Acute respiratory distress syndrome epidemiology and pathophysiology

Acute respiratory distress syndrome is a devastating syndrome of lung injury following known risk factors, with a persistently high mortality. A consensus conference definition of ARDS has been adopted by clinical researchers, but potential problems remain. ARDS may represent more than one entity, and radiographic and mechanical differences between pulmonary versus extrapulmonary initiated ARDS have been described. There is increasing recognition of inflammatory mediators in the pathophysiology of acute lung injury. Surfactant abnormalities contribute to the associated lung dysfunction. A growing body of evidence supports the presence of VILI and a potential mechanism for developing MOSF, and has led to new management strategies. The importances of apoptosis to the repair process, and mechanisms that may lead to persistent fibrosis, such as the activation of the coagulant pathway with fibrin deposition, are increasingly recognized.     

肺泡上皮细胞在急性呼吸窘迫综合征的作用

背景 肺泡上皮是急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)的发病机制和康复机制所涉及的一种重要结构.肺泡上皮细胞(alveolar epithelial cells,AEC)在ARDS中对维护肺血屏障的完整性和受损屏障的修复有着关键的作用. 目的 了解AEC在ARDS中的作用,启发临床治疗ARDS的新思路. 内容 从AEC的基本作用、在ARDS的免疫调节、损伤与修复、凋亡及其机制方面进行文献综述. 趋向 目前临床上仍然没有有效的措施治疗ARDS,今后仍需要在寻找新的治疗方向上做出进一步的探索.     

Quantification of asymmetric lung pathophysiology as a guide to the use of simultaneous independent lung ventilation in posttraumatic and septic adult respiratory distress syndrome.

The management of impaired respiratory gas exchange in patients with nonuniform posttraumatic and septic adult respiratory distress syndrome (ARDS) contains its own therapeutic paradox, since the need for volume-controlled ventilation and PEEP in the lung with the most reduced compliance increases pulmonary barotrauma to the better lung. A computer-based system has been developed by which respiratory pressure-flow-volume relations and gas exchange characteristics can be obtained and respiratory dynamic and static compliance curves computed and displayed for each lung, as a means of evaluating the effectiveness of ventilation therapy in ARDS. Using these techniques, eight patients with asymmetrical posttraumatic or septic ARDS, or both, have been managed using simultaneous independent lung ventilation (SILV). The computer assessment technique allows quantification of the nonuniform ARDS pattern between the two lungs. This enabled SILV to be utilized using two synchronized servo-ventilators at different pressure-flow-volumes, inspiratory/expiratory ratios, and PEEP settings to optimize the ventilatory volumes and gas exchange of each lung, without inducing excess barotrauma in the better lung. In the patients with nonuniform ARDS, conventional ventilation was not effective in reducing shunt (QS/QT) or in permitting a lower FIO2 to be used for maintenance of an acceptable PaO2. SILV reduced per cent v-a shunt and permitted a higher PaO2 at lower FIO2. Also, there was x-ray evidence of ARDS improvement in the poorer lung. While the ultimate outcome was largely dependent on the patient's injury and the adequacy of the septic host defense, by utilizing the SILV technique to match the quantitative aspects of respiratory dysfunction in each lung at specific times in the clinical course, it was possible to optimize gas exchange, to reduce barotrauma, and often to reverse apparently fixed ARDS changes. In some instances, this type of physiologically directed ventilatory therapy appeared to contribute to a successful recovery.     

Complement-mediated neutrophil activation in sepsis- and trauma-related adult respiratory distress syndrome. Clarification with radioaerosol lung scans

Complement-mediated neutrophil activation (CMNA) has been proposed as an important pathogenic mechanism causing acute microvascular lung injury in the adult respiratory distress syndrome (ARDS). To clarify the relationship between CMNA and evolving lung injury, we studied 26 patients with multiple trauma and sepsis within 24 hours of risk establishment for ARDS. Pulmonary alveolar-capillary permeability (PACP) was quantified as the clearance rate of a particulate radioaerosol. Seventeen patients (65%) had increased PACP (six developed ARDS) while nine (35%) had normal PACP (none developed ARDS; clearance rates of 3.4%/min and 1.5%/min, respectively). These patients, regardless of evidence of early lung injury, had elevated plasma C3adesArg levels and neutrophil chemotactic desensitization to C5a/C5adesArg. Plasma C3adesArg levels correlated weakly, but significantly, with PACP. Thus, CMNA may be a necessary, but not a sufficient, pathogenic mechanism in the evolution of ARDS.     

(K)eine Surfactant-Therapie bei Patienten mit „acute respiratory distress syndrome“?

Acute respiratory distress syndrome (ARDS) is a common, devastating clinical problem arising from a number of conditions, such as pneumonia, trauma or sepsis. Because of its significant mortality and morbidity, ARDS has been in the focus of extensive experimental and clinical research. Since there is little doubt that alterations of the surfactant system contribute to lung dysfunction and the onset of ARDS, several clinical studies examined the therapeutic safety and efficacy of a surfactant replacement therapy. Clinical experience with exogenous surfactant has proven inconsistent as a therapeutic modality for adult patients with ARDS. This is mainly due to a number of confounding factors, e.g. severity of injury at the time of treatment, dosing regimes and delivery methods used in different trials. However, current data suggest that patients with direct ARDS (e.g. pneumonia, aspiration) could benefit from surfactant replacement therapy rather than patients with indirect ARDS (e.g. sepsis, trauma). Although surfactant replacement therapy has been shown to significantly reduce mortality in neonates with ARDS, there has been no large randomised clinical trial showing that exogenous surfactant improves outcome in adults with respiratory failure. Therefore, surfactant therapy cannot be recommended for routine clinical use in adult patients and has to be considered as a last resort treatment.     

