Course Of Acute Respiratory Distress Syndrome Research Articles

Mesenchymal stem cell therapy modulates macrophage dynamics in ARDS-associated liver injury in rats

Acute Respiratory Distress Syndrome (ARDS) is a life-threatening pulmonary condition characterized by severe hypoxemia and respiratory failure. Beyond its devastating impact on the lungs, ARDS often triggers systemic responses affecting vital organs throughout the body. One such organ commonly affected is the liver, which experiences various degrees of injury during the course of ARDS. Pathophysiological changes in liver during ARDS, particularly polarization of Kupffer cells during the disease and its treatment, have drawn increasing attention. Purpose. To explore the macrophage transformation in liver injury associated with ARDS and investigate the potential of mesenchymal stem cell (MSC) therapy as a means to modulate macrophage responses and mitigate liver injury. Materials and methods. 72 mature male Wistar rats were randomly allocated to nine experimental groups as follows: the control group, groups assessed at 3 days, 7 days, and 28 days following intranasal LPS administration, groups that received 24 hours of LPS followed by 2 days of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs), groups exposed to 4 days of LPS and 3 days of hUC-MSCs, groups subjected to 14 days of LPS and 14 days of hUC-MSCs, groups treated with LPS 21 days and 7 days with hUC-MSCs injection, and a control group assessed 3 days after hUC-MSCs injection. For the administration of hUC-MSCs, intraperitoneal injections were performed at a dose of 1∙106 cells/kg body weight. Immunohistochemistry was employed to analyze macrophage subpopulations in liver tissues. Animal experiments adhered to ethical guidelines. Results. Early ARDS stages showed increased M1 macrophages, indicating pro-inflammatory responses, while later stages showed M2 macrophage activation, suggestive of anti-inflammatory and tissue repair roles. MSC administration facilitated the transition from M1 to M2 macrophages, promoting an anti-inflammatory milieu. Conclusions. MSCs demonstrate the potential to modulate macrophage polarization into M2 anti-inflammatory phenotype. Such findings reflect one of the mechanisms of MSC action which holds practical significance for future ARDS therapies, aiming to mitigate excessive inflammation and enhance tissue repair.

Differential effects of two-hit models of acute and ventilator-induced lung injury on lung structure, function, and inflammation.

Acute respiratory distress syndrome (ARDS) and acute lung injury have a diverse spectrum of causative factors including sepsis, aspiration of gastric contents, and near drowning. Clinical management of severe lung injury typically includes mechanical ventilation to maintain gas exchange which can lead to ventilator-induced lung injury (VILI). The cause of respiratory failure is acknowledged to affect the degree of lung inflammation, changes in lung structure, and the mechanical function of the injured lung. However, these differential effects of injury and the role of etiology in the structure-function relationship are not fully understood. To address this knowledge gap we caused lung injury with intratracheal hydrochloric acid (HCL) or endotoxin (LPS) 2days prior to ventilation or with an injurious lavage (LAV) immediately prior to ventilation. These injury groups were then ventilated with high inspiratory pressures and positive end expiratory pressure (PEEP) = 0cmH2O to cause VILI and model the clinical course of ARDS followed by supportive ventilation. The effects of injury were quantified using invasive lung function measurements recorded during PEEP ladders where the end-expiratory pressure was increased from 0 to 15cm H2O and decreased back to 0cmH2O in steps of 3cmH2O. Design-based stereology was used to quantify the parenchymal structure of lungs air-inflated to 2, 5, and 10cmH2O. Pro-inflammatory gene expression was measured with real-time quantitative polymerase chain reaction and alveolocapillary leak was estimated by measuring bronchoalveolar lavage protein content. The LAV group had small, stiff lungs that were recruitable at higher pressures, but did not demonstrate substantial inflammation. The LPS group showed septal swelling and high pro-inflammatory gene expression that was exacerbated by VILI. Despite widespread alveolar collapse, elastance in LPS was only modestly elevated above healthy mice (CTL) and there was no evidence of recruitability. The HCL group showed increased elastance and some recruitability, although to a lesser degree than LAV. Pro-inflammatory gene expression was elevated, but less than LPS, and the airspace dimensions were reduced. Taken together, those data highlight how different modes of injury, in combination with a 2nd hit of VILI, yield markedly different effects.

