scholarly journals Effect of losartan on hospitalized patients with COVID-19-induced lung injury: A randomized clinical trial

2021 ◽  
Author(s):  
Michael A Puskarich ◽  
Nicholas E Ingraham ◽  
Lisa H Merck ◽  
Brian E Driver ◽  
David A Wacker ◽  
...  
Keyword(s):  
Lung Injury ◽  
Viral Entry ◽  
Primary Outcome ◽  
Hospitalized Patients ◽  
Ang Ii ◽  
Preclinical Models ◽  
Failure Assessment ◽  
Fraction Of Inspired Oxygen ◽  
Inspired Oxygen

Background: SARS-CoV-2 viral entry may disrupt angiotensin II (Ang II) homeostasis in part via ACE2 downregulation, potentially contributing to COVID-19 induced lung injury. Preclinical models of viral pneumonias that utilize ACE2 demonstrate Ang II type 1 receptor (AT1R) blockade mitigates lung injury, though observational COVID-19 data addressing the effect of AT1R blockade remain mixed. Methods: Multicenter, blinded, placebo-controlled randomized trial of losartan (50 mg PO twice daily for 10 days) versus placebo. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already taking a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible. The primary outcome was the imputed partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity, oxygen, ventilator, and vasopressor-free days, and mortality. Losartan pharmacokinetics (PK) and RAAS components [Ang II, angiotensin-(1-7) (Ang-(1-7)), ACE, ACE2] were measured in a subgroup of participants. Findings: From April 2020 - February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO2/FiO2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0.12)]. Losartan did not improve any secondary clinical outcome, but worsened vasopressor-free days. PK data were consistent with appropriate steady-state concentrations, but we observed no significant effect of losartan on RAAS components. Interpretation: Initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury does not improve PaO2 / FiO2 ratio at 7 days. These data may have implications for ongoing clinical trials.

scholarly journals Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study

Rheumatology ◽  
2020 ◽  
Vol 60 (1) ◽  
pp. 399-407 ◽  
Author(s):  
Jose Luis Rodriguez-Garcia ◽  
Gines Sanchez-Nievas ◽  
Juan Arevalo-Serrano ◽  
Cristina Garcia-Gomez ◽  
Jose Maria Jimenez-Vizuete ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Viral Entry ◽  
Supplemental Oxygen ◽  
Janus Kinase ◽  
Arterial Oxygen ◽  
High Dose ◽  
Observational Cohort ◽  
Fraction Of Inspired Oxygen ◽  
Mean Differences ◽  
Inspired Oxygen

Abstract Objectives The Janus kinase (JAK) inhibitor baricitinib may block viral entry into pneumocytes and prevent cytokine storm in patients with SARS-CoV-2 pneumonia. We aimed to assess whether baricitinib improved pulmonary function in patients treated with high-dose corticosteroids for moderate to severe SARS-CoV-2 pneumonia. Methods This observational study enrolled patients with moderate to severe SARS-CoV-2 pneumonia [arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) <200 mmHg] who received lopinavir/ritonavir and HCQ plus either corticosteroids (CS group, n = 50) or corticosteroids and baricitinib (BCT-CS group, n = 62). The primary end point was the change in oxygen saturation as measured by pulse oximetry (SpO2)/FiO2 from hospitalization to discharge. Secondary end points included the proportion of patients requiring supplemental oxygen at discharge and 1 month later. Statistics were adjusted by the inverse propensity score weighting (IPSW). Results A greater improvement in SpO2/FiO2 from hospitalization to discharge was observed in the BCT-CS vs CS group (mean differences adjusted for IPSW, 49; 95% CI: 22, 77; P < 0.001). A higher proportion of patients required supplemental oxygen both at discharge (62.0% vs 25.8%; reduction of the risk by 82%, OR adjusted for IPSW, 0.18; 95% CI: 0.08, 0.43; P < 0.001) and 1 month later (28.0% vs 12.9%, reduction of the risk by 69%, OR adjusted for IPSW, 0.31; 95% CI: 0.11, 0.86; P = 0.024) in the CS vs BCT-CS group. Conclusions . In patients with moderate to severe SARS-CoV-2 pneumonia a combination of baricitinib with corticosteroids was associated with greater improvement in pulmonary function when compared with corticosteroids alone. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, ENCEPP (EUPAS34966, http://www.encepp.eu/encepp/viewResource.htm? id = 34967)

