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1.
Shock ; 57(1): 1-6, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-2191212

ABSTRACT

BACKGROUND: The pathomechanisms of hypoxemia and treatment strategies for type H and type L acute respiratory distress syndrome (ARDS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) have not been elucidated. MAIN TEXT: SARS-CoV-2 mainly targets the lungs and blood, leading to ARDS, and systemic thrombosis or bleeding. Angiotensin II-induced coagulopathy, SARS-CoV-2-induced hyperfibrin(ogen)olysis, and pulmonary and/or disseminated intravascular coagulation due to immunothrombosis contribute to COVID-19-associated coagulopathy. Type H ARDS is associated with hypoxemia due to diffuse alveolar damage-induced high right-to-left shunts. Immunothrombosis occurs at the site of infection due to innate immune inflammatory and coagulofibrinolytic responses to SARS-CoV-2, resulting in microvascular occlusion with hypoperfusion of the lungs. Lung immunothrombosis in type L ARDS results from neutrophil extracellular traps containing platelets and fibrin in the lung microvasculature, leading to hypoxemia due to impaired blood flow and a high ventilation/perfusion (VA/Q) ratio. COVID-19-associated ARDS is more vascular centric than the other types of ARDS. D-dimer levels have been monitored for the progression of microvascular thrombosis in COVID-19 patients. Early anticoagulation therapy in critical patients with high D-dimer levels may improve prognosis, including the prevention and/or alleviation of ARDS. CONCLUSIONS: Right-to-left shunts and high VA/Q ratios caused by lung microvascular thrombosis contribute to hypoxemia in type H and L ARDS, respectively. D-dimer monitoring-based anticoagulation therapy may prevent the progression to and/or worsening of ARDS in COVID-19 patients.


Subject(s)
COVID-19/physiopathology , Hemostasis/physiology , Hypoxia/physiopathology , Respiratory Distress Syndrome/physiopathology , Thrombosis/physiopathology , Anticoagulants/therapeutic use , Biomarkers/blood , Blood Platelets/metabolism , COVID-19/drug therapy , Extracellular Traps/metabolism , Fibrin/metabolism , Fibrin Fibrinogen Degradation Products/analysis , Fibrinolysis , Humans , Lung/blood supply , Microvessels/physiopathology , Phenotype , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2 , Thrombosis/drug therapy
2.
PLoS One ; 17(11): e0277790, 2022.
Article in English | MEDLINE | ID: covidwho-2119391

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may cause severe life-threatening diseases called acute respiratory distress syndrome (ARDS) owing to cytokine storms. The mortality rate of COVID-19-related ARDS is as high as 40% to 50%. However, effective treatment for the extensive release of acute inflammatory mediators induced by hyperactive and inappropriate immune responses is very limited. Many anti-inflammatory drugs with variable efficacies have been investigated. Colchicine inhibits interleukin 1 beta (IL-1ß) and its subsequent inflammatory cascade by primarily blocking pyrin and nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) activation. Therefore, this cheap, widely available, oral drug might provide an added benefit in combating the cytokine storm in COVID-19. Here, we sought to determine whether adding colchicine to other standards of care could be beneficial for moderate COVID-19 pneumonia in terms of the requirement for advanced respiratory support and mortality. METHODS AND FINDINGS: This blinded placebo-controlled drug trial was conducted at the Dhaka Medical College Hospital, Dhaka, Bangladesh. A total of 300 patients with moderate COVID-19 based on a positive RT-PCR result were enrolled based on strict selection criteria from June 2020 to November 2020. Patients were randomly assigned to either treatment group in a 1:1 ratio. Patients were administered 1.2 mg of colchicine on day 1 followed by daily treatment with 0.6 mg of colchicine for 13 days or placebo along with the standard of care. The primary outcome was the time to clinical deterioration from randomization to two or more points on a seven-category ordinal scale within the 14 days post-randomization. Clinical outcomes were also recorded on day 28. The primary endpoint was met by 9 (6.2%) patients in the placebo group and 4 (2.7%) patients in the colchicine group (P = 0.171), which corresponds to a hazard ratio (95% CI) of 0.44 (0.13-1.43). Additional analysis of the outcomes on day 28 revealed significantly lower clinical deterioration (defined as a decrease by two or more points) in the colchicine group, with a hazard ratio [95%CI] of 0.29 [0.098-0.917], (P = 0.035). Despite a 56% reduction in the need for mechanical ventilation and death with colchicine treatment on day 14, the reduction was not statistically significant. On day 28, colchicine significantly reduced clinical deterioration measured as the need for mechanical ventilation and all-cause mortality. CONCLUSION: Colchicine was not found to have a significant beneficial effect on reducing mortality and the need for mechanical ventilation. However, a delayed beneficial effect was observed. Therefore, further studies should be conducted to evaluate the late benefits of colchicine. CLINICAL TRIAL REGISTRATION: Clinical trial registration no: ClinicalTrials.gov Identifier: NCT04527562 https://www.google.com/search?client=firefox-b-d&q=NCT04527562.


