investigators before completion of the whole randomisation process. The following stratification factors will be applied: • Age <65 and ≥ 65; • Charlson Comorbidity index (CCI) <3 and ≥3; • CRP <150 mg/L and ≥150 mg/L • Trial centre. Patients will be randomised in a 1 : 1 ratio into one of the two treatment arms. Randomisation through the eCRF will be available 24 hours every day. BLINDING (MASKING): This is an open-label trial in which the participants and the study staff will be aware of the allocated intervention. Blinded pre-planned statistical analysis will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size is calculated to detect the difference of 3 VFDs at 28 days (primary efficacy endpoint) between the two treatment arms with a two-sided type I error of 0.05 and power of 80%. Based on data from a multi-centre randomised controlled trial in COVID-19 ARDS patients in Brazil and a multi-centre observational study from French and Belgian ICUs regarding moderate to severe ARDS related to COVID-19, investigators assumed a standard deviation of VFD at 28 days as 9. Using these assumptions, a total of 142 patients per treatment arm would be needed. After adjustment for a drop-out rate, 150 per treatment arm (300 patients per study) will be enrolled. TRIAL STATUS: This is protocol version 1.1, 15.01.2021. The trial is due to start on 2 February 2021 and recruitment is expected to be completed by December 2021. TRIAL REGISTRATION: The study protocol was registered on EudraCT No.:2020-005887-70, and on December 11, 2020 on ClinicalTrials.gov (Title: Effect of Two Different Doses of Dexamethasone in Patients With ARDS and COVID-19 (REMED)) Identifier: NCT04663555 with a last update posted on February 1, 2021. FULL PROTOCOL: The full protocol (version 1.1) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the standard formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19/therapy , Dexamethasone/administration & dosage , Glucocorticoids/administration & dosage , Respiration, Artificial , Respiratory Distress Syndrome/therapy , COVID-19/complications , Clinical Trials, Phase II as Topic , Disease Progression , Dose-Response Relationship, Drug , Equivalence Trials as Topic , Humans , Length of Stay , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/etiology , SARS-CoV-2
2.
J Immunotoxicol ; 18(1): 23-29, 2021 12.
Article in English | MEDLINE | ID: covidwho-1593522

ABSTRACT

The coronavirus SARS-CoV-2 of 2019 (COVID-19) causes a pandemic that has been diagnosed in more than 70 million people worldwide. Mild-to-moderate COVID-19 symptoms include coughing, fever, myalgia, shortness of breath, and acute inflammatory lung injury (ALI). In contrast, acute respiratory distress syndrome (ARDS) and respiratory failure occur in patients diagnosed with severe COVID-19. ARDS is mediated, at least in part, by a dysregulated inflammatory response due to excessive levels of circulating cytokines, a condition known as the "cytokine-storm syndrome." Currently, there are FDA-approved therapies that attenuate the dysregulated inflammation that occurs in COVID-19 patients, such as dexamethasone or other corticosteroids and IL-6 inhibitors, including sarilumab, tocilizumab, and siltuximab. However, the efficacy of these treatments have been shown to be inconsistent. Compounds that activate the vagus nerve-mediated cholinergic anti-inflammatory reflex, such as the α7 nicotinic acetylcholine receptor agonist, GTS-21, attenuate ARDS/inflammatory lung injury by decreasing the extracellular levels of high mobility group box-1 (HMGB1) in the airways and the circulation. It is possible that HMGB1 may be an important mediator of the "cytokine-storm syndrome." Notably, high plasma levels of HMGB1 have been reported in patients diagnosed with severe COVID-19, and there is a significant negative correlation between HMGB1 plasma levels and clinical outcomes. Nicotine can activate the cholinergic anti-inflammatory reflex, which attenuates the up-regulation and the excessive release of pro-inflammatory cytokines/chemokines. Therefore, we hypothesize that low molecular weight compounds that activate the cholinergic anti-inflammatory reflex, such as nicotine or GTS-21, may represent a potential therapeutic approach to attenuate the dysregulated inflammatory responses in patients with severe COVID-19.


Subject(s)
Benzylidene Compounds/pharmacology , COVID-19/drug therapy , Cholinergic Agents/pharmacology , Inflammation/drug therapy , Nicotine/metabolism , Pyridines/pharmacology , SARS-CoV-2/physiology , Tobacco Use Disorder/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Cigarette Smoking/adverse effects , Dexamethasone/therapeutic use , HMGB1 Protein/blood , Humans , Pandemics , alpha7 Nicotinic Acetylcholine Receptor/agonists
3.
J Med Internet Res ; 23(2): e23026, 2021 02 22.
Article in English | MEDLINE | ID: covidwho-1575588