Angiotensin II and the fibroproliferative response to acute lung injury

2004 ◽  
Vol 286 (1) ◽  
pp. L156-L164 ◽  
Author(s):  
Richard P. Marshall ◽  
Peter Gohlke ◽  
Rachel C. Chambers ◽  
David C. Howell ◽  
Steve E. Bottoms ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Angiotensin Ii ◽  
Lung Injury ◽  
Ace Inhibitors ◽  
Transforming Growth Factor ◽  
Lung Fibroblasts ◽  
Collagen Deposition ◽  
Ang Ii ◽  
Potent Inducer

Angiotensin II (ANG II), generated by activation of local renin-angiotensin systems, is believed to play an important role in tissue repair and remodeling, in part via transforming growth factor-β (TGF-β). Angiotensin-converting enzyme (ACE) inhibitors have been shown to abrogate experimental lung injury via a number of potential mechanisms; however, the potentially fibroproliferative role for ANG II in the lung has not been characterized. We hypothesized that, after lung injury, ANG II would stimulate fibroblast procollagen synthesis and promote lung collagen deposition in rats. In vitro, ANG II was a potent inducer of procollagen production in human lung fibroblasts via activation of the type 1 receptor and, at least in part, via the autocrine action of TGF-β. After bleomycin-induced lung injury, an increase in lung ANG II concentration was observed by day 3 that preceded increases in lung collagen and was maintained until death at day 21. Administration of an ACE inhibitor (ramipril) reduced ACE activity, ANG II concentration, TGF-β expression, and collagen deposition. Losartan (an ANG II type 1 receptor antagonist) also attenuated the increase in TGF-β expression and lung collagen deposition. These observations suggest that ANG II, possibly generated locally within the lung, may play an important role in the fibrotic response to acute lung injury, at least in part via the action of TGF-β. ACE inhibitors and receptor antagonists, already widely used clinically, should be assessed as potential new therapies for fibrotic lung disease.

scholarly journals Association of ROX Index with Mechanical Ventilator Use in Sepsis Patients in the Emergency Department

2022 ◽  
Vol 11 (2) ◽  
pp. 342
Author(s):  
Sejoong Ahn ◽  
Jonghak Park ◽  
Juhyun Song ◽  
Jooyeong Kim ◽  
Hanjin Cho ◽  
...  
Keyword(s):  
Respiratory Rate ◽  
Operating Characteristic ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Tissue Oxygen Saturation ◽  
Mechanical Ventilator ◽  
Tissue Oxygen ◽  
Failure Assessment ◽  
Fraction Of Inspired Oxygen ◽  
Inspired Oxygen

Detecting sepsis patients who are at a high-risk of mechanical ventilation is important in emergency departments (ED). The respiratory rate oxygenation (ROX) index is the ratio of tissue oxygen saturation/fraction of inspired oxygen to the respiratory rate. This study aimed to investigate whether the ROX index could predict mechanical ventilator use in sepsis patients in an ED. This retrospective observational study included quick sequential organ failure assessment (qSOFA) ≥ 2 sepsis patients that presented to the ED between September 2019 and April 2020. The ROX and ROX-heart rate (HR) indices were significantly lower in patients with mechanical ventilator use within 24 h than in those without the use of a mechanical ventilator (4.0 [3.2–5.4] vs. 10.0 [5.9–15.2], p < 0.001 and 3.9 [2.7–5.8] vs. 10.1 [5.4–16.3], p < 0.001, respectively). The area under the receiver operating characteristic (ROC) curve of the ROX and ROX-HR indices were 0.854 and 0.816 (both p < 0.001). The ROX and ROX-HR indices were independently associated with mechanical ventilator use within 24 h (adjusted hazard ratio = 0.78, 95% CI: 0.68–0.90, p < 0.001 and adjusted hazard ratio = 0.87, 95% CI 0.79–0.96, p = 0.004, respectively). The 28-day mortality was higher in the low ROX and low ROX-HR groups. The ROX and ROX-HR indices were associated with mechanical ventilator use within 24 h in qSOFA ≥ 2 patients in the ED.