Subject(s)
COVID-19 , Clinical Deterioration , Respiratory Distress Syndrome , Humans , COVID-19/drug therapy , SARS-CoV-2 , Colchicine/therapeutic use , Bangladesh , Cytokine Release Syndrome , Treatment Outcome , Respiratory Distress Syndrome/drug therapy
3.
Respir Res ; 23(1): 301, 2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2108780

ABSTRACT

PURPOSE: Acute respiratory distress syndrome (ARDS) is an acute and critical disease among children and adults, and previous studies have shown that the administration of corticosteroids remains controversial. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to evaluate the safety and efficacy of corticosteroids. METHODS: The RCTs investigating the safety and efficacy of corticosteroids in ARDS were searched from electronic databases (Embase, Medline, and the Cochrane Central Register of Controlled Trials). The primary outcome was 28-day mortality. Heterogeneity was assessed using the Chi square test and I2 with the inspection level of 0.1 and 50%, respectively. RESULTS: Fourteen RCTs (n = 1607) were included for analysis. Corticosteroids were found to reduce the risk of death in patients with ARDS (relative risk (RR) = 0.78, 95% confidence interval (CI): 0.70-0.87; P < 0.01). Moreover, no significant adverse events were observed, compared to placebo or standard support therapy. Further subgroup analysis showed that variables, such as adults (RR = 0.78; 95% CI: 0.70-0.88; P < 0.01), non-COVID-19 (RR = 0.71; 95% CI: 0.62-0.83; P < 0.01), methylprednisolone (RR = 0.70; 95% CI: 0.56-0.88; P < 0.01), and hydrocortisone (RR = 0.79; 95% CI: 0.63-0.98; P = 0.03) were associated with 28-day mortality among patients who used corticosteroids. However, no association was found, regarding children (RR = 0.21; 95% CI: 0.01-4.10; P = 0.30). CONCLUSION: The use of corticosteroids is an effective approach to reduce the risk of death in ARDS patients. However, this effect is associated with age, non-COVID-19 diseases, and methylprednisolone and hydrocortisone use. Therefore, evidence suggests patients with age ≥ 18 years and non-COVID-19 should be encouraged during the corticosteroid treatment. However, due to substantial differences in the use of corticosteroids among these studies, questions still remain regarding the dosage, optimal corticosteroid agent, and treatment duration in patients with ARDS.


Subject(s)
Hydrocortisone , Respiratory Distress Syndrome , Child , Adult , Humans , Adolescent , Hydrocortisone/therapeutic use , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/drug therapy , Adrenal Cortex Hormones/adverse effects , Methylprednisolone/adverse effects , Randomized Controlled Trials as Topic
4.
PLoS One ; 17(10): e0275181, 2022.
Article in English | MEDLINE | ID: covidwho-2079742

ABSTRACT

BACKGROUND: Glycyrrhizin, an active component of liquorice root extract, exhibits antiviral and immunomodulatory properties by direct inhibition of the pro-inflammatory alarmin HMGB1 (High-mobility group box 1). OBJECTIVE: The aim of this study was to explore the role of liquorice intake on the viral entry receptor ACE2 (angiotensin-converting enzyme 2) and the immunoregulatory HMGB1 in healthy individuals and to explore HMGB1 expression in coronavirus disease 2019 (COVID-19) or non-COVID-19 in ARDS (acute respiratory distress syndrome patients). MATERIAL AND METHODS: This study enrolled 43 individuals, including hospitalised patients with i) acute respiratory distress syndrome (ARDS) due to COVID-19 (n = 7) or other underlying causes (n = 12), ii) mild COVID-19 (n = 4) and iii) healthy volunteers (n = 20). Healthy individuals took 50 g of liquorice (containing 3% liquorice root extract) daily for 7 days, while blood samples were collected at baseline and on day 3 and 7. Changes in ACE2 and HMGB1 levels were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. Additionally, HMGB1 levels were measured in hospitalised COVID-19 patients with mild disease or COVID-19 associated acute respiratory distress syndrome (ARDS) and compared with a non-COVID-19-ARDS group. RESULTS: Liquorice intake significantly reduced after 7 days both cellular membranous ACE2 expression (-51% compared to baseline levels, p = 0.008) and plasma HMGB1 levels (-17% compared to baseline levels, p<0.001) in healthy individuals. Half of the individuals had a reduction in ACE2 levels of at least 30%. HMGB1 levels in patients with mild COVID-19 and ARDS patients with and without COVID-19 were significantly higher compared with those of healthy individuals (+317%, p = 0.002), but they were not different between COVID-19 and non-COVID-19 ARDS. CONCLUSIONS: Liquorice intake modulates ACE2 and HMGB1 levels in healthy individuals. HMGB1 is enhanced in mild COVID-19 and in ARDS with and without COVID-19, warranting evaluation of HMGB1 as a potential treatment target and glycyrrhizin, which is an active component of liquorice root extract, as a potential treatment in COVID-19 and non-COVID-19 respiratory disease.