ABSTRACT

BACKGROUND: For the clinical care of patients with well-established diseases, randomized trials, literature, and research are supplemented with clinical judgment to understand disease prognosis and inform treatment choices. In the void created by a lack of clinical experience with COVID-19, artificial intelligence (AI) may be an important tool to bolster clinical judgment and decision making. However, a lack of clinical data restricts the design and development of such AI tools, particularly in preparation for an impending crisis or pandemic. OBJECTIVE: This study aimed to develop and test the feasibility of a "patients-like-me" framework to predict the deterioration of patients with COVID-19 using a retrospective cohort of patients with similar respiratory diseases. METHODS: Our framework used COVID-19-like cohorts to design and train AI models that were then validated on the COVID-19 population. The COVID-19-like cohorts included patients diagnosed with bacterial pneumonia, viral pneumonia, unspecified pneumonia, influenza, and acute respiratory distress syndrome (ARDS) at an academic medical center from 2008 to 2019. In total, 15 training cohorts were created using different combinations of the COVID-19-like cohorts with the ARDS cohort for exploratory purposes. In this study, two machine learning models were developed: one to predict invasive mechanical ventilation (IMV) within 48 hours for each hospitalized day, and one to predict all-cause mortality at the time of admission. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive predictive value, and negative predictive value. We established model interpretability by calculating SHapley Additive exPlanations (SHAP) scores to identify important features. RESULTS: Compared to the COVID-19-like cohorts (n=16,509), the patients hospitalized with COVID-19 (n=159) were significantly younger, with a higher proportion of patients of Hispanic ethnicity, a lower proportion of patients with smoking history, and fewer patients with comorbidities (P<.001). Patients with COVID-19 had a lower IMV rate (15.1 versus 23.2, P=.02) and shorter time to IMV (2.9 versus 4.1 days, P<.001) compared to the COVID-19-like patients. In the COVID-19-like training data, the top models achieved excellent performance (AUROC>0.90). Validating in the COVID-19 cohort, the top-performing model for predicting IMV was the XGBoost model (AUROC=0.826) trained on the viral pneumonia cohort. Similarly, the XGBoost model trained on all 4 COVID-19-like cohorts without ARDS achieved the best performance (AUROC=0.928) in predicting mortality. Important predictors included demographic information (age), vital signs (oxygen saturation), and laboratory values (white blood cell count, cardiac troponin, albumin, etc). Our models had class imbalance, which resulted in high negative predictive values and low positive predictive values. CONCLUSIONS: We provided a feasible framework for modeling patient deterioration using existing data and AI technology to address data limitations during the onset of a novel, rapidly changing pandemic.


Subject(s)
COVID-19/diagnosis , COVID-19/mortality , Machine Learning , Pneumonia, Viral/diagnosis , Aged , Area Under Curve , Cohort Studies , Comorbidity , Female , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Predictive Value of Tests , Prognosis , ROC Curve , Respiration, Artificial/statistics & numerical data , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
4.
PLoS One ; 16(3): e0248675, 2021.
Article in English | MEDLINE | ID: covidwho-1574573

ABSTRACT

BACKGROUND: In December 2019, a new disease named coronavirus disease 2019 (COVID-19) was occurred. Patients who are critically ill with COVID-19 are more likely to die, especially elderly patients. We aimed to describe the effect of age on the clinical and immune characteristics of critically ill patients with COVID-19. METHODS: We retrospectively included 32 patients with COVID-19 who were confirmed to have COVID-19 by the local health authority and who were admitted to the first affiliated hospital of Zhengzhou University in Zhengzhou, China between January 3 and March 20, 2020. Clinical information and experimental test data were retrospectively collected for the patients. The 32 patients in this study were all in a critical condition and were classified as severe, according to the guidelines of 2019-nCoV infection from the National Health Commission of the People's Republic of China. Data were compared between those <60 years old and ≥60 years old. RESULTS: Of 32 patients, 13 were under 60 years old, and 19 patients were ≥60 years old. The most common symptom among all patients upon admission was fever (93.8%, 30/32). Compared to younger patients, older patients exhibited increased comorbidities. Among patients who were 60 years and older, platelet count, direct bilirubin (DBIL), indirect bilirubin(IBIL), lactate dehydrogenase (LDH), B-type natriuretic peptide (BNP), C-reactive protein (CRP), procalcitonin (PCT), and interleukin-10 (IL-10) were significantly higher than in younger patients who were less than 60 years old. CD4+ T lymphocytes, CD8+ T lymphocytes, and NKT lymphocytes were decreased, CD4+/CD8+ T lymphocytes were significantly increased in all 32 patients, while there were no evident differences between younger and older patients. The CURB-65 (confusion, urea, respiratory, rate, blood pressure plus age ≥65 years), Acute Physiology and Chronic Health Evaluation (APACHE) II and pH value were significantly higher in older patients than in patients who were under 60 years old. However, the PaO2 and PaO2:FiO2 were lower in older patients than the younger. Compared to patients under 60 years old, patients who were 60 years and older tended to develop ARDS (15 [78.9%] vs 5 [38.5%]), septic shock (7 [36.8%] vs 0 [0.0%]) and were more likely to receive mechanical ventilation (13 [68.4%] vs 3[23.1%]). Dynamic trajectories of seven laboratory parameters were tracked on days 1, 3, 5 and 7, and significant differences in lymphocyte count (P = 0.026), D-dimer (P = 0.010), lactate dehydrogenase (P = 0.000) and C-reactive protein (P = 0.000) were observed between the two age groups. CONCLUSIONS: A high proportion of critically ill patients were 60 or older. Furthermore, rapid disease progression was noted in elderly patients. Therefore, close monitoring and timely treatment should be performed in elderly COVID-19 patients.


