Resolution Of Acute Respiratory Distress Syndrome Research Articles

Steroids in acute respiratory distress syndrome: A panacea or still a puzzle?

Acute respiratory distress syndrome (ARDS) is a unique entity marked by various etiologies and heterogenous pathophysiologies. There remain concerns regarding the efficacy of particular medications for each severity level apart from respiratory support. Among several pharmacotherapies which have been examined in the treatment of ARDS, corticosteroids, in particular, have demonstrated potential for improving the resolution of ARDS. Nevertheless, it is imperative to consider the potential adverse effects of hyperglycemia, susceptibility to hospital-acquired infections, and the development of intensive care unit acquired weakness when administering corticosteroids. Thus far, a multitude of trials spanning several decades have investigated the role of corticosteroids in ARDS. Further stringent trials are necessary to identify particular subgroups before implementing corticosteroids more widely in the treatment of ARDS. This review article provides a concise overview of the most recent evidence regarding the role and impact of corticosteroids in the management of ARDS.

Function of KvLQT1 potassium channels in a mouse model of bleomycin-induced acute lung injury.

Acute respiratory distress syndrome (ARDS) is characterized by an exacerbated inflammatory response, severe damage to the alveolar-capillary barrier and a secondary infiltration of protein-rich fluid into the airspaces, ultimately leading to respiratory failure. Resolution of ARDS depends on the ability of the alveolar epithelium to reabsorb lung fluid through active transepithelial ion transport, to control the inflammatory response, and to restore a cohesive and functional epithelium through effective repair processes. Interestingly, several lines of evidence have demonstrated the important role of potassium (K+) channels in the regulation of epithelial repair processes. Furthermore, these channels have previously been shown to be involved in sodium/fluid absorption across alveolar epithelial cells, and we have recently demonstrated the contribution of KvLQT1 channels to the resolution of thiourea-induced pulmonary edema in vivo. The aim of our study was to investigate the role of the KCNQ1 pore-forming subunit of KvLQT1 channels in the outcome of ARDS parameters in a model of acute lung injury (ALI). We used a molecular approach with KvLQT1-KO mice challenged with bleomycin, a well-established ALI model that mimics the key features of the exudative phase of ARDS on day 7. Our data showed that KvLQT1 deletion exacerbated the negative outcome of bleomycin on lung function (resistance, elastance and compliance). An alteration in the profile of infiltrating immune cells was also observed in KvLQT1-KO mice while histological analysis showed less interstitial and/or alveolar inflammatory response induced by bleomycin in KvLQT1-KO mice. Finally, a reduced repair rate of KvLQT1-KO alveolar cells after injury was observed. This work highlights the complex contribution of KvLQT1 in the development and resolution of ARDS parameters in a model of ALI.

Regulatory T cells in inflammation and resolution of acute lung injury.

IntroductionAcute respiratory distress syndrome (ARDS) is characterized by hypoxemia and increased lung permeability and would result in acute respiratory failure and with high mortality. In patients who survive from acute lung injury (ALI)/ARDS, it is an active process of the transition from injury to resolution depending on the coordinated immune system. The roles of regulatory CD4+T cells (Tregs) are now gradually being clarified during inflammation and resolution of ARDS. However, clear conclusions about roles of Tregs in ALI/ARDS are only a few.ObjectiveThis review provides an overview of phenotype, differentiation, and suppressive mechanisms of Tregs and focuses on keys of biology of Tregs in alveolar space during the inflammatory response and resolution of ALI/ARDS.Data SourceLiterature search of Web of Science, PubMed, and EMBASE was made to find relative articles about Tregs in ALI/ARDS. We used the following search terms: Tregs, ALI, ARDS, inflammation, and resolution.ConclusionMore and more studies have indicated Tregs involved in the processes of inflammation and resolution of ALI/ARDS. A deep understanding of the roles of Tregs may indicate new treatments for patients of ARDS. Therapies aimed at expansion or adaptive transfer of Tregs could be an effective therapy to ARDS patients.

Lung Microbiota of Critically Ill Patients with COVID-19 Are Associated with Nonresolving Acute Respiratory Distress Syndrome.

Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19-related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42-0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42-0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19-related ARDS.