Subject(s)
COVID-19 , Glycyrrhiza , HMGB1 Protein , Respiratory Distress Syndrome , Alarmins , Angiotensin-Converting Enzyme 2 , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Glycyrrhiza/metabolism , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , HMGB1 Protein/metabolism , Humans , Pilot Projects , Receptors, Virus/metabolism , Respiratory Distress Syndrome/drug therapy
5.
Curr Top Microbiol Immunol ; 436: 437-466, 2022.
Article in English | MEDLINE | ID: covidwho-2075205

ABSTRACT

A number of different experimental models using both non-selective and selective PI3K inhibitors have shown that many pathogenic steps of respiratory disorders, such as bronchial asthma, Chronic Obstructive Pulmonary Disease (COPD), Idiopathic Pulmonary Fibrosis (IPF), Acute Respiratory Distress Syndrome (ARDS) and Lung Cancer (LC) are, at least in part, regulated by the PI3K signaling pathway, suggesting that the inhibition of PI3K could represent an ideal therapeutic target for the treatment of respiratory diseases. This chapter summarizes the current state of the therapeutic strategies aimed to exploit the inhibition of PI3K in this context. In animal models of asthma, selective δ and γ inhibitors have shown to be effective, and when administered by inhalation, reasonably safe. Nevertheless, very few clinical trials have been performed so far. The efficacy of current traditional therapies for allergic bronchial asthma has likely diminished the need for new alternative treatments. Surprisingly, in COPD, where instead there is an urgent need for new and more effective therapeutic approaches, the number of clinical studies is still low and not capable yet, with the exception for an acceptable safety profile, to show a significant improvement of clinical outcomes. In IPF, a disease with a disappointing prognosis, PI3K inhibitors have been bound to a FAP ligand with the aim to selectively target myofibroblasts, showing to significantly reduce collagen production and the development of lung fibrosis in an animal model of lung fibrosis. Due to its role in cell activation and cell replication, the PI3K pathway is obviously largely involved in lung cancer. Several studies, currently ongoing, are testing the effect of PI3K inhibitors mainly in NSCLC. Some evidence in the treatment of cancer patients suggests the possibility that PI3K inhibitors may enhance the response to conventional treatment. The involvement of PI3Kδ in the modulation of airway neutrophil recruitment and bronchial epithelial functional alterations also suggest a potential role in the treatment of ARDS, but at the current state the ongoing trials are aimed to the treatment of ARDS in COVID-19 patients. In general, few clinical trials investigating PI3K inhibitors in respiratory disorders have been performed so far. This relatively new approach of treatment is just at its beginning and certainly needs further efforts and additional studies.


Subject(s)
Asthma , COVID-19 , Idiopathic Pulmonary Fibrosis , Lung Neoplasms , Pulmonary Disease, Chronic Obstructive , Respiratory Distress Syndrome , Animals , Asthma/drug therapy , Collagen/therapeutic use , Idiopathic Pulmonary Fibrosis/drug therapy , Idiopathic Pulmonary Fibrosis/metabolism , Idiopathic Pulmonary Fibrosis/pathology , Ligands , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Pulmonary Disease, Chronic Obstructive/drug therapy , Respiratory Distress Syndrome/drug therapy
6.
Int J Environ Res Public Health ; 19(19)2022 Oct 06.
Article in English | MEDLINE | ID: covidwho-2066063

