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Differential response to treatment between two phenotypes of acute respiratory distress syndrome. a) High and low positive end-expiratory pressure (PEEP); b) conservative and liberal fluid management.
Source publication
This review discusses the clinical challenges associated with ventilatory support and pharmacological interventions in patients with acute respiratory distress syndrome (ARDS). In addition, it discusses current scientific challenges facing researchers when planning and performing trials of ventilatory support or pharmacological interventions in the...
Context in source publication
Context 1
... management was steered by a strict protocol relying on the central venous pressure or pulmonary artery occlusion pressure, need for vasopressors and an "effective circulation" (combination of cardiac index and physical examination) [71] resulting in the advice for vasopressor use, furosemide administration or fluid administration. The hyper-inflammatory phenotype seemed to benefit from a higher PEEP strategy and conservative fluid management, while the hypo-inflammatory phenotype did not seem to benefit and might even be harmed by the intervention ( figure 1). Of course, post hoc analyses of RCTs do not provide definitive answers, as research questions are not stated beforehand and the randomisation process is disturbed, but it indicates that our simplistic views on the management of ARDS may need to be revised in the near future. ...
Similar publications
Considerable progress has been made over the last decades in the management of acute respiratory distress syndrome (ARDS). Mechanical ventilation(MV) remains the cornerstone of supportive therapy for ARDS. Lung-protective MV minimizes the risk of ventilator-induced lung injury (VILI) and improves survival. Several parameters contribute to the risk...
Citations
... Xu et al., 2009;Yubero et al., 2012) have investigated the efficacy of anti-inflammatory therapies, particularly with systemic corticosteroids. However, the available evidence on the benefit of glucocorticoids is conflicting, and their use in ARDS remains controversial (Bein et al., 2016;Bihari et al., 2016;Bos et al., 2018;Meduri & Siemieniuk, 2017;Seam & Suffredini, 2016;Sweeney & McAuley, 2017;. ...
The acute exudative phase of acute respiratory distress syndrome (ARDS), a severe form of respiratory failure, is characterized by alveolar damage, pulmonary oedema, and an exacerbated inflammatory response. There is no effective treatment for this condition, but based on the major contribution of inflammation, anti‐inflammatory strategies have been evaluated in animal models and clinical trials, with conflicting results. In COVID‐19 ARDS patients, interleukin (IL)‐1 and IL‐6 receptor antagonists (IL‐1Ra and IL‐6Ra, kineret and tocilizumab, respectively) have shown some efficacy. Moreover, we have previously developed novel peptides modulating IL‐1R and IL‐6R activity (rytvela and HSJ633, respectively) while preserving immune vigilance and cytoprotective pathways. We aimed to assess the efficacy of these novel IL‐1Ra and IL‐6Ra, compared to commercially available drugs (kineret, tocilizumab) during the exudative phase (day 7) of bleomycin‐induced acute lung injury (ALI) in mice. Our results first showed that none of the IL‐1Ra and IL‐6Ra compounds attenuated bleomycin‐induced weight loss and venous PCO2${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ increase. Histological analyses and lung water content measurements also showed that these drugs did not improve lung injury scores or pulmonary oedema, after the bleomycin challenge. Finally, IL‐1Ra and IL‐6Ra failed to alleviate the inflammatory status of the mice, as indicated by cytokine levels and alveolar neutrophil infiltration. Altogether, these results indicate a lack of beneficial effects of IL‐1R and IL‐6R antagonists on key parameters of ALI in the bleomycin mouse model.
... From rodent models, the studies that compared elderly to younger animals found a different biological response (Bos et al., 2018). In this regard, it is well established that there is a general profibrotic response with aging in several organs and tissues, with particular relevance in the lungs. ...
Introduction: Aging induces functional and structural changes in the lung, characterized by a decline in elasticity and diminished pulmonary remodeling and regenerative capacity. Emerging evidence suggests that most biomechanical alterations in the lung result from changes in the composition of the lung extracellular matrix (ECM), potentially modulating the behavior of pulmonary cells and increasing the susceptibility to chronic lung diseases. Therefore, it is crucial to investigate the mechanical properties of the aged lung. This study aims to assess the mechanical alterations in the lung ECM due to aging at both residual (RV) and functional (FV) lung volumes and to evaluate their effects on the survival and proliferation of mesenchymal stromal cells (MSCs).