New insights in ARDS pathogenesis

Acute respiratory distress syndrome (ARDS) is a life-threatening condition in critically ill patients characterized by hypoxemia and non-compliant lung. In this review, we discuss the pathophysiology of ARDS, including the mechanisms involved in the formation of pulmonary edema, the dysregulated inflammatory and immune responses, the activation of procoagulant events, the cellular communication by extracellular vesicles (EVs) between different types of cells and the interaction of the lung with other organs. Activation of inflammation, coagulation, and cell death processes result in the disruption of the alveolar-capillary membrane and the consequent protein-rich edema formation in the alveoli, in which structural and functional alterations of the alveolar epithelium play an essential role. Inflammation and activated endothelial cells trigger coagulation cascades and platelets that generate a procoagulant state in both the airspace and the intravascular compartment with the formation of fibrin in airspaces and thrombi in the microvasculature that aggravate alveolar injury and gas exchange. The crosstalk between epithelial/endothelial cells, platelets, and immune cells is mediated by EVs, whose role in the pathogenesis of ARDS is not known. Finally, the interaction of the lung with other organs has become an important determinant in the development and resolution of ARDS. Understanding the pathophysiological mechanisms involved in ARDS is crucial to developing new therapeutic strategies.

RvD1 accelerates the resolution of inflammation by promoting apoptosis of the recruited macrophages via the ALX/FasL-FasR/caspase-3 signaling pathway

The uncontrolled inflammatory response caused by a disorder in inflammation resolution is one of the reasons for acute respiratory distress syndrome (ARDS). The macrophage pool markedly expands when inflammatory monocytes, known as recruited macrophages, migrate from the circulation to the lung. The persistent presence of recruited macrophages leads to chronic inflammation in the resolution phase of inflammation. On the contrary, elimination of the recruited macrophages at the injury site leads to the rapid resolution of inflammation. Resolvin D1 (RvD1) is an endogenous lipid mediator derived from docosahexaenoic acid. Mice were administered RvD1 via the tail vein 3 and 4 days after stimulation with lipopolysaccharide. RvD1 reduced the levels of the inflammatory factors in the lung tissue, promoted the anti-inflammatory M2 phenotype, and enhanced the phagocytic function of recruited macrophages to alleviate acute lung injury. We also found that the number of macrophages was decreased in BAL fluid after treatment with RvD1. RvD1 increased the apoptosis of recruited macrophages partly via the FasL-FasR/caspase-3 signaling pathway, and this effect could be blocked by Boc-2, an ALX/PRP2 inhibitor. Taken together, our findings reinforce the concept of therapeutic targeting leading to the apoptosis of recruited macrophages. Thus, RvD1 may provide a new therapy for the resolution of ARDS.

Liver\u2013lung interactions in acute respiratory distress syndrome

Patients with liver diseases are at high risk for the development of acute respiratory distress syndrome (ARDS). The liver is an important organ that regulates a complex network of mediators and modulates organ interactions during inflammatory disorders. Liver function is increasingly recognized as a critical determinant of the pathogenesis and resolution of ARDS, significantly influencing the prognosis of these patients. The liver plays a central role in the synthesis of proteins, metabolism of toxins and drugs, and in the modulation of immunity and host defense. However, the tools for assessing liver function are limited in the clinical setting, and patients with liver diseases are frequently excluded from clinical studies of ARDS. Therefore, the mechanisms by which the liver participates in the pathogenesis of acute lung injury are not totally understood. Several functions of the liver, including endotoxin and bacterial clearance, release and clearance of pro-inflammatory cytokines and eicosanoids, and synthesis of acute-phase proteins can modulate lung injury in the setting of sepsis and other severe inflammatory diseases. In this review, we summarized clinical and experimental support for the notion that the liver critically regulates systemic and pulmonary responses following inflammatory insults. Although promoting inflammation can be detrimental in the context of acute lung injury, the liver response to an inflammatory insult is also pro-defense and pro-survival. A better understanding of the liver–lung axis will provide valuable insights into new diagnostic targets and therapeutic strategies for clinical intervention in patients with or at risk for ARDS.

High dose subcutaneous Anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill COVID-19 patients