ABSTRACT

BACKGROUND: Severe COVID-19 is associated with hypoxemia and acute respiratory distress syndrome (ARDS), which may predispose multiorgan failure and death. Inhaled nitric oxide (iNO) is a clinical vasodilator used in the management of acute respiratory distress syndrome (ARDS). This study evaluated the response rate to iNO in patients with COVID-19-ARDS. METHOD: We searched Medline and Embase databases in May 2022, and data on the use of iNO in the treatment of ARDS in COVID-19 patients were synthesized from studies that satisfied predefined inclusion criteria. A systematic synthesis of data was performed followed by meta-analysis. We performed the funnel plot and leave-one-out sensitivity test on the included studies to assess publication bias and possible exaggerated effect size. We compared the effect size of the studies from the Unites States with those from other countries and performed meta-regression to assess the effect of age, year of publication, and concomitant vasodilator use on the effect size. RESULTS: A total of 17 studies (including 712 COVID-19 patients) were included in this systematic review of which 8 studies (involving 265 COVID-19 patients) were subjected to meta-analysis. The overall response rate was 66% (95% CI, 47-84%) with significantly high between-studies heterogeneity (I2 = 94%, p < 0.001). The funnel plot showed publication bias, although the sensitivity test using leave-one-out analysis showed that removing any of the study does not remove the significance of the result. The response rate was higher in the Unites States, and meta-regression showed that age, year of publication, and use of concomitant vasodilators did not influence the response rate to iNO. CONCLUSION: iNO therapy is valuable in the treatment of hypoxemia in COVID-19 patients and may improve systemic oxygenation in patients with COVID-19-ARDS. Future studies should investigate the mechanism of the activity of iNO in COVID-19 patients to provide insight into the unexplored potential of iNO in general ARDS.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Administration, Inhalation , COVID-19/drug therapy , Humans , Hypoxia/drug therapy , Nitric Oxide/therapeutic use , Respiratory Distress Syndrome/drug therapy , Vasodilator Agents/adverse effects , Vasodilator Agents/therapeutic use
7.
Crit Care Med ; 50(12): 1701-1713, 2022 12 01.
Article in English | MEDLINE | ID: covidwho-2063012

ABSTRACT

OBJECTIVES: Evaluate the safety and efficacy of the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib in COVID-19-associated acute respiratory distress syndrome requiring mechanical ventilation. DESIGN: Phase 3 randomized, double-blind, placebo-controlled trial Ruxolitinib in Participants With COVID-19-Associated Acute Respiratory Distress Syndrome Who Require Mechanical Ventilation (RUXCOVID-DEVENT; NCT04377620). SETTING: Hospitals and community-based private or group practices in the United States (29 sites) and Russia (4 sites). PATIENTS: Eligible patients were greater than or equal to 12 years old, hospitalized with severe acute respiratory syndrome coronavirus 2 infection, and mechanically ventilated with a Pa o2 /F io2 of less than or equal to 300 mm Hg within 6 hours of randomization. INTERVENTIONS: Patients were randomized 2:2:1 to receive twice-daily ruxolitinib 15 mg, ruxolitinib 5 mg, or placebo, each plus standard therapy. MEASUREMENTS AND MAIN RESULTS: The primary endpoint, 28-day mortality, was tested for each ruxolitinib group versus placebo using a mixed-effects logistic regression model and one-tailed significance test (significance threshold: p < 0.025); no type 1 error was allocated to secondary endpoints. Between May 24, 2020 and December 15, 2020, 211 patients (age range, 24-87 yr) were randomized (ruxolitinib 15/5 mg, n = 77/87; placebo, n = 47). Acute respiratory distress syndrome was categorized as severe in 27% of patients (58/211) at randomization; 90% (190/211) received concomitant steroids. Day-28 mortality was 51% (39/77; 95% CI, 39-62%) for ruxolitinib 15 mg, 53% (45/85; 95% CI, 42-64%) for ruxolitinib 5 mg, and 70% (33/47; 95% CI, 55-83%) for placebo. Neither ruxolitinib 15 mg (odds ratio, 0.46 [95% CI, 0.201-1.028]; one-sided p = 0.029) nor 5 mg (odds ratio, 0.42 [95% CI, 0.171-1.023]; one-sided p = 0.028) significantly reduced 28-day mortality versus placebo. Numerical improvements with ruxolitinib 15 mg versus placebo were observed in secondary outcomes including ventilator-, ICU-, and vasopressor-free days. Rates of overall and serious treatment-emergent adverse events were similar across treatments. CONCLUSIONS: The observed reduction in 28-day mortality rate between ruxolitinib and placebo in mechanically ventilated patients with COVID-19-associated acute respiratory distress syndrome was not statistically significant; however, the trial was underpowered owing to early termination.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Humans , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/drug therapy , SARS-CoV-2 , Respiratory Distress Syndrome/drug therapy , Respiration, Artificial , Treatment Outcome
8.
J Crit Care ; 72: 154165, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2061478

ABSTRACT

PURPOSE: The 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 METHODS: After extensive development and testing, an electronic survey was distributed to 342 ICU physicians from three geographically-diverse U.S. health systems(n = 12 hospitals). RESULTS: The 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). CONCLUSIONS: Most 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.