scholarly journals Effects of photobiomodulation therapy combined with static magnetic field (PBMT-sMF) in patients with severe COVID-19 requiring intubation: a pragmatic randomized placebo-controlled trial

2020 ◽  
Author(s):  
Thiago De Marchi ◽  
Fabiano Frâncio ◽  
João Vitor Ferlito ◽  
Renata Monteiro Weigert ◽  
Cristiane Aparecida de Oliveira ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Length Of Stay ◽  
Primary Outcome ◽  
Controlled Trial ◽  
Invasive Mechanical Ventilation ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Secondary Outcomes ◽  
Fraction Of Inspired Oxygen ◽  
Inspired Oxygen

ABSTRACTBackgroundPhotobiomodulation therapy (PBMT) when used isolated or combined with static magnetic field (PBMT-sMF) has been proven benefits on skeletal muscle increasing performance and reducing fatigue, increasing oxygen saturation, and modulating inflammatory process. However, it is unknown whether the effects observed with this therapy on respiratory muscles will be similar to the effects previously observed on skeletal muscles.ObjectiveWe aimed to investigate whether PBMT-sMF is able to decrease the length of stay in the intensive care unit (ICU) and to reduce the mortality rate of patients with severe COVID-19 requiring invasive mechanical ventilation, increasing the respiratory function and modulating the inflammatory process.MethodsWe conducted a prospectively registered, pragmatic, triple-blinded (patients, therapists and outcome assessors), randomized, placebo-controlled trial of PBMT-sMF in patients with severe COVID-19, requiring invasive mechanical ventilation, admitted to the ICU. Patients were randomly assigned to receive either PBMT-sMF (6 sites at the lower thorax – 189 J total, and 2 sites at the neck area – 63 J total) or placebo PBMT-sMF daily during all the ICU stay. The primary outcome was length of stay in the ICU defined by either discharge or death. The secondary outcomes were survival rate, muscle function of diaphragm, change in blood tests, change in mechanical ventilation parameters and change in arterial blood gas analysis.ResultsA total of 30 patients underwent randomization (with 15 assigned to PBMT-sMF and 15 to placebo) and were analyzed. The length of stay in the ICU for the placebo group was 23.06 days while for the PBMT-sMF group was 16.26. However, there was no statistically difference between groups for the length of stay in the ICU (mean difference - MD = - 6.80; 95% CI = - 18.71 to 5.11). Regarding the secondary outcomes were observed statistically differences in favor of PBMT-sMF for diaphragm thickness, fraction of inspired oxygen, partial pressure of oxygen/fraction of inspired oxygen ratio, C-reactive protein, lymphocytes count, and hemoglobin (p<0.05).ConclusionAmong patients with severe COVID-19 requiring invasive mechanical ventilation, PBMT-sMF was not statistically different than placebo to the length of stay in the ICU. However, it is important to highlight that our sample size was underpowered to detect statistical differences to the primary outcome. In contrast, PBMT-sMF increased muscle function of diaphragm, improved ventilatory parameters, decreased C-reactive protein levels and hemoglobin count, and increased lymphocytes count.

scholarly journals Disequilibrium between the classic renin-angiotensin system and its opposing arm in SARS-CoV-2-related lung injury

2020 ◽  
Vol 319 (2) ◽  
pp. L325-L336 ◽  
Author(s):  
Riccardo Sarzani ◽  
Federico Giulietti ◽  
Chiara Di Pentima ◽  
Piero Giordano ◽  
Francesco Spannella
Keyword(s):  
Lung Injury ◽  
Clinical Studies ◽  
Renin Angiotensin System ◽  
Experimental Models ◽  
Lung Damage ◽  
Ang Ii ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Preclinical And Clinical Studies