ObjectiveSeverely ill COVID-19 patients may end in acute respiratory distress syndrome (ARDS) and multi-organ failure. Some of them develop a systemic hyperinflammatory state produced by the massive release of inflammatory agents, known as cytokine storm syndrome (CSS). Inhibition of IL-1 by Anakinra (ANK) is a potential life-saving therapy for severe CSS cases. We propose a rationale for the use of subcutaneous ANK and review our initial experience in a small cohort of severe COVID-19 CSS patients. MethodsRetrospective cohort study of COVID-19 patients developing ARDS (PaO2/FiO2 <300) and exhibiting signs of hyperinflammation (ferritin >1000 ng/mL and/or d-dimers > 1.5 μg/mL, plus IL-6 < 40 mg/mL) that received ANK. For comparison, a propensity score matched historical cohort of patients treated with IL-6 inhibitor Tocilizumab (TCZ) was used. Patients had previously received combinations of azithromycin, hydroxy-chloroquine, and methyl-prednisolone. Laboratory findings, respiratory function and adverse effects were monitored. Resolution of ARDS within the first 7 days of treatment was considered a favorable outcome. ResultsSubcutaneous ANK (100 mg every 6 h) was given to 9 COVID-19 ARDS CSS patients (77.8% males). Median age was 62 years (range, 42 to 87). A TCZ cohort of 18 patients was selected by propensity score matching and treated with intravenous single dose of 600 mg for patients weighing >75 Kg, or 400 mg if < 75 Kg. Prior to treatment, median PaO2/FiO2 ratio of the ANK and TCZ cohorts were 193 and 249, respectively (p = 0.131). After 7 days of treatment, PaO2/FiO2 ratio improved in both groups to 279 (104–335) and 331 (140–476, p = 0.099) respectively. On day 7, there was significant reduction of ferritin (p = 0.046), CRP (p = 0.043), and IL-6 (p = 0.043) levels in the ANK cohort but only of CRP (p = 0.001) in the TCZ group. Favorable outcome was achieved in 55.6% and 88.9% of the ANK and TCZ cohorts, respectively (p = 0.281). Two patients that failed to respond to TCZ improved after ANK treatment. Aminotransferase levels significantly increased between day 1 and day 7 (p = 0.004) in the TCZ group. Mortality was the same in both groups (11%). There were not any opportunistic infection in the groups nor other adverse effects attributable to treatment. ConclusionOverall, 55.6% of COVID-19 ARDS CSS patients treated with ANK exhibited favorable outcome, not inferior to a TCZ treated matched cohort. ANK may be a potential alternative to TCZ for patients with elevated aminotransferases, and may be useful in non-responders to TCZ.

Recovery of COVID-19 Acute Respiratory Distress Syndrome with Tocilizumab: Successful Outcome in Two Critically Ill Patients

Background: Severe pneumonia and acute respiratory distress syndrome (ARDS) due to COVID-19 is a challenge for nowadays medical practice. Although there is no clarity in the principal mechanism of lung damage and ARDS development, it has been suggested that one of the main reasons of this pathology is the hyperactivation of the immune system, better known as cytokine storm syndrome. Tocilizumab has been proposed to treat COVID-19 severe cases associated to ARDS. Results & methodology: Here we present two successful cases of tocilizumab administration in two COVID-19 patients with prior administration of antiviral therapy (hydroxychloroquine, azithromycin, lopinavir and ritonavir) with adequate response and resolution of ARDS, septic shock and severe pneumonia within the first 72 h. Discussion & conclusion: This case supports the usage of tocilizumab as an effective therapy in COVID-19 associated cytokine storm syndrome. Further studies should be done in order to assess its effectiveness and security.

Effects of IFN-γ on immune cell kinetics during the resolution of acute lung injury.

The immunologic responses that occur early in the acute respiratory distress syndrome (ARDS) elicit immune‐mediated damage. The mechanisms underlying the resolution of ARDS, particularly the role of signaling molecules in regulating immune cell kinetics, remain important questions. Th1‐mediated responses can contribute to the pathogenesis of acute lung injury (ALI). Interferon‐gamma (IFN‐γ) orchestrates early inflammatory events, enhancing immune‐mediated damage. The current study investigated IFN‐γ during resolution in several experimental models of ALI. The absence of IFN‐γ resulted in altered kinetics of lymphocyte and macrophage responses, suggesting that IFN‐γ present in this microenvironment is influential in ALI resolution. Genetic deficiency of IFN‐γ or administering neutralizing IFN‐γ antibodies accelerated the pace of resolution. Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased alveolar macrophage numbers during resolution. Our results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution. Identifying and elucidating the mechanisms critical to ALI resolution will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the response to injury.

Platelet biology of the rapidly failing lung.