Methods: The lungs from young (4-6-month-old) and aged (20-24-month-old) mice were inflated with optimal cutting temperature compound to reach FV or non-inflated (RV). ECM proteins laminin, collagen I and fibronectin were quantified by immunofluorescence and the mechanical properties of the decellularized lung sections were assessed using atomic force microscopy. To investigate whether changes in ECM composition by aging and/or mechanical properties at RV and FV volumes affects MSCs, their viability and proliferation were evaluated after 72 h.
Results: Laminin presence was significantly reduced in aged mice compared to young mice, while fibronectin and collagen I were significantly increased in aged mice. In RV conditions, the acellular lungs from aged mice were significantly softer than from young mice. By contrast, in FV conditions, the aged lung ECM becomes stiffer than that of in young mice, revealing that strain hardening significantly depends on aging. Results after MSCs recellularization showed similar viability and proliferation rate in all conditions.
Discussion: This data strongly suggests that biomechanical measurements, especially in aging models, should be carried out in physiomimetic conditions rather than following the conventional non-inflated lung (RV) approach. The use of decellularized lung scaffolds from aged and/or other lung disease murine/human models at physiomimetic conditions will help to better understand the potential role of mechanotransduction on the susceptibility and progression of chronic lung diseases, lung regeneration and cancer.
... This research illustrated that the magnitude of ARDS was notably higher at 98.1 per 100,000 personyears compared to previous studies (39)(40)(41)(42)(43)(44)(45). Prior studies in three Scandinavian nations, for instance, documented an incidence of 13.5 per 100,000 person-years (29). ...
... For instance, a global observational study by Villar J. et al found that the in-hospital mortality rate for ARDS patients was 40% (43). Similarly, a study in the Netherlands reported a range of in-hospital mortality rates from 32.7% to 57.9% (39,42). %. ...
Purpose
Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome with substantial morbidity and mortality globally. Body of evidence revealed that the epidemiologic estimates are currently disproportional due to differences in patient populations, risk factors, resources, and practice protocols around the world, and the rate of mortality and its predictors are uncertain in Ethiopia.
Method
A multi-centre longitudinal study was conducted in Ethiopia from January 2018 to June 2023. After receiving ethical clearance from the Institutional Review Board (IRB) of Dilla University College of Health Science and Medicine, 356 ARDS patients’ records were retrieved with a systematic random sampling technique. A multilevel multivariate analysis was used to control the effect of clustering. A P < 0.05 was taken as statistically significant.
Results
This study demonstrated that the cumulative mortality rate of patients with ARDS was 59% (95% CI: 53.5 to 63.9). The multilevel multivariable model analysis showed that GCS < 8 (AOR = 7.4; 95% CI: 2.79, 19.75), severe form of ARDS (AOR 4.7 95% CI 1.64, 13.36), invasive ventilation (AOR 3.2, 95% CI 1.56, 6.42), and respiratory comorbidity (AOR 4.9, 95% CI 1.71, 14.32) were independent predictors of in-hospital mortality among patients with ARDS.
Conclusion
The study revealed that the hospital mortality rate was substantially higher than that of developed nations. The study also highlighted various risk factors that independently predicted in-hospital mortality.The findings of this study call for mitigating strategies to improve ICU care for ARDS patients.
... While some patients can recover naturally or after supportive care and pharmacological interventions in the initial phases targeting the initial insult, a significant gap persists in clinical treatments directed towards the pathophysiological mechanisms of ARDS. Patients who are unable to undergo efficient lung repair and regeneration tend to develop interstitial pulmonary fibrosis, which prolongs ventilator dependence, leading to restrictive lung disease later in life, and carries high morbidity and mortality rates [9]. ...
... In the quest to understand the impact of GSK-3 inhibition by CHIR99021 in AEC regeneration in ALI, this study used the LPS-induced ALI model, targeting the acute inflammatory phase characterised by a pro-inflammatory response driven mainly by the innate immune system and the late stages characterised by repair and regeneration processes [9]. Therapeutic interventions in the late stages are almost noneffective in targeting with faster disease progression and higher mortality and morbidity [9]. ...