A dysregulation of the renin-angiotensin system (RAS) has been involved in the genesis of lung injury and acute respiratory distress syndrome from different causes, including several viral infections. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of pneumocytes, the hallmark of the pandemic coronavirus disease 2019 (COVID-19) involving both alveolar interstitium and capillaries, is linked to angiotensin-converting enzyme 2 (ACE2) binding and its functional downregulation. ACE2 is a key enzyme for the balance between the two main arms of the RAS: the ACE/angiotensin (Ang) II/Ang II type 1 receptor axis (“classic RAS”) and the ACE2/Ang(1–7)/Mas receptor (MasR) axis (“anti-RAS”). The ACE2 downregulation, as a result of SARS-coronaviruses binding, enhances the classic RAS, leading to lung damage and inflammation with leaky pulmonary blood vessels and fibrosis, when the attenuation mediated by the anti-RAS arm is reduced. ACE inhibitors (ACE-I) and Ang II type 1 receptor blockers (ARB), effective in cardiovascular diseases, were found to prevent and counteract acute lung injury in several experimental models by restoring the balance between these two opposing arms. The evidence of RAS arm disequilibrium in COVID-19 and the hypothesis of a beneficial role of RAS modulation supported by preclinical and clinical studies are the focus of the present review. Preclinical and clinical studies on drugs balancing RAS arms might be the right way to counter COVID-19.

Pronation Technique in ARDS Patients

ABOUTOPEN ◽  
2020 ◽  
Vol 7 (1) ◽  
pp. 21-23
Author(s):  
Raffaele Di Fenza ◽  
Hedwige Gay ◽  
Martina Favarato ◽  
Isabella Fontana ◽  
Roberto Fumagalli
Keyword(s):  
Intensive Care ◽  
Intensive Care Units ◽  
Distress Syndrome ◽  
Daily Practice ◽  
Volume Distribution ◽  
Intensive Care Unit Staff ◽  
Safe Technique ◽  
Fraction Of Inspired Oxygen ◽  
And Diffusion ◽  
Inspired Oxygen

In severe acute respiratory distress syndrome (ARDS), characterized by the ratio of arterial partial pressure of oxygen over fraction of inspired oxygen (P/F) less than 150 mm Hg, pronation cycles are the only intervention that showed improved survival, in combination with protective ventilation. The physiological advantages of performing pronation cycles, such as the improvement of oxygenation, better tidal volume distribution with increased involvement of dorsal regions, and easier drainage of secretions, overcome the possible complications, that is, endotracheal tube occlusion or misplacement, pressure ulcers, and brachial plexus injury. However, the incidence of complications is dramatically lower in intensive care units with expertise, adopting prone positioning in daily practice. In this video we are proposing step by step an easy and ergonomic technique to perform pronation maneuvers in patients with severe ARDS. Recent literature suggests that a high percentage of these patients are treated without undergoing pronation cycles. The main purpose of this video is to help increase the number of intensive care units worldwide commonly performing pronation cycles in patients that have indications to be pronated, in order to decrease healthcare burden and costs directly caused by ARDS. Proper intensive care unit staff training is fundamental in minimizing the risks associated with the maneuver for both patients and operators; and diffusion of a safe technique encouraging the operators is the second main purpose of this video.

scholarly journals Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial

Diabetologia ◽  
2021 ◽  
Author(s):  
Robin Assfalg ◽  
Jan Knoop ◽  
Kristi L. Hoffman ◽  
Markus Pfirrmann ◽  
Jose Maria Zapardiel-Gonzalo ◽  
...  
Keyword(s):  
Immune Response ◽  
Type 1 Diabetes ◽  
Randomised Controlled Trial ◽  
Primary Outcome ◽  
Controlled Trial ◽  
Antibody Responses ◽  
Oral Insulin ◽  
Cell Responses ◽  
Randomised Controlled

Abstract Aims/hypothesis Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome. Methods A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. Results Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. Conclusions/interpretation The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. Trial registration Clinicaltrials.gov NCT02547519 Funding The main funding source was the German Center for Diabetes Research (DZD e.V.) Graphical abstract

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