Acute respiratory distress syndrome (ARDS) is characterized by a rapid-onset respiratory failure with a mortality rate of approximately 40%. This physiologic inflammatory process is mediated by disruption of the alveolar-vascular interface, leading to pulmonary oedema and impaired oxygen exchange, which often warrants mechanical ventilation to increase survival in the acute setting. One of the least understood aspects of ARDS is the role of the platelets in this process. Platelets, which protect vascular integrity, play a pivotal role in the progression and resolution of ARDS. The recent substantiation of the age-old theory that megakaryocytes are found in the lungs has rejuvenated interest in and raised new questions about the importance of platelets for pulmonary function. In addition to primary haemostasis, platelets provide a myriad of inflammatory functions that are poised to aid the innate immune system. This review focuses on the evidence for regulatory roles of platelets in pulmonary inflammation, with an emphasis on two receptors, CLEC-2 and TLT-1. Studies of these receptors identify novel pathways through which platelets may regulate vascular integrity and inflammation in the lungs, thereby influencing the development of ARDS.

Acute Respiratory Distress Syndrome as the Initial Clinical Manifestation of an Antisynthetase Syndrome.

Antisynthetase syndrome has been recognized as an important cause of autoimmune inflammatory myopathy in a subset of patients with polymyositis and dermatomyositis. It is associated with serum antibody to aminoacyl-transfer RNA synthetases and is characterized by a constellation of manifestations, including fever, myositis, interstitial lung disease, mechanic's hand-like cutaneous involvement, Raynaud phenomenon, and polyarthritis. Lung disease is the presenting feature in 50% of the cases. We report a case of a 60-year-old female with acute respiratory distress syndrome (ARDS), which later proved to be an unexpected and initial manifestation of anti-Jo-1 antibody–positive antisynthetase syndrome. The present case showed resolution of ARDS after treatment with high-dose corticosteroids. Given that steroids are not greatly beneficial in the treatment of ARDS, it is likely that the improvement of the respiratory symptoms in this patient also resulted from the prompt suppression of the inflammatory systemic response by corticosteroids.

Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature.

To investigate the effect of prolonged glucocorticoid treatment for patients with acute respiratory distress syndrome (ARDS). We conducted two sets of intention-to-treat analyses: (1) a primary analysis of individual patients' data (IPD) of four randomized controlled trials (RCTs) which investigated methylprednisolone treatment (n=322) and (2) a trial-level meta-analysis incorporating four additional RCTs which investigated hydrocortisone treatment in early ARDS (n=297). We standardized definitions to derive outcomes in all datasets. The primary outcome for the IPD analysis wastime to achieving unassisted breathing (UAB) by study day 28. Secondary outcomes included mechanical ventilation (MV) and intensive care unit (ICU)-free days, hospital mortality, and time to hospital mortality by day 28. By study day 28, compared to the placebo group, the methylprednisolone group had fewer patients who died before achieving UAB (12 vs. 29%; p<0.001) and more patients who achieved UAB (80 vs. 50%; p<0.001). In the methylprednisolone group, time to achieving UAB was shorter [hazard ratio 2.59, 95%confidence interval (CI) 1.95-3.43; p<0.001], and hospital mortality was decreased (20 vs. 33%; p=0.006), leading to increased MV (13.3±11.8 vs. 7.6±5.7; p<0.001) and ICU-free days (10.8±0.71 vs. 6.4±0.85; p<0.001). In those patients randomized before day 14 of ARDS onset, the trial-level meta-analysis indicated decreased hospital mortality (36 vs. 49%; risk ratio 0.76, 95%CI 0.59-0.98, I (2) = 17%, p=0.035; moderate certainty). Treatment was not associated with increased risk for infections (risk ratio 0.77, 95%CI 0.56-1.08, I (2)=26%; p=0.13; moderate certainty). Prolonged methylprednisolone treatment accelerates the resolution of ARDS, improving a broad spectrum of interrelated clinical outcomes and decreasing hospital mortality and healthcare utilization.

Influenza causes prolonged disruption of the alveolar-capillary barrier in mice unresponsive to mesenchymal stem cell therapy.