Subject(s)
COVID-19 , Neuromuscular Blocking Agents , Physicians , Respiratory Distress Syndrome , Adult , Humans , SARS-CoV-2 , Respiratory Distress Syndrome/drug therapy , Neuromuscular Blocking Agents/therapeutic use , Paralysis
9.
BMJ Open ; 12(9): e063855, 2022 09 26.
Article in English | MEDLINE | ID: covidwho-2053218

ABSTRACT

INTRODUCTION: The use of fibrinolytic therapy has been proposed in severe acute respiratory distress syndrome (ARDS). During the COVID-19 pandemic, anticoagulation has received special attention due to the frequent findings of microthrombi and fibrin deposits in the lungs and other organs. Therefore, the use of fibrinolysis has been regarded as a potential rescue therapy in these patients. In this prospective meta-analysis, we plan to synthesise evidence from ongoing clinical trials and thus assess whether fibrinolytic therapy can improve the ventilation/perfusion ratio in patients with severe COVID-19-caused ARDS as compared with standard of care. METHODS AND ANALYSIS: This protocol was registered in PROSPERO. All randomised controlled trials and prospective observational trials that compare fibrinolytic therapy with standard of care in adult patients with COVID-19 and define their primary or secondary outcome as improvement in oxygenation and/or gas exchange, or mortality will be considered eligible. Safety outcomes will include bleeding event rate and requirement for transfusion. Our search on 25 January 2022 identified five eligible ongoing clinical trials. A formal search of MEDLINE (via PubMed), Embase, CENTRAL will be performed every month to identify published results and to search for further trials that meet our eligibility criteria. DISSEMINATION: This could be the first qualitative and quantitative synthesis summarising evidence of the efficacy and safety of fibrinolytic therapy in critically ill patients with COVID-19. We plan to publish our results in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021285281.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , Anticoagulants/therapeutic use , Critical Illness/therapy , Fibrin , Humans , Meta-Analysis as Topic , Observational Studies as Topic , Pandemics , Prospective Studies , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2 , Thrombolytic Therapy , Treatment Outcome
10.
Crit Care ; 26(1): 304, 2022 10 03.
Article in English | MEDLINE | ID: covidwho-2053942

ABSTRACT

BACKGROUND: Inhaled nitric oxide (iNO) is used as rescue therapy in patients with refractory hypoxemia due to severe COVID-19 acute respiratory distress syndrome (ARDS) despite the recommendation against the use of this treatment. To date, the effect of iNO on the clinical outcomes of critically ill COVID-19 patients with moderate-to-severe ARDS remains arguable. Therefore, this study aimed to evaluate the use of iNO in critically ill COVID-19 patients with moderate-to-severe ARDS. METHODS: This multicenter, retrospective cohort study included critically ill adult patients with confirmed COVID-19 treated from March 01, 2020, until July 31, 2021. Eligible patients with moderate-to-severe ARDS were subsequently categorized into two groups based on inhaled nitric oxide (iNO) use throughout their ICU stay. The primary endpoint was the improvement in oxygenation parameters 24 h after iNO use. Other outcomes were considered secondary. Propensity score matching (1:2) was used based on the predefined criteria. RESULTS: A total of 1598 patients were screened, and 815 were included based on the eligibility criteria. Among them, 210 patients were matched based on predefined criteria. Oxygenation parameters (PaO2, FiO2 requirement, P/F ratio, oxygenation index) were significantly improved 24 h after iNO administration within a median of six days of ICU admission. However, the risk of 30-day and in-hospital mortality were found to be similar between the two groups (HR: 1.18; 95% CI: 0.77, 1.82; p = 0.45 and HR: 1.40; 95% CI: 0.94, 2.11; p= 0.10, respectively). On the other hand, ventilator-free days (VFDs) were significantly fewer, and  ICU and hospital LOS were significantly longer in the iNO group. In addition, patients who received iNO had higher odds of acute kidney injury (AKI) (OR (95% CI): 2.35 (1.30, 4.26), p value = 0.005) and hospital/ventilator-acquired pneumonia (OR (95% CI): 3.2 (1.76, 5.83), p value = 0.001). CONCLUSION: In critically ill COVID-19 patients with moderate-to-severe ARDS, iNO rescue therapy is associated with improved oxygenation parameters but no mortality benefits. Moreover, iNO use is associated with higher odds of AKI, pneumonia, longer LOS, and fewer VFDs.


Subject(s)
Acute Kidney Injury , COVID-19 , Respiratory Distress Syndrome , Acute Kidney Injury/drug therapy , Administration, Inhalation , Adult , COVID-19/complications , COVID-19/drug therapy , Cohort Studies , Critical Illness/therapy , Humans , Nitric Oxide , Respiratory Distress Syndrome/drug therapy , Retrospective Studies
12.
Trials ; 23(1): 790, 2022 Sep 20.
Article in English | MEDLINE | ID: covidwho-2038854