... In the quest to understand the impact of GSK-3 inhibition by CHIR99021 in AEC regeneration in ALI, this study used the LPS-induced ALI model, targeting the acute inflammatory phase characterised by a pro-inflammatory response driven mainly by the innate immune system and the late stages characterised by repair and regeneration processes [9]. Therapeutic interventions in the late stages are almost noneffective in targeting with faster disease progression and higher mortality and morbidity [9]. Considering this, we conducted a pilot study to determine whether late administration of CHIR99021 could be used as a therapeutic alternative to target the late phase of LPS-induced ALI. ...
Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury that currently lacks effective clinical treatments. Evidence highlights the potential role of glycogen synthase kinase-3 (GSK-3) inhibition in mitigating severe inflammation. The inhibition of GSK-3α/β by CHIR99021 promoted fetal lung progenitor proliferation and maturation of alveolar epithelial cells (AECs). The precise impact of CHIR99021 in lung repair and regeneration during acute lung injury (ALI) remains unexplored. This study intends to elucidate the influence of CHIR99021 on AEC behaviour during the peak of the inflammatory phase of ALI and, after its attenuation, during the repair and regeneration stage. Furthermore, a long-term evaluation was conducted post CHIR99021 treatment at a late phase of the disease. Our results disclosed the role of GSK-3α/β inhibition in promoting AECI and AECII proliferation. Later administration of CHIR99021 during ALI progression contributed to the transdifferentiation of AECII into AECI and an AECI/AECII increase, suggesting its contribution to the renewal of the alveolar epithelial population and lung regeneration. This effect was confirmed to be maintained histologically in the long term. These findings underscore the potential of targeted therapies that modulate GSK-3α/β inhibition, offering innovative approaches for managing acute lung diseases, mostly in later stages where no treatment is available.
... drugs found to be beneficial and safe in preclinical investigations are implemented in daily practice and included in recommendations in the guidelines. 16 Although the antiinflammatory effect of corticosteroids might improve the prognosis of ARDS, many studies have failed to show their benefits thus far, and thus, the efficacy of corticosteroids in ARDS remains controversial. A recent clinical trial showed that early administration of dexamethasone could reduce the duration of mechanical ventilation and overall mortality in patients with moderate-to-severe ARDS. ...
Acute respiratory distress syndrome (ARDS) is characterized by the heterogeneous distribution of lung aeration along a gravitational direction due to increased lung density. Therefore, the lung available for ventilation is usually limited to ventral, nondependent lung regions and has been called the “baby” lung. In ARDS, ventilator‐induced lung injury is known to occur in nondependent “baby” lungs, as ventilation is shifted to ventral, nondependent lung regions, increasing stress and strain. To protect this nondependent “baby” lung, the clinician targets and limits global parameters such as tidal volume and plateau pressure. In addition, positive end‐expiratory pressure (PEEP) is used to prevent dorsal, dependent atelectasis and, if successful, increases the size of the baby lung and lessens its susceptibility to injury from inspiratory stretch. Although many clinical trials have been performed in patients with ARDS over the last two decades, there are few successfully showing benefits on mortality (ie, prone positioning and neuromuscular blocking agents). These disappointing results contrast with other medical disciplines, especially in oncology, where the heterogeneity of diseases is recognized widely and precision medicine has been promoted. Thus, lung‐protective ventilation strategies need to take an innovative approach that accounts for the heterogeneity of injured lungs. This article summarizes ventilator‐induced lung injury and ARDS and discusses how to implement precision medicine in the field of ARDS. Potentially useful methods to individualize PEEP with esophageal balloon manometry, lung recruitability, and electrical impedance tomography were discussed.
... The main focus of the treatment is support. A significant part is played by mechanical ventilation and the proper usage of oxygen (Bos et al., 2018). Knowing that lung transduction with positive pressure can aggravate the current illness is a crucial development in therapy (Bos et al., 2018). ...