Viral pneumonia is a major cause of acute respiratory distress syndrome (ARDS). Anti-inflammatory therapies for viral-induced lung injury show promise in preclinical models. Mesenchymal stem/stromal cells (MSCs) are multipotent, self-renewing cells that secrete anti-inflammatory cytokines and epithelial and endothelial growth factors. We inoculated mice intranasally with influenza A (murine-adapted Puerto Rico/8/34) or PBS, and the mice were killed at multiple time points after infection for measures of lung injury and viral load. We report that influenza induces marked, long-lasting dysfunction of the alveolar-capillary barrier peaking at 1 wk but lasting longer than 3 wk postinfection. Weight loss, commonly employed as a criterion for euthanasia (and hence "survival"), was found to be poorly predictive of the severity of lung injury at its peak; rather, persistent weight loss 11 days postinfection identified mice with impaired injury resolution. Murine and human bone marrow-derived MSCs (obtained from the National Institutes of Health repository) were then administered intravenously during the rapid phase of injury progression. Murine MSCs (mMSCs) given two times 24 h apart failed to improve weight loss, lung water, bronchoalveolar lavage inflammation, or histology. However, mMSCs prevented influenza-induced thrombocytosis and caused a modest reduction in lung viral load at day 7. Human MSCs administered intravenously showed a similar lack of efficacy. The results demonstrate that the influenza murine model bears important similarities to the slow resolution of ARDS in patients. Despite their potent therapeutic effects in many models of acute inflammation and lung injury, MSCs do not improve influenza-mediated lung injury in mice.

β2-Agonists and Acute Respiratory Distress Syndrome

β₂-Agonists and Acute Respiratory Distress Syndrome

Revisiting opioid overdose induced acute respiratory distress syndrome

Sir, Opioids are commonly used analgesic drug class with morphine like activity. Although respiratory system is the most affected organ system in opioid overdose; acute lung injury and acute respiratory distress syndrome (ARDS) are infrequently reported. A 25-year-old male presented after ingesting unknown amounts of hydrocodone. Patient was found to be unresponsive, with agonal respiration. Initial vital signs showed blood pressure 100/60 mmHg, pulse 110 beats/min, respiratory rate 8 breaths/min and oxygen saturation (SpO2) of 70%. Chest examination revealed decreased air entry bilaterally with bibasal crackles. Initial arterial blood gas (ABG) analysis showed respiratory acidosis with pH 7.22, partial pressure of carbon dioxide (PaCO2) at 70 mmHg, partial pressure of oxygen (PaO2) at 42 mmHg and SpO2 of 72%. An emergent orotracheal intubation was performed due to severe hypoxemia and to maintain a patent airway. Pink frothy secretions were seen in the endotracheal tube immediately after intubation and a chest radiograph showed diffuse bilateral infiltrates [Figure 1]. Mechanical ventilation was started at assist control mode with initial tidal volume of 500 ml, fraction of inspired oxygen (FiO2) at 100% and positive end expiratory pressure (PEEP) at 5 cm H2 O. Patient remained hypoxemic and repeat ABG analysis showed partial pressure of PaO2 42 mm Hg and SpO2 80% prompting increase in the PEEP up to 10 cm H2O, which improved PaO2 to 85 mm Hg. Based on initial PaO2/FiO2 ratio of 52 and characteristic radiographic bilateral opacities, severe ARDS was diagnosed. An echocardiogram showed normal left ventricular function and serum levels of brain natriuretic peptide (BNP) was normal at 88 pg/ml. Lung protective ventilation to achieve adequate oxygenation was continued. Furosemide was given to maintain a negative fluid balance. Patient could be successfully extubated on the 2nd day. Chest radiograph on day 3 showed complete resolution of ARDS [Figure 2]. Figure 1 An antero-posterior chest radiograph demonstrating diffuse pulmonary edema in the intubated patient Figure 2 A postero-anterior chest radiograph in the same patient 48 h later demonstrates complete resolution of the pulmonary edema Opioid overdose has been implicated as a cause of ARDS.[1] Sporer and Dorn described 27 patients of non-cardiogenic pulmonary edema (NCPE) secondary to heroin overdose.[2] Overall, clinical presentation of opioid-induced ARDS is generally indistinguishable from other causes of ARDS. Presence of frothy, sometimes blood tinged pulmonary secretions and bilateral diffuse infiltrates on chest radiograph are characteristic. Occasionally, it may be necessary to demonstrate normal cardiac pump function through measurements of serum BNP levels, echocardiogram and rarely right heart catheterization. The mechanisms behind opioid induced NCPE and ARDS remain largely unknown. The role of increased pulmonary capillary permeability due to hypoxemia, potent histamine release and respiratory acidosis caused by depression of medullary respiratory centers have been implicated.[3,4] Interestingly, the use of reversal agents like naloxone itself has also been described as the primary cause of pulmonary edema.[5] Patients with opioid-induced NCPE and ARDS can have severe hypoxemia frequently needing invasive mechanical ventilation. An early orotracheal intubation should be considered in obtunded or severely hypoxemic patients. Following intubation, general management strategies used in any form of ARDS comprising of lung protective strategies of ventilation, appropriate PEEP and diuretics are used. Overall prognosis remains good with most patients recovering within 24 h. In summary, our case demonstrates an infrequently seen respiratory complication in opioid overdose. Timely management decisions about adequate use of reversal agents and considering early mechanical ventilation in severely hypoxemic patients can be lifesaving.