Early human albumin administration is associated with reduced mortality in septic shock patients with acute respiratory distress syndrome: A retrospective study from the MIMIC-III database.

Background: Sepsis-induced acute respiratory distress syndrome (ARDS) was associated with higher mortality. It is unclear whether albumin supplementation early in the course of ARDS can affect the prognostic outcomes of septic shock (SS) patients with ARDS. Methods: The MIMIC-III database was employed to identify SS patients with ARDS. The effect of early application (<24h after ICU admission) of human albumin on 28-day mortality in SS patients with ARDS was explored. The propensity score matching was used to minimize the bias between the non-albumin and early albumin treatment groups. Results: The analysis for all eligible patients who received human albumin showed significantly lower 28-hospital mortality rates than the non-albumin group (37% versus 47%, p = 0.018). After propensity matching, the difference between the two groups also significantly (34.8% versus 48.1%, p = 0.031). Moreover, we found that the relationship between albumin use and reduced 28-day mortality was inconsistent across SOFA score subgroups (Pinteraction = 0.004, non-adjustment for multiple testing). Conclusion: Early human albumin administration in SS patients with ARDS was independently associated with a reduction of 28-day mortality. Furthermore, the benefit of human albumin treatment appeared to be more pronounced in patients with a SOFA score of ≤ 10.

Extracorporeal support for trauma: A trauma quality improvement project (TQIP) analysis in patients with acute respiratory distress syndrome.

The use of extracorporeal membrane oxygenation (ECMO) in trauma patients with severe acute respiratory distress syndrome (ARDS) continues to evolve. The objective of this study was to perform a comparative analysis of trauma patients with ARDS who received ECMO to a propensity matched cohort of patients who underwent conventional management. The Trauma Quality Improvement Program (TQIP) database was queried from 2013 to 2016 for all patients with ARDS and those who received ECMO. Demographics, as well as clinical, injury, intervention, and outcome data were collected and analyzed. Patients with ARDS were divided into two groups, those who received ECMO and those who did not. A propensity score analysis was performed using the following criteria: age, gender, vital signs (HR, SBP) and GCS on admission, Injury Severity Score (ISS), and Abbreviated Injury Scale (AIS) score in several body regions. Outcomes between the groups were subsequently compared using univariate as well as Cox regression analyses. Secondary outcomes such as hospitalization (HLOS), ICU length-of-stay (LOS) and ventilation days stratified for patient demographics, timing of ECMO and anticoagulation status were compared. Over the 3-year study period, 8990 patients with ARDS were identified from the TQIP registry. Following exclusion, 3680 were included in the final analysis, of which 97 (2.6%) received ECMO. On univariate analysis following matching, patients who underwent ECMO had lower overall hospital mortality (23 vs 50%, p < 0.001) with higher rates of complications (p < 0.005), including longer HLOS. In those undergoing ECMO, early initiation (<7 days) was associated with shorter HLOS, ICU LOS, and fewer ventilator days. No difference was observed between the two groups with regard to anticoagulation. Extracorporeal membrane oxygenation use in trauma patients with ARDS may be associated with improved survival, especially for young patients with thoracic injuries, early in the course of ARDS. Anticoagulation while on circuit was not associated with increased risk of hemorrhage or mortality, even in the setting of head injuries. The mortality benefit suggested with ECMO comes at the expense of a potential increase in complication rate and prolonged hospitalization.

Fluid administration and monitoring in ARDS: which management?