ABSTRACT

BACKGROUND: Despite the fast establishment of new therapeutic agents in the management of COVID-19 and large-scale vaccination campaigns since the beginning of the SARS-CoV-2 pandemic in early 2020, severe disease courses still represent a threat, especially to patients with risk factors. This indicates the need for alternative strategies to prevent respiratory complications like acute respiratory distress syndrome (ARDS) associated with COVID-19. Aviptadil, a synthetic form of human vasoactive intestinal peptide, might be beneficial for COVID-19 patients at high risk of developing ARDS because of its ability to influence the regulation of exaggerated pro-inflammatory proteins and orchestrate the lung homeostasis. Aviptadil has recently been shown to considerably improve the prognosis of ARDS in COVID-19 when applied intravenously. An inhaled application of aviptadil has the advantages of achieving a higher concentration in the lung tissue, fast onset of activity, avoiding the hepatic first-pass metabolism, and the reduction of adverse effects. The overall objective of this project is to assess the efficacy and safety of inhaled aviptadil in patients hospitalized for COVID-19 at high risk of developing ARDS. METHODS: This multicenter, placebo-controlled, double-blinded, randomized trial with 132 adult patients hospitalized for COVID-19 and at high risk for ARDS (adapted early acute lung injury score ≥ 2 points) is conducted in five public hospitals in Europe. Key exclusion criteria are mechanical ventilation at baseline, need for intensive care at baseline, and severe hemodynamic instability. Patients are randomly allocated to either inhale 67 µg aviptadil or normal saline (three times a day for 10 days), in addition to standard care, stratified by center. The primary endpoint is time from hospitalization to clinical improvement, defined as either hospital discharge, or improvement of at least two levels on the nine-level scale for clinical status suggested by the World Health Organization. DISCUSSION: Treatment strategies for COVID-19 are still limited. In the context of upcoming new variants of SARS-CoV-2 and possible inefficacy of the available vaccines and antibody therapies, the investigation of alternative therapy options plays a crucial role in decreasing associated mortality and improving prognosis. Due to its unique immunomodulating properties also targeting the SARS-CoV-2 pathways, inhaled aviptadil may have the potential to prevent ARDS in COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04536350 . Registered 02 September 2020.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Adult , Drug Combinations , Humans , Multicenter Studies as Topic , Phentolamine , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2 , Saline Solution , Vasoactive Intestinal Peptide
13.
Respir Res ; 23(1): 249, 2022 Sep 17.
Article in English | MEDLINE | ID: covidwho-2038754

ABSTRACT

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening disease caused by the induction of inflammatory cytokines and chemokines in the lungs. There is a dearth of drug applications that can be used to prevent cytokine storms in ARDS treatment. This study was designed to investigate the effects of tocilizumab and dexamethasone on oxidative stress, antioxidant parameters, and cytokine storms in acute lung injury caused by oleic acid in rats. METHODS: Adult male rats were divided into five groups: the CN (healthy rats, n = 6), OA (oleic acid administration, n = 6), OA + TCZ-2 (oleic acid and tocilizumab at 2 mg/kg, n = 6), OA + TCZ-4 (oleic acid and tocilizumab at 4 mg/kg, n = 6), and OA + DEX-10 (oleic acid and dexamethasone at 10 mg/kg, n = 6) groups. All animals were euthanized after treatment for histopathological, immunohistochemical, biochemical, PCR, and SEM analyses. RESULTS: Expressions of TNF-α, IL-1ß, IL-6, and IL-8 cytokines in rats with acute lung injury induced by oleic acid were downregulated in the TCZ and DEX groups compared to the OA group (P < 0.05). The MDA level in lung tissues was statistically lower in the OA + TCZ-4 group compared to the OA group. It was further determined that SOD, GSH, and CAT levels were decreased in the OA group and increased in the TCZ and DEX groups (P < 0.05). Histopathological findings such as thickening of the alveoli, hyperemia, and peribronchial cell infiltration were found to be similar when lung tissues of the TCZ and DEX groups were compared to the control group. With SEM imaging of the lung tissues, it was found that the alveolar lining layer had become indistinct in the OA, OA + TCZ-2, and OA + TCZ-4 groups. CONCLUSIONS: In this model of acute lung injury caused by oleic acid, tocilizumab and dexamethasone were effective in preventing cytokine storms by downregulating the expression of proinflammatory cytokines including TNF-α, IL-1ß, IL-6, and IL-8. Against the downregulation of antioxidant parameters such as SOD and GSH in the lung tissues caused by oleic acid, tocilizumab and dexamethasone upregulated them and showed protective effects against cell damage.


Subject(s)
Acute Lung Injury , Respiratory Distress Syndrome , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/prevention & control , Animals , Antibodies, Monoclonal, Humanized , Antioxidants/adverse effects , Cytokine Release Syndrome , Cytokines/pharmacology , Dexamethasone/pharmacology , Down-Regulation , Interleukin-6 , Interleukin-8 , Lung , Male , Oleic Acid/toxicity , Rats , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/drug therapy , Superoxide Dismutase , Tumor Necrosis Factor-alpha/pharmacology , Up-Regulation
14.
Trials ; 23(1): 774, 2022 Sep 14.
Article in English | MEDLINE | ID: covidwho-2029729

ABSTRACT

BACKGROUND: COVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia. METHODS: This is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1ß, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1ß/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP. DISCUSSION: This trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT04511923 . Registered on 13 August 2020. Protocol version 8, 22/12/2021 Protocol identifier: NUIG-2020-003 EudraCT registration number: 2020-003349-12 9 October 2020.