... A significant part is played by mechanical ventilation and the proper usage of oxygen (Bos et al., 2018). Knowing that lung transduction with positive pressure can aggravate the current illness is a crucial development in therapy (Bos et al., 2018). This mindset has helped to design a new approach to treating mechanical ventilation that combines positive endexpiratory pressure (PEEP) and small breathing volumes (6ml/kg) (Candan et al., 2020). ...
ARDS is a life-threatening condition requiring intensive care unit monitoring. We present a 46-year-old male patient with ARDS and its complications, ventilator-associated pneumonia (VAP) and critcal illness polyneuropathy after extensive bilateral viral pneumonia. The objective of this case report is to understand better and manage the complications of ARDS. This study addresses ARDS and its complications, providing a comprehensive clinical understanding. It details a 46-year-old male patient’s case, treatment strategies, complications, weaning processes, and rehabilitation and emphasises the importance of physical therapy. This case report discusses the successful management and weaning of a patient with extensive viral pneumonia complicated with acute respiratory distress syndrome (ARDS), impending organ dysfunction, and critical illness polyneuropathy. The patient had a medical history of diabetes, hypertension, and dyslipidemia. Initial treatment involved oxygen therapy, nebulization, and empirical antiviral for seasonal flu. However, the patient required invasive ventilation with sedation and muscle relaxants following the ARDSNET protocol due to worsening respiratory status and extensive lung infiltrates. Secondary bacterial infections were also identified and treated accordingly. The weaning process was initiated but was complicated by re-intubation and the development of critical illness polyneuropathy. After successful weaning and recovery from ARDS and associated lung infections, physical therapy was provided for polyneuropathy regularly to overcome the manifest weakness all over the body muscles, including respiratory muscle weakness. The case report highlights the successful management of a patient with viral pneumonia, ARDS, and critical illness polyneuropathy, highlighting the importance of comprehensive treatment and physical therapy.
... Its impact is extensive and far-reaching (25), imposing a substantial economic burden on individuals and society. Moreover, it severely impairs the quality of life of patients, with lasting effects persisting for up to 5 years after recovery (26). Unfortunately, there is currently no specific treatment available for this disease in the clinical practice (27). ...
Chuanfangyihao (CFYH) is an effective treatment for acute lung injury (ALI) in clinical practice; however, its underlying mechanism of action remains unclear. Therefore, the aim of the present study was to elucidate the pharmacological mechanism of action of CFYH in ALI through experimental validation. First, a rat model of ALI was established using lipopolysaccharide (LPS). Next, the pathological changes in the lungs of the rats and the pathological damage were scored. The wet/dry weight ratios were measured, and ROS content was detected using flow cytometry. ELISA was used to examine IL-6, TNF-α, IL-1β, IL-18, and LDH levels. Immunohistochemistry was used to detect Beclin-1 and NLRP3 expression. Western blotting was performed to analyze the expression of HMGB1, RAGE, TLR4, NF-κB p65, AMPK, p-AMPK, mTOR, p-mTOR, Beclin-1, LC3-II/I, p62, Bcl-2, Bax, Caspase-3, Caspase-1, and GSDMD-NT. The mRNA levels of HMGB1, RAGE, AMPK, mTOR, and HIF-1α were determined using reverse transcription quantitative PCR. CFYH alleviated pulmonary edema and decreased the expression of IL-6, TNF-α, TLR4, NF-κB p65, HMGB1/RAGE, ROS, and HIF-1α. In addition, pretreatment with CFYH reversed ALI-induced programmed cell death. In conclusion, CFYH alleviates LPS-induced ALI, and these findings provide a preliminary clarification of the predominant mechanism of action of CFYH in ALI.
... Many strategies appear promising at the preclinical level only to fail in human clinical trials. The poor translation of potential therapies from pre-clinical to clinical models can be attributed to numerous factors, such as species-specific differences between humans and mice and the simplistic nature of pre-clinical models compared to the complexity of critically ill human patients [75,76]. Patients often have comorbidities such as diabetes mellitus, chronic obstructive pulmonary disease or cancer, while mice used for studies are relatively young and healthy. ...