Modalities of fluid management in patients sustaining the acute respiratory distress syndrome (ARDS) are challenging and controversial. Optimal fluid management should provide adequate oxygen delivery to the body, while avoiding inadvertent increase in lung edema which further impairs gas exchange. In ARDS patients, positive fluid balance has been associated with prolonged mechanical ventilation, longer ICU and hospital stay, and higher mortality. Accordingly, a restrictive strategy has been compared to a more liberal approach in randomized controlled trials conducted in various clinical settings. Restrictive strategies included fluid restriction guided by the monitoring of extravascular lung water, pulmonary capillary wedge or central venous pressure, and furosemide targeted to diuresis and/or albumin replacement in hypoproteinemic patients. Overall, restrictive strategies improved oxygenation significantly and reduced duration of mechanical ventilation, but had no significant effect on mortality. Fluid management may require different approaches depending on the time course of ARDS (i.e., early vs. late period). The effects of fluid strategy management according to ARDS phenotypes remain to be evaluated. Since ARDS is frequently associated with sepsis-induced acute circulatory failure, the prediction of fluid responsiveness is crucial in these patients to avoid hemodynamically inefficient—hence respiratory detrimental—fluid administration. Specific hemodynamic indices of fluid responsiveness or mini-fluid challenges should be preferably used. Since the positive airway pressure contributes to positive fluid balance in ventilated ARDS patients, it should be kept as low as possible. As soon as the hemodynamic status is stabilized, correction of cumulated fluid retention may rely on diuretics administration or renal replacement therapy.

Estimated dead space fraction and the ventilatory ratio are associated with mortality in early ARDS

BackgroundIndirect indices for measuring impaired ventilation, such as the estimated dead space fraction and the ventilatory ratio, have been shown to be independently associated with an increased risk of mortality. This study aimed to compare various methods for dead space estimation and the ventilatory ratio in patients with acute respiratory distress syndrome (ARDS) and to determine their independent values for predicting death at day 30. The present study is a post hoc analysis of a prospective observational cohort study of ICUs of two tertiary care hospitals in the Netherlands.ResultsIndividual patient data from 940 ARDS patients were analyzed. Estimated dead space fraction and the ventilatory ratio at days 1 and 2 were significantly higher among non-survivors (p < 0.01). Dead space fraction calculation using the estimate from physiological variables [VD/VT phys] and the ventilatory ratio at day 2 showed independent association with mortality at 30 days (odds ratio 1.28 [95% CI 1.02–1.61], p < 0.03 and 1.20 [95% CI, 1.01–1.40], p < 0.03, respectively); whereas, the Harris–Benedict [VD/VT HB] and Penn State [VD/VT PS] estimations were not associated with mortality. The predicted validity of the estimated dead space fraction and the ventilatory ratio improved the baseline model based on PEEP, PaO2/FiO2, driving pressure and compliance of the respiratory system at day 2 (AUROCC 0.72 vs. 0.69, p < 0.05).ConclusionsEstimated methods for dead space calculation and the ventilatory ratio during the early course of ARDS are associated with mortality at day 30 and add statistically significant but limited improvement in the predictive accuracy to indices of oxygenation and respiratory system mechanics at the second day of mechanical ventilation.

БИОМАРКЕРЫ ОСТРОГО РЕСПИРАТОРНОГО ДИСТРЕСС-СИНДРОМА: ПРОБЛЕМЫ И ПЕРСПЕКТИВЫ ИХ ПРИМЕНЕНИЯ

The review analyzes the results of modern clinical and experimental studies on the search and informative value of biomarkers for acute respiratory distress syndrome (ARDS). It describes ARDS biomarkers of the main morphological changes in the lungs and severity of the systemic inflammatory response syndrome. Biomarkers of injury of bronchial epithelium, alveolar epithelium, vascular endothelium and pulmonary extracellular matrix were analyzed to determine the most informative indicators of ARDS of different etiology. It was found that for diagnosis and prognosis of the course of ARDS, the following biomarkers were the most informative: interleukin-6, a soluble form of the receptor for advanced glycation end products (sRAGE), surfactant protein D, protein KL-6, vascular endothelial growth factor, and angiopoietin-2. Using a multimarker panel for simultaneous determination of these indicators can promote rapid diagnostics of ARDS.

Lung-protective Ventilation for Acute Respiratory Distress Syndrome.

Lung-protective Ventilation for Acute Respiratory Distress Syndrome.

Salvage therapies for refractory hypoxemia in ARDS.