Subject(s)
Acute Lung Injury , COVID-19 , Respiratory Distress Syndrome , Acute Lung Injury/diagnosis , Acute Lung Injury/etiology , Animals , Fibrin , Heparin/adverse effects , Humans , Interleukin-10 , Ireland , Mammals , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2
15.
Kardiologiia ; 62(8): 27-32, 2022 Aug 30.
Article in Russian, English | MEDLINE | ID: covidwho-2025893

ABSTRACT

Aim      To study the effectiveness of nebulized surfactant therapy as a part of a multimodality treatment of severe and extremely severe COVID-19 viral pneumonia with concomitant cardiovascular diseases (CVDs).Material and methods  This retrospective controlled study analyzed a multimodality treatment of 38 patients with severe and extremely severe COVID-19 viral pneumonia and concomitant CVDs who were administered nebulized surfactant for correction of acute respiratory distress syndrome (ARDS). The control group consisted of 105 patients with severe and extremely severe novel coronavirus infection with concomitant CVDs who were not administered surfactant as a part of the multimodality therapy.Results Administration of nebulized surfactant as a part of the multimodality treatment in patients with COVID-19 allowed alleviating the severity of respiratory insufficiency (р<0.001), which decreased the death rate of patients with severe and extremely severe COVID-19 and undoubtedly demonstrated the effectiveness of this medicine. The timely multimodality therapy, including nebulized surfactant, improves the course of the disease. Thus, the absence of a possibility for administering nebulized surfactant for more than 4 days was associated with fatal outcomes (р=0.045).Conclusion      Administration of nebulized surfactant as a part of the multimodality treatment of severe and extremely severe COVID-19 and concomitant CVDs increases the survival (р<0.001) and reduces the mortality by 46 %. The risk factors of an unfavorable outcome of this disease include an age older than 65 (р=0.020), a positive polymerase chain reaction test (р=0.037), a ferritin concentration at baseline >600 mg /ml (р<0.001), and a surfactant treatment duration < 4 days (р=0.045). Further study of the efficacy of nebulized surfactants as a part of the multimodality therapy is required and should include randomized clinical trials with a large number of patients and the development of distinct criteria for the treatment of ARDS.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , COVID-19/complications , Humans , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/drug therapy , Retrospective Studies , SARS-CoV-2 , Surface-Active Agents
16.
AACN Adv Crit Care ; 33(3): 253-261, 2022 Sep 15.
Article in English | MEDLINE | ID: covidwho-2024642

ABSTRACT

BACKGROUND: Clinical assessments of depth of sedation are insufficient for patients undergoing neuromuscular blockade during treatment of acute respiratory distress syndrome (ARDS). This quality initiative was aimed to augment objective assessment and improve sedation during therapeutic paralysis using the bispectral index (BIS). METHODS: This quality improvement intervention provided education and subsequent implementation of a BIS monitoring and sedation/analgesia bundle in a large, urban, safety-net intensive care unit. After the intervention, a retrospective review of the first 70 admissions with ARDS assessed use and documented sedation changes in response to BIS. RESULTS: Therapeutic neuromuscular blockade was initiated for 58 of 70 patients (82.8%) with ARDS, of whom 43 (74%) had BIS monitoring and 29.3% had bundled BIS sedation-titration orders. Explicit documentation of sedation titration in response to BIS values occurred in 27 (62.8%) of those with BIS recordings. CONCLUSIONS: BIS sedation/analgesia bundled order sets are underused, but education and access to BIS monitoring led to high use of monitoring alone and subsequent sedation changes.


Subject(s)
Anesthesia , Neuromuscular Blockade , Respiratory Distress Syndrome , Conscious Sedation , Humans , Hypnotics and Sedatives/therapeutic use , Intensive Care Units , Monitoring, Physiologic , Pain , Paralysis , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/drug therapy
17.
Expert Opin Investig Drugs ; 31(10): 995-1015, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2008423