Subject(s)
COVID-19/epidemiology , Age Factors , Aged , CD4-CD8 Ratio , COVID-19/blood , COVID-19/diagnosis , COVID-19/immunology , Critical Illness , Female , Humans , Immunity , Lymphocyte Count , Male , Middle Aged , Preliminary Data , Retrospective Studies , SARS-CoV-2/isolation & purification , Severity of Illness Index
5.
Lancet Respir Med ; 9(5): 487-497, 2021 05.
Article in English | MEDLINE | ID: covidwho-1537196

ABSTRACT

BACKGROUND: Lung transplantation is a life-saving treatment for patients with end-stage lung disease; however, it is infrequently considered for patients with acute respiratory distress syndrome (ARDS) attributable to infectious causes. We aimed to describe the course of disease and early post-transplantation outcomes in critically ill patients with COVID-19 who failed to show lung recovery despite optimal medical management and were deemed to be at imminent risk of dying due to pulmonary complications. METHODS: We established a multi-institutional case series that included the first consecutive transplants for severe COVID-19-associated ARDS known to us in the USA, Italy, Austria, and India. De-identified data from participating centres-including information relating to patient demographics and pre-COVID-19 characteristics, pretransplantation disease course, perioperative challenges, pathology of explanted lungs, and post-transplantation outcomes-were collected by Northwestern University (Chicago, IL, USA) and analysed. FINDINGS: Between May 1 and Sept 30, 2020, 12 patients with COVID-19-associated ARDS underwent bilateral lung transplantation at six high-volume transplant centres in the USA (eight recipients at three centres), Italy (two recipients at one centre), Austria (one recipient), and India (one recipient). The median age of recipients was 48 years (IQR 41-51); three of the 12 patients were female. Chest imaging before transplantation showed severe lung damage that did not improve despite prolonged mechanical ventilation and extracorporeal membrane oxygenation. The lung transplant procedure was technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. Pathology of the explanted lungs showed extensive, ongoing acute lung injury with features of lung fibrosis. There was no recurrence of SARS-CoV-2 in the allografts. All patients with COVID-19 could be weaned off extracorporeal support and showed short-term survival similar to that of transplant recipients without COVID-19. INTERPRETATION: The findings from our report show that lung transplantation is the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS, and that the procedure can be done successfully, with good early post-transplantation outcomes, in carefully selected patients. FUNDING: National Institutes of Health. VIDEO ABSTRACT.


Subject(s)
COVID-19 , Critical Illness/therapy , Lung Transplantation/methods , Lung , Respiratory Distress Syndrome , Blood Transfusion/methods , COVID-19/complications , COVID-19/diagnosis , COVID-19/physiopathology , COVID-19/surgery , Critical Care/methods , Extracorporeal Membrane Oxygenation/methods , Female , Humans , Intraoperative Care/methods , Lung/diagnostic imaging , Lung/pathology , Male , Middle Aged , Outcome and Process Assessment, Health Care , Pulmonary Fibrosis/etiology , Pulmonary Fibrosis/pathology , Respiration, Artificial/methods , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/surgery , SARS-CoV-2/pathogenicity
6.
Surg Infect (Larchmt) ; 22(9): 948-954, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1522102

ABSTRACT

Background: In trauma, direct pulmonary injury and innate immune response activation primes the lungs for acute respiratory distress syndrome (ARDS). The inflammasome-dependent release of interleukin-18 (IL-18) was recently identified as a key mediator in ARDS pathogenesis, leading us to hypothesize that plasma IL-18 is a diagnostic predictor of ARDS in severe blunt trauma. Patients and Methods: Secondary analysis of the Inflammation and Host Response to Injury database was performed on plasma cytokines collected within 12 hours of severe blunt trauma. Trauma-related cytokines, including IL-18, were compared between patients with and without ARDS and were evaluated for association with ARDS using regression analysis. Threshold cytokine concentrations predictive of ARDS were determined using receiver-operating curve (ROC) analysis. Results: Cytokine analysis of patients without ARDS patients (n = 61) compared with patients with ARDS (n = 19) demonstrated elevated plasma IL-18 concentration in ARDS and IL-18 remained correlated with ARDS on logistic regression after confounder adjustment (p = 0.008). Additionally, ROC analysis revealed IL-18 as a strong ARDS predictor (area under the curve [AUC] = 0.83), with a threshold IL-18 value of 170 pg/mL (Youden index, 0.3). Unlike in patients without ARDS, elevated IL-18 persisted in patients with ARDS during the acute injury phase (p ≤ 0.02). Other trauma-related cytokines did not correlate with ARDS. Conclusions: In severe blunt trauma, IL-18 is a robust predictor of ARDS and remains elevated throughout the acute injury phase. These findings support the use of IL-18 as a key ARDS biomarker, promoting early identification of trauma patients at greater risk of developing ARDS. Timely recognition of ARDS and implementation of advantageous supportive care practices may reduce trauma-related ARDS morbidity and costs.