Respiratory pathogens such as influenza and SARS-CoV-2 can cause severe lung infections leading to acute respiratory distress syndrome (ARDS). The pathophysiology of ARDS includes an excessive host immune response, lung epithelial and endothelial cell death and loss of the epithelial and endothelial barrier integrity, culminating in pulmonary oedema and respiratory failure. Traditional approaches for the treatment of respiratory infections include drugs that exert direct anti-pathogen effects (e.g., antivirals). However, such agents are typically ineffective or insufficient after the development of ARDS. Modulation of the host response has emerged as a promising alternative therapeutic approach to mitigate damage to the host for the treatment of respiratory infections; in principle, this strategy should also be less susceptible to the development of pathogen resistance. In this review, we discuss different host-targeting strategies against pathogen-induced ARDS. Developing therapeutics that enhance the host response is a pathogen-agnostic approach that will help prepare for the next pandemic.
... The survivors of the disease may exhibit more persistent physical, psychological, and neurocognitive defects, which seriously affect their quality of life. The effects of ARDS usually last for more than 5 years after ARDS recovery (Bos et al. 2018;Kumar 2020). Currently, no specific clinical treatments are available for ARDS. ...
Paritaprevir is a potent inhibitor of the NS3/4A protease used to treat chronic hepatitis C virus infection. However, its therapeutic effect on acute lung injury (ALI) remains to be elucidated. In this study, we investigated the effect of paritaprevir on a lipopolysaccharide (LPS)-induced two-hit rat ALI model. The anti-ALI mechanism of paritaprevir was also studied in human pulmonary microvascular endothelial (HM) cells following LPS-induced injury in vitro. Administration of 30 mg/kg paritaprevir for 3 days protected rats from LPS-induced ALI, as reflected by the changes in the lung coefficient (from 0.75 to 0.64) and lung pathology scores (from 5.17 to 5.20). Furthermore, the levels of the protective adhesion protein VE-cadherin and tight junction protein claudin-5 increased, and the cytoplasmic p-FOX-O1 and nuclear β-catenin and FOX-O1 levels decreased. Similar effects were observed in vitro with LPS-treated HM cells, including decreased nuclear β-catenin and FOX-O1 levels and higher VE-cadherin and claudin-5 levels. Moreover, β-catenin inhibition resulted in higher p-FOX-O1 levels in the cytoplasm. These results suggested that paritaprevir could alleviate experimental ALI via the β-catenin/p-Akt/ FOX-O1 signaling pathway.
... The first description of ARDS was given by Ashbaugh and colleagues in 1967 [109]. Since then, numerous pharmacological interventions have targeted the principal pathophysiological mechanism of ARDS in clinical trials and almost all of them had shown negative results in terms of improving the patient outcome; nonetheless, the findings were promising in animal models [110]. It is worth mentioning that both antibiotics and nanosized drugs have been used in ARDS, but they did not bring substantial positive results on the patient outcome in terms of lowering morbidity and mortality in large trials [111], being controversial to be administered. ...
The Acute Respiratory Distress Syndrome (ARDS) is one of the major heterogeneous clinical manifestations of severe respiratory failure developing in response to pathogenetic mechanisms and several inflammatory insults. The translocation of gut microbiota has a crucial impact on the pathogenesis of ARDS. Hence, a deeper understanding of the interplay of the gut microbiota would allow shedding valuable insights into both the pathogenesis of ARDS and the development of effective therapeutic interventions. Moreover, the modulation of gut-lung axis could also play a pivotal role in minimizing the lung dysbiosis with gut microbiota. There is little question that greater study of the gut-lung axis in critically ill patients is required to establish causal links between the shifted microbiota, infections, inflammation, and acute lung damage. It is worth mentioning that the lack of effective preventative measures is one of the main reasons for the increased mortality rate of 30-40% in ARDS patients. Some antibiotics and nanosized drugs showed positive results in ARDS management to some extent in pre-clinical or even first stages of clinical trials but large-scale results had been controversial. However, Sphingosine-1-Phosphate (S1P) showed hopeful results in ARDS patients by facilitating both systemic and endothelial integrity. Numerous investigations have shown the immunological connection between the gastrointestinal tract and the respiratory system. As the SphKs /S1P /S1PL metabolic pathway is associated with a wide variety of human illnesses (including respiratory diseases), it should come as no surprise that influencing intracellular S1P levels would have therapeutic promise in reducing the severity of lung diseases like ARDS.