Acute Respiratory Distress Syndrome (ARDS) is a condition of varied etiology characterized by the acute onset (within 1 week of the inciting event) of hypoxemia, reduced lung compliance, diffuse lung inflammation and bilateral opacities on chest imaging attributable to noncardiogenic (increased permeability) pulmonary edema. Although multi-organ failure is the most common cause of death in ARDS, an estimated 10-15% of the deaths in ARDS are caused due to refractory hypoxemia, i.e.- hypoxemia despite lung protective conventional ventilator modes. In these cases, clinicians may resort to other measures with less robust evidence -referred to as "salvage therapies". These include proning, 48 h of paralysis early in the course of ARDS, various recruitment maneuvers, unconventional ventilator modes, inhaled pulmonary vasodilators, and Extracorporeal membrane oxygenation (ECMO). All the salvage therapies described have been associated with improved oxygenation, but with the exception of proning and 48 h of paralysis early in the course of ARDS, none of them have a proven mortality benefit. Based on the current evidence, no salvage therapy has been shown to be superior to the others and each of them is associated with its own risks and benefits. Hence, the order of application of these therapies varies in different institutions and should be applied following a risk-benefit analysis specific to the patient and local experience. This review explores the rationale, evidence, advantages and risks behind each of these strategies.

Effects of hypercapnia in acute respiratory distress syndrome.

In patients with acute respiratory distress syndrome (ARDS) hypercapnia is a marker of poor prognosis, however there is controversial information regarding the effect of hypercapnia on outcomes. Recently two studies in a large population of mechanical ventilation patients showed higher mortality associated independently to hypercapnia. Key roles responsible for the poor clinical outcomes observed in critically ill patients exposed to hypercapnia are not well known, two possible mechanisms involved are the effect of CO2 on the muscle and the alveolar epithelium. Hypercapnia frequently coexists with muscle atrophy and dysfunction, moreover patients surviving ARDS present reduced muscle strength and decreased physical quality of life. One of the possible mechanisms responsible for these abnormalities could be the effects of hypercapnia during the course of ARDS. More over controversy persists about the hypercapnia role in the alveolar space, in the last years there is abundant experimental information on its deleterious effects on essential functions of the alveolar epithelium.

Aerosolized tobramycin for Pseudomonas aeruginosa ventilator-associated pneumonia in patients with acute respiratory distress syndrome

BackgroundVentilator-associated pneumonia (VAP) due to Pseudomonas aeruginosa has a high mortality and recurrence rate, especially in patients with acute respiratory distress syndrome (ARDS). Therefore, new therapeutic strategies against severe pneumonia are needed. This study evaluated the efficacy of aerosolized tobramycin for P. aeruginosa VAP in ARDS patients. MethodsA retrospective analysis was performed on patients who developed VAP caused by P. aeruginosa during the course of ARDS at the intensive care unit (ICU) of Kumamoto University Hospital. Aerosolized tobramycin inhalation solution (TIS) 240 mg was administered daily for 14 days in addition to systemic antibiotics. ResultsA total of 44 patients (TIS group, n = 22; control group, n = 22) were included in the analysis. No significant differences were found between the two groups in terms of clinical characteristics, including acute physiology and chronic health evaluation II score upon ICU admission. The TIS group had significantly lower recurrence of P. aeruginosa VAP (22.7% vs. 52.4%, P = 0.04) and ICU mortality (22.7% vs. 63.6%, P < 0.01) than the control group. Bacterial concentration in tracheal aspirate (mean log 10 cfu/mL ± SD on days 2–5: 1.2 ± 1.3 vs. 5.0 ± 2.3, P < 0.01) decreased more rapidly and markedly in the TIS group compared with the control group. ConclusionAerosolized tobramycin was an effective therapeutic strategy for P. aeruginosa VAP patients with ARDS.

Effect of Preadmission Metformin Use on Clinical Outcome of Acute Respiratory Distress Syndrome among Critically Ill Patients with Diabetes.