Subject(s)
Respiratory Distress Syndrome , Wounds, Nonpenetrating , Humans , Interleukin-18 , Logistic Models , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Risk Assessment , Wounds, Nonpenetrating/complications , Wounds, Nonpenetrating/diagnosis
7.
Ann Thorac Surg ; 112(6): 1983-1989, 2021 12.
Article in English | MEDLINE | ID: covidwho-1520703

ABSTRACT

BACKGROUND: A life-threatening complication of coronavirus disease 2019 (COVID-19) is acute respiratory distress syndrome (ARDS) refractory to conventional management. Venovenous (VV) extracorporeal membrane oxygenation (ECMO) (VV-ECMO) is used to support patients with ARDS in whom conventional management fails. Scoring systems to predict mortality in VV-ECMO remain unvalidated in COVID-19 ARDS. This report describes a large single-center experience with VV-ECMO in COVID-19 and assesses the utility of standard risk calculators. METHODS: A retrospective review of a prospective database of all patients with COVID-19 who underwent VV-ECMO cannulation between March 15 and June 27, 2020 at a single academic center was performed. Demographic, clinical, and ECMO characteristics were collected. The primary outcome was in-hospital mortality; survivor and nonsurvivor cohorts were compared by using univariate and bivariate analyses. RESULTS: Forty patients who had COVID-19 and underwent ECMO were identified. Of the 33 patients (82.5%) in whom ECMO had been discontinued at the time of analysis, 18 patients (54.5%) survived to hospital discharge, and 15 (45.5%) died during ECMO. Nonsurvivors presented with a statistically significant higher Prediction of Survival on ECMO Therapy (PRESET)-Score (mean ± SD, 8.33 ± 0.8 vs 6.17 ± 1.8; P = .001). The PRESET score demonstrated accurate mortality prediction. All patients with a PRESET-Score of 6 or lowers survived, and a score of 7 or higher was associated with a dramatic increase in mortality. CONCLUSIONS: These results suggest that favorable outcomes are possible in patients with COVID-19 who undergo ECMO at high-volume centers. This study demonstrated an association between the PRESET-Score and survival in patients with COVID-19 who underwent VV-ECMO. Standard risk calculators may aid in appropriate selection of patients with COVID-19 ARDS for ECMO.

8.
Qual Life Res ; 30(8): 2123-2135, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1509285

ABSTRACT

BACKGROUND: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) has been used successfully for the past decade in adult patients with acute respiratory distress syndrome (ARDS) refractory to conventional ventilatory support. However, knowledge of the health-related quality of life (HRQoL) in VV-ECMO patients is still limited. Thus, this study aimed to provide a comprehensive overview of the HRQoL following VV-ECMO support in ARDS patients. METHODS: A systematic search was performed on PubMed and Web of Science databases from January 1st, 2009 to October 19th, 2020. Studies reporting on HRQoL following VV-ECMO for ARDS in adults were included. Two authors independently selected studies, extracted data, and assessed methodological quality. RESULTS: Eight studies were eligible for inclusion, consisting of seven observational studies and one randomized controlled trial (total N = 441). All eight studies had a quantitative design and reported 265 VV-ECMO survivors to have a reduced HRQoL compared to a generally healthy population. Follow-up time varied between six months to three years. Additionally, only four studies (total N = 335) compared the HRQoL of VV-ECMO (N = 159) to conventionally treated survivors (N = 176), with one study showing a significantly better HRQoL in VV-ECMO survivors, while three studies were stating comparable HRQoL across groups. Notably, most survivors in these studies appeared to experience varying degrees of anxiety, depression, and post-traumatic stress disorder (PTSD). CONCLUSIONS: ARDS survivors supported by VV-ECMO have a decline in HRQoL and suffered from physical and psychological impairments. This HRQoL reduction is comparable or even better to the HRQoL in conventionally treated ARDS survivors.