ABSTRACT

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic has put a strain on global healthcare systems. Despite admirable efforts to develop rapidly new pharmacotherapies, supportive treatments remain the standard of care. Multiple clinical trials have failed due to design issues, biased patient enrollment, small sample sizes, inadequate control groups, and lack of long-term outcomes monitoring. AREAS COVERED: This narrative review depicts the current situation around failed and success COVID-19 clinical trials and recommendations in hospitalized patients with COVID-19, oversights and streamlining of clinically effective therapeutics. PubMed, EBSCO, Cochrane Library, and WHO and NIH guidelines were searched for relevant literature up to 5 August 2022. EXPERT OPINION: The WHO, NIH, and IDSA have issued recommendations to better clarify which drugs should be used during the different phases of the disease. Given the biases and high heterogeneity of published studies, interpretation of the current literature is difficult. Future clinical trials should be designed to standardize clinical approaches, with appropriate organization, patient selection, addition of control groups, and careful identification of disease phase to reduce heterogeneity and bias and should rely on the integration of scientific societies to promote a consensus on interpretation of the data and recommendations for optimal COVID-19 therapies.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , COVID-19/drug therapy , Humans , Pandemics , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2
18.
Int J Mol Sci ; 23(16)2022 Aug 18.
Article in English | MEDLINE | ID: covidwho-1997643

ABSTRACT

Acute lung injury (ALI) as a model of acute respiratory distress syndrome is characterized by inflammation, complex coagulation, and hematologic abnormalities which result in the formation of fibrin-platelet microthrombi in the pulmonary vessels with the rapid development of progressive respiratory dysfunction. We hypothesize that a nebulized fibrinolytic agent, non-immunogenic staphylokinase (nSta), may be useful for ALI therapy. First, the effect of the nebulized nSta (0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg) on the coagulogram parameters was studied in healthy rats. ALI was induced in mice by nebulized administration of lipopolysaccharide (LPS) at a dose of 10 mg/kg. nSta (0.2 mg/kg, 0.4 mg/kg or 0.6 mg/kg) was nebulized 30 min, 24 h, and 48 h after LPS administration. The level of pro-inflammatory cytokines was determined in the blood on the 8th day after LPS and nSta administration. The assessment of lung damage was based on their weighing and microscopic analysis. Fibrin/fibrinogen deposition in the lungs was determined by immunohistochemistry. After nSta nebulization in healthy rats, the fibrinogen blood level as well as activated partial thromboplastin time and prothrombin time did not change. In the nebulized ALI model, the mice showed an increase in lung weight due to their edema and rising fibrin deposition. An imbalance of proinflammatory cytokines was also found. Forty percent of mice with ALI without nSta nebulization had died. Nebulized nSta at a dose of 0.2 mg/kg reduced the severity of ALI: a decrease in interstitial edema and inflammatory infiltration was noted. At a dose of 0.4 mg/kg of nebulized nSta, the animals showed no peribronchial edema and the bronchi had an open clear lumen. At a dose of 0.6 mg/kg of nebulized nSta, the manifestations of ALI were completely eliminated. A significant dose-dependent reduction of the fibrin-positive areas in the lungs of mice with ALI was established. Nebulized nSta had a normalizing effect on the proinflammatory cytokines in blood- interleukin (IL)-1α, IL-17A, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These data showed the effectiveness of nebulized nSta and the perspectives of its clinical usage in COVID-19 patients with acute respiratory distress syndrome (ARDS).


Subject(s)
Acute Lung Injury , COVID-19 , Respiratory Distress Syndrome , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Animals , Disease Models, Animal , Fibrin/pharmacology , Fibrinogen/therapeutic use , Lipopolysaccharides/toxicity , Lung , Metalloendopeptidases , Mice , Rats , Respiratory Distress Syndrome/drug therapy
20.
Expert Opin Emerg Drugs ; 27(2): 187-209, 2022 06.
Article in English | MEDLINE | ID: covidwho-1965653

ABSTRACT

INTRODUCTION: Ventilatory management and general supportive care of acute respiratory distress syndrome (ARDS) in the adult population have led to significant clinical improvements, but morbidity and mortality remain high. Pharmacologic strategies acting on the coagulation cascade, inflammation, oxidative stress, and endothelial cell injury have been targeted in the last decade for patients with ARDS, but only a few of these have shown potential benefits with a meaningful clinical response and improved patient outcomes. The lack of availability of specific pharmacologic treatments for ARDS can be attributed to its complex pathophysiology, different risk factors, huge heterogeneity, and difficult classification into specific biological phenotypes and genotypes. AREAS COVERED: In this narrative review, we briefly discuss the relevance and current advances in pharmacologic treatments for ARDS in adults and the need for the development of new pharmacological strategies. EXPERT OPINION: Identification of ARDS phenotypes, risk factors, heterogeneity, and pathophysiology may help to design clinical trials personalized according to ARDS-specific features, thus hopefully decreasing the rate of failed clinical pharmacologic trials. This concept is still under clinical investigation and needs further development.


Subject(s)
Respiratory Distress Syndrome , Clinical Trials, Phase II as Topic , Humans , Inflammation , Respiratory Distress Syndrome/drug therapy , Risk Factors
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