BackgroundAcute respiratory distress syndrome (ARDS) is related to high mortality and morbidity. There are no proven therapeutic measures however, to improve the clinical course of ARDS, except using low tidal volume ventilation. Metformin is known to have pleiotropic effects including anti-inflammatory activity. We hypothesized that pre-admission metformin might alter the progress of ARDS among intensive care unit (ICU) patients with diabetes mellitus (DM).MethodsWe performed a retrospective cohort study from January 1, 2005, to April 30, 2005 of patients who were admitted to the medical ICU at Seoul National University Hospital because of ARDS, and reviewed ARDS patients with DM. Metformin use was defined as prescribed within 3-month pre-admission.ResultsOf 558 patients diagnosed with ARDS, 128 (23.3%) patients had diabetes and 33 patients were treated with metformin monotherapy or in combination with other antidiabetic medications. Demographic characteristics, cause of ARDS, and comorbid conditions (except chronic kidney disease) were not different between metformin users and nonusers. Several severity indexes of ARDS were similar in both groups. The 30-day mortality was 42.42% in metformin users and 55.32% in metformin nonusers. On multivariable regression analysis, use of metformin was not significantly related to a reduced 30-day mortality (adjusted β-coefficient, −0.19; 95% confidence interval, −1.76 to 1.39; p=0.816). Propensity score-matched analyses showed similar results.ConclusionPre-admission metformin use was not associated with reduced 30-day mortality among ARDS patients with DM in our medical ICU.

Early Hepatic Dysfunction Is Associated with a Worse Outcome in Patients Presenting with Acute Respiratory Distress Syndrome: A Post-Hoc Analysis of the ACURASYS and PROSEVA Studies.

IntroductionBilirubin is well-recognized marker of hepatic dysfunction in intensive care unit (ICU) patients. Multiple organ failure often complicates acute respiratory distress syndrome (ARDS) evolution and is associated with high mortality. The effect of early hepatic dysfunction on ARDS mortality has been poorly investigated. We evaluated the incidence and the prognostic significance of increased serum bilirubin levels in the initial phase of ARDS.MethodsThe data of 805 patients with ARDS were retrospectively analysed. This population was extracted from two recent multicenter, prospective and randomised trials. Patients presenting with ARDS with a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen < 150 mmHg measured with a PEEP ≥ 5 cm of water were included. The total serum bilirubin was measured at inclusion and at days 2, 4, 7 and 14. The primary objective was to analyse the bilirubin at inclusion according to the 90-day mortality rate.ResultsThe 90-day mortality rate was 33.8% (n = 272). The non-survivors were older, had higher Sepsis-related Organ Failure Assessment (SOFA) score and were more likely to have a medical diagnosis on admission than the survivors. At inclusion, the SOFA score without the liver score (10.3±2.9 vs. 9.0±3.0, p<0.0001) and the serum bilirubin levels (36.1±57.0 vs. 20.5±31.5 μmol/L, p<0.0001) were significantly higher in the non-survivors than in the survivors. Age, the hepatic SOFA score, the coagulation SOFA score, the arterial pH level, and the plateau pressure were independently associated with 90-day mortality in patients with ARDS.ConclusionBilirubin used as a surrogate marker of hepatic dysfunction and measured early in the course of ARDS was associated with the 90-day mortality rate.

Albumin rather than C-reactive protein may be valuable in predicting and monitoring the severity and course of acute respiratory distress syndrome in critically ill patients with or at risk for the syndrome after new onset fever.

BackgroundWe studied the value of routine biochemical variables albumin, C-reactive protein (CRP) and lactate dehydrogenase (LDH) to improve prediction and monitoring of acute respiratory distress syndrome (ARDS) severity in the intensive care unit.MethodsIn 101 critically ill patients, with or at risk for ARDS after new onset fever, data were collected on days (D) 0, 1, 2, and 7 after inclusion. ARDS was defined by the Berlin definition and lung injury score (LIS).ResultsAt baseline, 48 patients had mild to severe ARDS according to Berlin and 87 according to LIS (Rs = 0.54, P < 0.001). Low baseline albumin levels were moderately associated with maximum Berlin and LIS categories within 7 days; an elevated CRP level was moderately associated with maximum Berlin categories only. The day-by-day Berlin and LIS categories were inversely associated with albumin levels (P = 0.01, P < 0.001) and directly with CRP levels (P = 0.02, P = 0.04, respectively). Low albumin levels had monitoring value for ARDS severity on all study days (area under the receiver operating characteristic curve, AUROC, 0.62-0.82, P < 0.001-0.03), whereas supranormal CRP levels performed less . When the Berlin or LIS category increased, albumin levels decreased ≥1 g/L (AUROC 0.72-0.77, P = 0.001) and CRP increased ≥104 mg/L (only significant for Berlin, AUROC 0.69, P = 0.04). When the LIS decreased, albumin levels increased ≥1 g/L (AUROC 0.68, P = 0.02). LDH was higher in 28-day non-survivors than survivors (P = 0.007).ConclusionsOverall, albumin may be of greater value than CRP in predicting and monitoring the severity and course of ARDS in critically patients with or at risk for the syndrome after new onset fever. Albumin levels below 20 g/L as well as a decline over a week are associated with ARDS of increasing severity, irrespective of its definition. LDH levels predicted 28-day mortality.