Subject(s)
Extracorporeal Membrane Oxygenation/psychology , Quality of Life/psychology , Respiratory Distress Syndrome/therapy , Adult , Cross-Sectional Studies , Extracorporeal Membrane Oxygenation/methods , Health Status , Humans , Respiratory Distress Syndrome/psychology , Survivors , Treatment Outcome
10.
Wellcome Open Res ; 6: 38, 2021.
Article in English | MEDLINE | ID: covidwho-1478483

ABSTRACT

Background: Acute respiratory distress syndrome (ARDS) is a severe critical condition with a high mortality that is currently in focus given that it is associated with mortality caused by coronavirus disease 2019 (COVID-19). Neutrophils play a key role in the lung injury characteristic of non-COVID-19 ARDS and there is also accumulating evidence of neutrophil mediated lung injury in patients who succumb to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: We undertook a functional proteomic and metabolomic survey of circulating neutrophil populations, comparing patients with COVID-19 ARDS and non-COVID-19 ARDS to understand the molecular basis of neutrophil dysregulation. Results: Expansion of the circulating neutrophil compartment and the presence of activated low and normal density mature and immature neutrophil populations occurs in ARDS, irrespective of cause. Release of neutrophil granule proteins, neutrophil activation of the clotting cascade and upregulation of the Mac-1 platelet binding complex with formation of neutrophil platelet aggregates is exaggerated in COVID-19 ARDS. Importantly, activation of components of the neutrophil type I interferon responses is seen in ARDS following infection with SARS-CoV-2, with associated rewiring of neutrophil metabolism, and the upregulation of antigen processing and presentation. Whilst dexamethasone treatment constricts the immature low density neutrophil population, it does not impact upon prothrombotic hyperinflammatory neutrophil signatures. Conclusions: Given the crucial role of neutrophils in ARDS and the evidence of a disordered myeloid response observed in COVID-19 patients, this work maps the molecular basis for neutrophil reprogramming in the distinct clinical entities of COVID-19 and non-COVID-19 ARDS.

11.
Curr Anesthesiol Rep ; : 1-7, 2021 Mar 03.
Article in English | MEDLINE | ID: covidwho-1474172

ABSTRACT

Purpose of Review: To review clinical evidence on whether or not to allow mechanically ventilated patients with acute respiratory distress syndrome (ARDS) to breathe spontaneously. Recent Findings: Observational data (LUNG SAFE study) indicate that mechanical ventilation allowing for spontaneous breathing (SB) is associated with more ventilator-free days and a shorter stay in the intensive care unit without any effect on hospital mortality. A paediatric trial, comparing airway pressure release ventilation (APRV) and low-tidal volume ventilation, showed an increase in mortality in the APRV group. Conversely, in an unpublished trial comparing SB and controlled ventilation (NCT01862016), the authors concluded that SB is feasible but did not improve outcomes in ARDS patients. Summary: A paucity of clinical trial data continues to prevent firm guidance on if or when to allow SB during mechanical ventilation in patients with ARDS. No published large randomised controlled trial exists to inform practice about the benefits and harms of either mode.

12.
Perfusion ; 36(8): 798-802, 2021 11.
Article in English | MEDLINE | ID: covidwho-1455838

ABSTRACT

AIM: Patients with cardiogenic shock or ARDS, for example, in COVID-19/SARS-CoV-2, may require extracorporeal membrane oxygenation (ECMO). An ECLS/ECMO model simulating challenging vascular anatomy is desirable for cannula insertion training purposes. We assessed the ability of various 3D-printable materials to mimic the penetration properties of human tissue by using porcine aortae. METHODS: A test bench for needle penetration and piercing in sampled porcine aorta and preselected 3D-printable polymers was assembled. The 3D-printable materials had Shore A hardness of 10, 20, and 50. 17G Vygon 1.0 × 1.4 mm × 70 mm needles were used for penetration tests. RESULTS: For the porcine tissue and Shore A 10, Shore A 20, and Shore A 50 polymers, penetration forces of 0.9036 N, 0.9725 N, 1.0386 N, and 1.254 N were needed, respectively. For piercing through the porcine tissue and Shore A 10, Shore A 20, and Shore A 50 polymers, forces of 0.8399 N, 1.244 N, 1.475 N, and 1.482 N were needed, respectively. ANOVA showed different variances among the groups, and pairwise two-tailed t-tests showed significantly different needle penetration and piercing forces, except for penetration of Shore A 10 and 20 polymers (p = 0.234 and p = 0.0857). Significantly higher forces were required for all other materials. CONCLUSION: Shore A 10 and 20 polymers have similar needle penetration properties compared to the porcine tissue. Significantly more force is needed to pierce through the material fully. The most similar tested material to porcine aorta for needle penetration and piercing in ECMO-implantation is the silicon Shore A 10 polymer. This silicon could be a 3D-printable material in surgical training for ECMO-implantation.