Is there a place for pressure-support ventilation and high positive end-expiratory pressure combined to alpha-2 agonists early in severe diffuse acute respiratory distress syndrome?

Acute respiratory distress syndrome (ARDS) is associated with a high mortality linked primarily to co-morbidities (sepsis, cardiac failure, multiple organ failure, etc.). When the lung is the single failing organ, quick resolution of ARDS should skip some complications arising from a prolonged stay in the critical care unit. In severe ARDS (PaO2/FIO2=P/F<100 with positive end-expiratory pressure (PEEP)⩾5cm H2O), current recommendations are to intubate the trachea of the patient and use mechanical ventilation, low tidal volume, high PEEP, prone positioning and possibly neuromuscular blockade in association with intravenous sedation.Another strategy is possible. Firstly, spontaneous ventilation (SV) coupled with pressure support (PS) ventilation and high PEEP is possible from tracheal intubation onwards, with the possible exception of the short period following immediately tracheal intubation. Secondly, using alpha-2 adrenergic agonists (e.g. clonidine, dexmedetomidine) can provide first-line sedation from the beginning of mechanical ventilation, as they preserve respiratory drive, lower oxygen consumption and pulmonary hypertension and increase diuresis. Alpha-2 agonists are to be supplemented, if appropriate, by drugs devoid of effect on respiratory drive (neuroleptics, etc.). The expected benefits would be to prevent acquired diaphragmatic weakness, accumulation of sedation, cognitive dysfunction, and presumably improved outcome. This hypothesis should be tested in a double blind randomized controlled trial.

Role of platelet activating factor in pathogenesis of acute respiratory distress syndrome

Role of platelet activating factor in pathogenesis of acute respiratory distress syndrome

Constitutive activation of prosurvival signaling in alveolar mesenchymal cells isolated from patients with nonresolving acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by stereotypic host inflammatory and repair cellular responses; however, mechanisms regulating the resolution of ARDS are poorly understood. Here, we report the isolation and characterization of a novel population of mesenchymal cells from the alveolar space of ARDS patients via fiber-optic bronchoscopy with bronchoalveolar lavage (BAL). BAL was performed on 17 patients during the course of ARDS. Immunofluorescence staining and multiparameter flow cytometric analysis defined a population of alveolar mesenchymal cells (AMCs) that are CD45-/prolyl-4-hydroxylase+/alpha-smooth muscle actin+/-. AMCs proliferated in ex vivo cell culture for multiple passages; early passage (3-5) cells were subsequently analyzed in 13 patients. AMCs isolated from patients with persistent or nonresolving ARDS (ARDS-NR, n = 4) demonstrate enhanced constitutive activation of prosurvival signaling pathways involving PKB/Akt, FKHR, and BCL-2 family proteins compared with AMCs from patients with resolving ARDS (ARDS-R, n = 9). Exogenous transforming growth factor-beta1 markedly induces PKB/Akt activation in AMCs from ARDS-R. ARDS-NR cells are more resistant to serum deprivation-induced apoptosis compared with ARDS-R. This study identifies a novel population of mesenchymal cells that can be isolated from the alveolar spaces of ARDS patients. AMCs in patients with ARDS-NR acquire an activational profile characterized by enhanced prosurvival signaling and an antiapoptotic phenotype. These findings support the concept that apoptosis of mesenchymal cells may be an essential component of normal repair and resolution of ARDS and suggest that dysregulation of this process may contribute to persistent ARDS.

Controlled mechanical hypoventilation in a paediatric burn patient as treatment of acute respiratory distress syndrome

The paediatric patient we are describing suffered a scald injury covering 83 per cent of the total body surface area (TBSA). This injury was complicated by Klebsiella pneumoniae septicaemia resulting in multiorgan failure (MOF). Acute respiratory distress syndrome (ARDS), gastrointestinal insufficiency, hepathopathy and wound conversion to full thickness posed the main problems. The boy was ventilated with pressure-controlled mechanical ventilation. The concept of permissive hypercapnia (PHC) resulted in a complete resolution of ARDS within 4 weeks. From our experience, further lung injury among infants and children suffering from severe ARDS can be avoided by using controlled mechanical hypoventilation. It is a simple and safe technique that allows adequate oxygenation.