Albuterol in the treatment of acute respiratory distress syndrome: A meta-analysis of randomized controlled trials.

This meta-analysis of randomized controlled trials aimed to systematically evaluate the value of albuterol in the treatment of patients with acute respiratory distress syndrome (ARDS). Randomized controlled trials on albuterol treatment of ARDS from its inception to October 2014 were searched systematically. The databases searched included: PubMed, Ovid EMBASE, Ovid Cochrane, CNKI, WANFANG and VIP. The trials were screened according to the pre-designed inclusion and exclusion criteria. We performed a systematic review and meta-analysis of the randomized controlled trials (RCTs) on albuterol treatment, attempting to improve outcomes, i.e. lowering the 28-day mortality and ventilator-free days. Three RCTs involving 646 patients met the inclusion criteria. There was no significant decrease in the 28-day mortality (risk difference=0.09; P=0.07, P for heterogeneity=0.22, I (2)=33%). The ventilator-free days and organ failure-free days were significantly lower in the patients who received albuterol (mean difference=-2.20; P<0.001, P for heterogeneity=0.49, I (2)=0% and mean difference=-1.71, P<0.001, P for heterogeneity=0.60, I (2)=0%). Current evidences indicate that treatment with albuterol in the early course of ARDS was not effective in increasing the survival, but significantly decreasing the ventilator-free days and organ failure-free days. Owing to the limited number of included trails, strong recommendations cannot be made.

Intratracheal Administration of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in a Patient with Acute Respiratory Distress Syndrome

Umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) have been introduced as a possible therapy in acute lung injury and acute respiratory distress syndrome (ARDS). This case history is reported of a 59-yr-old man who was treated with MSCs in the course of ARDS and subsequent pulmonary fibrosis. He received a long period of mechanical ventilation and weaning proved difficult. On hospital day 114, he underwent the intratracheal administration of UCB-derived MSCs at a dose of 1 × 106/kg. After cell infusion, an immediate improvement was shown in his mental status, his lung compliance (from 22.7 mL/cmH2O to 27.9 mL/cmH2O), PaO2/FiO2 ratio (from 191 mmHg to 334 mmHg) and his chest radiography over the course of three days. Even though he finally died of repeated pulmonary infection, our current findings suggest the possibility of using MSCs therapy in an ARDS patient. It is the first clinical case of UCB-derived MSCs therapy ever reported.