Subject(s)
COVID-19 , Extracorporeal Membrane Oxygenation , Animals , Aorta , Humans , Needles , SARS-CoV-2 , Shock, Cardiogenic , Swine
13.
Anaesthesist ; 70(7): 573-581, 2021 07.
Article in German | MEDLINE | ID: covidwho-1453676

ABSTRACT

BACKGROUND: In a pandemic situation the overall mortality rate is of considerable interest; however, these data must always be seen in relation to the given healthcare system and the availability of local level of care. A recently published German data evaluation of more than 10,000 COVID-19 patients treated in 920 hospitals showed a high mortality rate of 22% in hospitalized patients and of more than 50% in patients requiring invasive ventilation. Because of the high infection rates in Bavaria, a large number of COVID-19 patients with considerable severity of disease were treated at the intensive care units of the LMU hospital. The LMU hospital is a university hospital and a specialized referral center for the treatment of patients with acute respiratory distress syndrome (ARDS). OBJECTIVE: Data of LMU intensive care unit (ICU) patients were systematically evaluated and compared with the recently published German data. METHODS: Data of all COVID-19 patients with invasive and noninvasive ventilation and with completed admission at the ICU of the LMU hospital until 31 July 2020 were collected. Data were processed using descriptive statistics. RESULTS: In total 70 critically ill patients were included in the data evaluation. The median SAPS II on admission to the ICU was 62 points. The median age was 66 years and 81% of the patients were male. More than 90% were diagnosed with ARDS and received invasive ventilation. Treatment with extracorporeal membrane oxygenation (ECMO) was necessary in 10% of the patients. The median duration of ventilation was 16 days, whereby 34.3% of patients required a tracheostomy. Of the patients 27.1% were transferred to the LMU hospital from external hospitals with reference to our ARDS/ECMO program. Patients from external hospitals had ARDS of higher severity than the total study population. In total, nine different substances were used for virus-specific treatment of COVID-19. The most frequently used substances were hydroxychloroquine and azithromycin. Immunomodulatory treatment, such as Cytosorb® (18.6%) and methylprednisolone (25.7%) were also frequently used. The overall in-hospital mortality rate of ICU patients requiring ventilation was 28.6%. The mortality rates of patients from external hospitals, patients with renal replacement therapy and patients with ECMO therapy were 47.4%, 56.7% and 85.7%, respectively. CONCLUSION: The mortality rate in the ventilated COVID-19 intensive care patients was considerably different from the general rate in Germany. The data showed that treatment in an ARDS referral center could result in a lower mortality rate. Low-dose administration of steroids may be another factor to improve patient outcome in a preselected patient population. In the authors' opinion, critically ill COVID-19 patients should be treated in an ARDS center provided that sufficient resources are available.


Subject(s)
COVID-19/therapy , Respiration, Artificial/statistics & numerical data , Aged , Aged, 80 and over , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/mortality , Critical Illness/therapy , Extracorporeal Membrane Oxygenation , Female , Germany , Hospital Mortality , Hospitals, University , Humans , Immunologic Factors/therapeutic use , Intensive Care Units/statistics & numerical data , Male , Middle Aged , Patient Transfer , Renal Replacement Therapy/statistics & numerical data , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , Treatment Outcome
14.
Perfusion ; 36(4): 374-381, 2021 May.
Article in English | MEDLINE | ID: covidwho-1453006

ABSTRACT

BACKGROUND: Patients with acute respiratory distress syndrome supported with veno-venous extracorporeal membrane oxygenation benefit from higher positive end-expiratory pressure combined with conventional ventilation during the early extracorporeal membrane oxygenation period. The role of incremental positive end-expiratory pressure titration in patients with severe acute respiratory distress syndrome supported with veno-venous extracorporeal membrane oxygenation remains unclear. This study aimed to determine the preferred method for setting positive end-expiratory pressure in patients with severe acute respiratory distress syndrome on veno-venous extracorporeal membrane oxygenation support. METHODS: We retrospectively reviewed all subjects supported with veno-venous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome from 2009 to 2019 in the intensive care units in Tianjin Third Central Hospital. Subjects were divided into two groups according to the positive end-expiratory pressure titration method used: P-V curve (quasi-static pressure-volume curve-guided positive end-expiratory pressure setting) group or Crs (respiratory system compliance-guided positive end-expiratory pressure setting) group. RESULTS: Forty-three subjects were included in the clinical outcome analysis: 20 in the P-V curve group and 23 in the Crs group. Initial positive end-expiratory pressure levels during veno-venous extracorporeal membrane oxygenation were similar in both groups. Incidence rates of barotrauma and hemodynamic events were significantly lower in the Crs group (all p < 0.05). Mechanical ventilation duration, intensive care unit length of stay, and hospital length of stay were significantly shorter in the Crs group than the P-V curve group (all p < 0.05). Subjects in the Crs group showed non-significant improvements in the duration of extracorporeal membrane oxygenation support and 28-day mortality (p > 0.05). CONCLUSION: Respiratory system compliance-guided positive end-expiratory pressure setting may lead to more optimal clinical outcomes for patients with severe acute respiratory distress syndrome supported by veno-venous extracorporeal membrane oxygenation. Moreover, the operation is simple, safe, and convenient in clinical practice.


Subject(s)
Extracorporeal Membrane Oxygenation , Respiratory Distress Syndrome , Humans , Positive-Pressure Respiration , Respiration, Artificial , Respiratory Distress Syndrome/therapy , Retrospective Studies
15.
JAMA ; 323(16): 1582-1589, 2020 04 28.
Article in English | MEDLINE | ID: covidwho-1453469

ABSTRACT

Importance: Coronavirus disease 2019 (COVID-19) is a pandemic with no specific therapeutic agents and substantial mortality. It is critical to find new treatments. Objective: To determine whether convalescent plasma transfusion may be beneficial in the treatment of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Design, Setting, and Participants: Case series of 5 critically ill patients with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment; Pao2/Fio2 <300; and mechanical ventilation. All 5 were treated with convalescent plasma transfusion. The study was conducted at the infectious disease department, Shenzhen Third People's Hospital in Shenzhen, China, from January 20, 2020, to March 25, 2020; final date of follow-up was March 25, 2020. Clinical outcomes were compared before and after convalescent plasma transfusion. Exposures: Patients received transfusion with convalescent plasma with a SARS-CoV-2-specific antibody (IgG) binding titer greater than 1:1000 (end point dilution titer, by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer greater than 40 (end point dilution titer) that had been obtained from 5 patients who recovered from COVID-19. Convalescent plasma was administered between 10 and 22 days after admission. Main Outcomes and Measures: Changes of body temperature, Sequential Organ Failure Assessment (SOFA) score (range 0-24, with higher scores indicating more severe illness), Pao2/Fio2, viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after convalescent plasma transfusion. Results: All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. Following plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and Pao2/Fio2 increased within 12 days (range, 172-276 before and 284-366 after). Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2-specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion. Conclusions and Relevance: In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.


Subject(s)
Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/therapeutic use , Betacoronavirus/immunology , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Respiratory Distress Syndrome/therapy , Adult , Aged , Antibodies, Viral/blood , Antiviral Agents/therapeutic use , Blood Donors , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/physiopathology , Critical Illness , Female , Glucocorticoids/therapeutic use , Humans , Immunization, Passive , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Methylprednisolone/therapeutic use , Middle Aged , Organ Dysfunction Scores , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/physiopathology , SARS-CoV-2
16.
Ann Intensive Care ; 10(1): 24, 2020 Feb 13.
Article in English | MEDLINE | ID: covidwho-1453061

ABSTRACT

BACKGROUND: Right ventricular (RV) function evaluation by echocardiography is key in the management of ICU patients with acute respiratory distress syndrome (ARDS), however, it remains challenging. Quantification of RV deformation by speckle-tracking echocardiography (STE) is a recently available and reproducible technique that provides an integrated analysis of the RV. However, data are scarce regarding its use in critically ill patients. The aim of this study was to assess its feasibility and clinical usefulness in moderate-severe ARDS patients. RESULTS: Forty-eight ARDS patients under invasive mechanical ventilation (MV) were consecutively enrolled in a prospective observational study. A full transthoracic echocardiography was performed within 36 h of MV initiation. STE-derived and conventional parameters were recorded. Strain imaging of the RV lateral, inferior and septal walls was highly feasible (47/48 (98%) patients). Interobserver reproducibility of RV strain values displayed good reliability (intraclass correlation coefficients (ICC) > 0.75 for all STE-derived parameters) in ARDS patients. ROC curve analysis showed that lateral, inferior, global (average of the 3 RV walls) longitudinal systolic strain (LSS) and global strain rate demonstrated significant diagnostic values when compared to several conventional indices (TAPSE, S', RV FAC). A RV global LSS value > - 13.7% differentiated patients with a TAPSE < vs > 12 mm with a sensitivity of 88% and a specificity of 83%. Regarding clinical outcomes, mortality and cumulative incidence of weaning from MV at day 28 were not different in patients with normal versus abnormal STE-derived parameters. CONCLUSIONS: Global STE assessment of the RV was highly achievable and reproducible in moderate-severe ARDS patients under MV and additionally correlated with several conventional parameters of RV function. In our cohort, STE-derived parameters did not provide any incremental value in terms of survival or weaning from MV prediction. Further investigations are needed to evaluate their theranostic usefulness. Trial registration NCT02638844: NCT.