Beta-Agonist Lung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind, placebo-controlled trial and economic evaluation of intravenous infusion of salbutamol versus placebo in patients with acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a major cause of mortality in intensive care patients and lacks effective treatments. A previous randomised controlled Phase II trial suggested that an intravenous (i.v.) infusion of salbutamol may be beneficial, as it reduced extravascular lung water and plateau airway pressure. The Beta-Agonist Lung injury TrIal-2 (BALTI-2) was initiated to evaluate the effects of this intervention on mortality in patients with ARDS. To evaluate whether or not, in patients with ARDS, an i.v. infusion of salbutamol given at 15 μg/kg ideal body weight (IBW)/hour for up to 7 days, compared with a placebo (0.9% sodium chloride) infusion, reduces 28-day all-cause mortality and other clinical outcomes. To evaluate salbutamol's clinical effectiveness and its cost-effectiveness in subgroups of patients. A multicentre, randomised, placebo-controlled trial. Forty-six intensive care units (ICUs) in the UK. Patients were eligible if they (1) were intubated and mechanically ventilated patients in participating ICUs; (2) were within 72 hours of onset of ARDS; (3) fulfilled American-European Consensus Conference definition for ARDS {acute-onset, severe hypoxaemic respiratory failure [partial pressure of oxygen in arterial blood/fraction of inspired oxygen ≤ 26.7 kPa (200 mmHg)] and bilateral infiltrates on the chest radiograph in the absence of clinical evidence of left atrial hypertension}; and (4) were aged ≥ 16 years. Intravenous infusion of salbutamol (15 μg/kg IBW/hour) or placebo (0.9% saline) for up to 7 days. All-cause mortality 28 days after randomisation, mortality at (first) discharge from ICU, mortality at (first) discharge from hospital, number of ventilator-free days, number of organ failure-free days, mortality at 12 months post randomisation, side effects (tachycardia/new arrhythmia/lactic acidosis) sufficient to stop treatment with trial drug, health-related quality of life (European Quality of Life-5 Dimensions and Short Form questionnaire-12 items at 6 and 12 months after randomisation), length of stay in critical care unit and length of stay in hospital. Forty-six ICUs recruited patients to the trial. A total of 326 patients were randomised; 162 were allocated to salbutamol and 164 to placebo. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality: 55 (34%) of 161 patients died in the salbutamol group compared with 38 (23%) of 163 in the placebo group (risk ratio 1.47, 95% confidence interval 1.03 to 2.08). Treatment with i.v. salbutamol early in the course of ARDS was poorly tolerated, is unlikely to be beneficial and could worsen outcomes. Further trials of β-agonists in patients with ARDS are unlikely to be conducted. Some questions remain, such as whether or not there may be benefit at a different dose or in specific populations, but any studies investigating these would require a very strong rationale. Current Controlled Trials ISRCTN38366450. The National Institute for Health Research Health Technology Assessment programme.

Alveolar neopterin, procalcitonin, and IL-6 in relation to serum levels and severity of lung injury in ARDS

To the Editor,Tsantes et al. evaluated plasma and bronchoalveolar lavage fluid (BALF) procalcitonin (PCT) and interleukin-6 (IL-6) in discriminating septic from non-septic causes of acute respiratory distress syndrome (ARDS) [1]. They concluded that early plasma, but not BALF-PCT concen-trations, can help distinguish between septic and non-septic ARDS causes and are associated with the severity of multiple organ dysfunction syndrome in septic ARDS patients. In addition to PCT and IL-6 we want to point out the role of alveolar and serum neopterin and PCT in the early phase of ARDS and acute lung injury (ALI) as a valu -able marker of increased activity of the cellular immune system [2]. Elevated levels of neopterin in serum and BALF in various lung diseases, e.g., sarcoidosis and interstitial lung disease, have been reported [3]. Pneumonia was associated with significantly elevated neopterin levels in BALF compared to controls [4]. Serum PCT determination in early ARDS was used to discriminate between septic and non-septic underlying disease [5]. PCT was detectable in BALF of patients with severe lung contusion, however, it failed to be a reliable parameter in the assessment of lung contusion severity [6]. IL-6 concentrations are high in the BALF of patients at risk for ARDS and remain elevated throughout the course of ARDS [7].We would like to contribute the so far unpublished results of a previous study concerning alveolar and serum neopterin, PCT and IL-6 in the early phase of ARDS and ALI. In our study, we measured neopterin, PCT, granulo-cyte colony-stimulating factor (G-CSF), TNF-α, IL-6, IL-8, epithelial neutrophil-activating peptide (ENA)-78, soluble TNF-α receptor type I (sTNF-RI), soluble TNF-α receptor type II (sTNF-RII), IL-1 receptor antagonist (IL-1RA), and IL-10 in BALF and serum within 12 and 24 h after onset of ARDS/ALI. Alveolar G-CSF, IL-8, and ENA-78 in relation to serum levels, pulmonary neutrophilia, and severity of lung injury in ARDS, and the association of endogenous G-CSF with anti-inflammatory mediators in patients with ARDS have been published previously [8, 9]. Addition-ally, we determined the concentration of neopterin, PCT, IL-6 in lung epithelial lining fluid (ELF) by using the urea dilution method for estimating the volume of ELF in the lavaged lung segment [10].We evaluated levels of neopterin, PCT, and IL-6 in BALF, ELF and serum for comparison of the concentra-tions of these compounds between the blood circulating compartment and the alveolar space. Furthermore, we evaluated whether there is a difference between ARDS and ALI, septic and non-septic ARDS/ALI, survivors and non-survivors or a correlation to lung injury expressed as PaO