17.
Am J Respir Crit Care Med ; 2020 Sep 02.
Article in English | MEDLINE | ID: covidwho-1452989

ABSTRACT

Rationale: Obesity is characterized by elevated pleural pressure (PPL) and worsening atelectasis during mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). Objectives: To determine the effects of lung recruitment maneuver (LRM) in the presence of elevated PPL on hemodynamics, left and right ventricular pressures and pulmonary vascular resistance. We hypothesized that elevated PPL protects the cardiovascular system against high airway pressures and prevents lung overdistension. Methods: First, an interventional crossover trial in adult subjects with ARDS and BMI ≥35 kg/m2 (n=21) was performed to explore the hemodynamic consequences of LRM. Second, cardiovascular function was studied during low/high PEEPs in a model of swine with ARDS and high PPL (n=9) versus healthy swine with normal PPL (n=6). Measurements and Main Results: Subjects with ARDS and obesity (BMI=57±12 kg/m2), following LRM, required an increase in PEEP of 8[7, 10] cmH2O above traditional ARDSnet settings to improve lung function, oxygenation and ventilation/perfusion matching, without impairment of hemodynamics or right heart function. ARDS swine with high PPL demonstrated unchanged transmural left ventricle pressure and systemic blood pressure after LRM protocol. Pulmonary artery hypertension decreased 8[13, 4] mmHg, as did vascular resistance 1.5[2.2, 0.9] WU, and transmural right ventricle pressure 10[15, 6] mmHg during exhalation. LRM and PEEP decreased pulmonary vascular resistance and normalized ventilation/perfusion ratio. Conclusions: High airway pressure is required to recruit lung atelectasis in patients with ARDS and class III obesity but causes minimal overdistension. Additionally, patients with ARDS and class III obesity tolerate hemodynamically LRM with high airway pressure.

18.
J Thorac Imaging ; 36(5): 286-293, 2021 Sep 01.
Article in English | MEDLINE | ID: covidwho-1440700

ABSTRACT

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.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , COVID-19/diagnostic imaging , COVID-19/therapy , Female , Humans , Lung/diagnostic imaging , Male , Middle Aged , Positive-Pressure Respiration , Respiratory Distress Syndrome/diagnostic imaging , Respiratory Distress Syndrome/therapy , Retrospective Studies , Tomography, X-Ray Computed
19.
Res Sq ; 2021 Mar 17.
Article in English | MEDLINE | ID: covidwho-1431222

ABSTRACT

Coronavirus-associated acute respiratory disease, called coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). More than 90 million people have been infected with SARS-CoV-2 and more than 2 million people have died of complications due to COVID-19 worldwide. COVID-19, in its severe form, presents with an uncontrolled, hyperactive immune response and severe immunological injury or organ damage that accounts for morbidity and mortality. Even in the absence of complications, COVID-19 can last for several months with lingering effects of an overactive immune system. Dysregulated myeloid and lymphocyte compartments have been implicated in lung immunopathology. Currently, there are limited clinically-tested treatments of COVID-19 with disparities in the apparent efficacy in patients. Accurate model systems are essential to rapidly evaluate promising discoveries but most currently available in mice, ferrets and hamsters do not recapitulate sustained immunopathology described in COVID19 patients. Here, we present a comprehensively humanized mouse COVID-19 model that faithfully recapitulates the innate and adaptive human immune responses during infection with SARS-CoV-2 by adapting recombinant adeno-associated virus (AAV)-driven gene therapy to deliver human ACE2 to the lungs 1 of MISTRG6 mice. Our unique model allows for the first time the study of chronic disease due to infection with SARS-CoV-2 in the context of patient-derived antibodies to characterize in real time the potential culprits of the observed human driving immunopathology; most importantly this model provides a live view into the aberrant macrophage response that is thought to be the effector of disease morbidity and ARDS in patients. Application of therapeutics such as patient-derived antibodies and steroids to our model allowed separation of the two aspects of the immune response, infectious viral clearance and immunopathology. Inflammatory cells seeded early in infection drove immune-patholgy later, but this very same early anti-viral response was also crucial to contain infection.

20.
ASAIO J ; 67(9): 982-988, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1393493

ABSTRACT

A significant proportion of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) with high risk of death. The efficacy of veno-venous extracorporeal membrane oxygenation (VV-ECMO) for COVID-19 on longer-term outcomes, unlike in other viral pneumonias, is unknown. In this study, we aimed to compare the 6 month mortality of patients receiving VV-ECMO support for COVID-19 with a historical viral ARDS cohort. Fifty-three consecutive patients with COVID-19 ARDS admitted for VV-ECMO to the Royal Brompton Hospital between March 17, 2020 and May 30, 2020 were identified. Mortality, patient characteristics, complications, and ECMO parameters were then compared to a historical cohort of patients with non-COVID-19 viral pneumonia. At 6 months survival was significantly higher in the COVID-19 than in the non-COVID-19 viral pneumonia cohort (84.9% vs. 66.0%, p = 0.040). Patients with COVID-19 had an increased Murray score (3.50 vs. 3.25, p = 0.005), a decreased burden of organ dysfunction (sequential organ failure score score [8.76 vs. 10.42, p = 0.004]), an increased incidence of pulmonary embolism (69.8% vs. 24.5%, p < 0.001) and in those who survived to decannulation longer ECMO runs (19 vs. 11 days, p = 0.001). Our results suggest that survival in patients supported with EMCO for COVID-19 are at least as good as those treated for non-COVID-19 viral ARDS.


Subject(s)
COVID-19/mortality , Extracorporeal Membrane Oxygenation/adverse effects , Pneumonia/mortality , Respiratory Distress Syndrome/therapy , Adult , Aged , Female , Humans , Male , Middle Aged , Pneumonia/virology , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
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