Pathogenesis of Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a common complication of many diseases. Its polyetiological pattern determines the specific features of lung morphological changes and the clinical course of ARDS. Objective: to analyze the pathogenesis of ARDS in the context of the general pathological processes underlying its development. Material and methods. More than 200 lungs from the people who had died from severe concomitant injury or ARDS-complicated pneumonia were investigated. More than 150 rat experiments simulated various types of lung injury: ventilator-induced lung injury with different ventilation parameters; reperfusion injuries (systemic circulation blockade due to 12-minute vascular fascicle ligation, followed by the recovery of cardiac performance and breathing); microcirculatory disorder (injection of a thromboplastin solution into the jugular vein); blood loss; betaine-pepsin aspiration; and closed chest injury. Different parts of the right and left lungs were histologically examined 1 and 3 hours and 1 and 3 days after initiation of the experiment. Lung pieces were fixed in 10% neutral formalin solution and embedded in paraffin. Histological sections were stained with hematoxylin and eosin and using the van Gieson and Weigert procedures; the Schiff test was used. Results. The influence of aggression factors (trauma, blood loss, aspiration, infection, etc.) results in damage to the lung and particularly air-blood barrier structures (endothelium, alveolar epithelium, their basement membrane). In turn the alteration of cellular and extracellular structures is followed by the increased permeability of hemomicrocirculatory bed vessels, leading to the development of non-cardiogenic (interstitial, alveolar) pulmonary edema that is a central component in the pathogenesis of ARDS. Conclusion. The diagnosis of the early manifestations of ARDS must account for the nature of an aggression factor, the signs confirming the alteration of the lung and particularly air-blood barrier structures, pulmonary oxygenizing dysfunction, the development of noncardiogenic pulmonary edema; the absence of left ventricular failure signs. Key words: acute respiratory distress syndrome, pathogenesis.

Effect of Xuebijing injection treatment on acute respiratory distress syndrome: a multicenter prospective randomized control clinical trial

To assess the therapeutic effect of Xuebijing injection on adult patients with acute respiratory distress syndrome (ARDS). A multicenter prospective randomized control study was conducted at 10 intensive care units in Jiangsu province. A total of 172 early ARDS patients were randomly divided into Xuebijing treatment and control groups. All patients received routine therapy of ARDS while additional Xuebijing injection 100 ml was administered in the treatment group intravenously for 7 days. Lung injury score, acute physiology and chronic health evaluation II (APACHE II) score, multiple organ dysfunction score (MODS) and PaO2/FiO2 of the patients was recorded before and after treatment. Mortality at 28 days and the duration of mechanical ventilation were compared between two groups. Ninety-one patients were assigned to receive Xuebijing injection and 81 patients as control; Mortality at Days 28 and 90, the duration of mechanical ventilation and ventilation free days showed no difference between two groups (P > 0.05). PaO2/FiO2 improved after randomization versus pre-treatment in all patients. There was no significant difference between two groups. Murray scores were not significantly different between two groups. In a subgroup analysis of patients with pulmonary infection, pulmonary contusion and extra-pulmonary cause, two groups had no difference in mortality at Day 28, mortality at Day 90, the duration of mechanical ventilation, ventilation free days and days of ICU stay (P > 0.05). The treatment of Xuebijing injection early in course of ARDS does not improve the mortality of ARDS patients. But it may improve lung function and oxygenation. Further studies are warranted.