How to prevent ventilator-induced lung injury?

The experimental evidence that ventilator could injure lungs through the application of excessive end-inspiratory volumes and transpulmonary pressures has led to major changes in the clinical management of patients suffering from the acute respiratory distress syndrome (ARDS). The prevention of ventilator-induced lung injury has become one of the main goals of current ventilator strategies for patients with ARDS as well as for patients with normal lungs that require mechanical ventilation. Tidal volume reduction allowed for a reduction in mortality that confirmed the clinical relevance of ventilator-induced lung injury. In contrast, strategies for setting positive end-expiratory pressure (PEEP) have been proposed but the optimal PEEP level remains unsettled. Considerable efforts have been made within the last decades to try to develop new ventilator strategies as well as pharmacological and mechanical measures in order to prevent VILI and further improve the outcome of ARDS patients. This review will strive to describe seminal experimental and clinical studies that aimed at preventing the development of VILI.     

Adult respiratory distress syndrome

Basic scientists and clinicians have written numerous articles on the diverse causes of adult respiratory distress syndrome (ARDS). There is no specific diagnostic test for ARDS; the condition is characterized by interstitial lung edema, reduction in lung compliance, alveolar and small airway closure, decrease in functional residual capacity, and persistent hypoxia with increasing amounts of pulmonary blood flow coursing through nonventilated or poorly ventilated alveoli. Recent studies have emphasized the roles of macrophages and polymorphonuclear neutrophils in lung defense and injury. Advances in understanding the pathophysiology of ARDS have produced little significant change in the clinical management of the syndrome. There is no specific treatment for ARDS. The cornerstone of therapy is the early recognition and elimination of initiating factors such as sepsis. ARDS is not a single disease process, but appears to represent a final common pathway for the manifestation of a variety of lung injuries. The goal of therapy is to eliminate the predisposing condition and support the patient. New modes of ventilatory and pharmacologic therapy are presented.     

Successful extracorporeal membranous oxygenation for a patient with life-threatening transfusion-related acute lung injury

A case of transfusion-related acute lung injury (TRALI) that was successfully treated with extracorporeal membranous oxygenation (ECMO) is reported. A 58-year-old male patient underwent hepatectomy, and pulmonary edema occurred after the administration of fresh-frozen plasma and packed red cells. In the postoperative period, the impaired oxygenation progressively worsened, resulting in life-threatening hypoxemia, despite vigorous treatments. ECMO was therefore applied to the patient as a method of safe emergency support. Aggressive treatments under ECMO led to the successful improvement of the impaired oxygenation. TRALI is recognized as part of acute respiratory distress syndrome (ARDS). As a treatment for ARDS, ECMO does not cure the underlying disease of the lungs, however, with ECMO, TRALI, usually improves within 96 h with respiratory support. ECMO for TRALI-induced lethal hypoxemia is useful for providing time to allow the injured lung to recover. It is suggested that ECMO might be a useful option for the treatment of TRALI-induced, potentially lethal hypoxemia.     

Strategies to reduce ventilator-associated lung injury (VALI)

Optimal management of the acute respiratory distress syndrome (ARDS) requires prompt recognition, treatment of the underlying cause and the prevention of secondary injury. Ventilator-associated lung injury (VALI) is one of the several iatrogenic factors that can exacerbate lung injury and ARDS. Reduction of VALI by protective low tidal volume ventilation is one of the only interventions with a proven survival benefit in ARDS. There are, however, several factors inhibiting the widespread use of this technique in patients with established lung injury. Prevention of ARDS and VALI by detecting at-risk patients and implementing protective ventilation early is a feasible strategy. Detection of injurious ventilation itself is possible, and potential biological markers of VALI have been investigated. Finally, facilitation of protective ventilation, including techniques such as extracorporeal support, can mitigate VALI.     

Acute respiratory distress syndrome is as important as inhalation injury for the development of respiratory dysfunction in major burns

Respiratory dysfunction is common after major burns. The pathogenesis is, however, still under debate. The aim was to classify and examine underlying reasons for respiratory dysfunction after major burns. Consecutive adult patients (n = 16) with a total burned body surface area of 20% or more who required mechanical ventilation were assessed for acute respiratory distress syndrome (ARDS), inhalation injury, sepsis, ventilator-associated pneumonia (VAP), ventilator-induced lung injury (VILI), using conventional criteria, together with measurements of cardiovascular variables and viscoelastic properties of the lung including extravascular lung water.

Nine patients developed ARDS within 6 days of injury. ARDS was characterized by a large reduction in the PEEP-adjusted PaO₂:FiO₂ ratio, pulmonary compliance, and increased extra vascular lung water together with increased renal dysfunction rates. Seven patients fulfilled the criteria for inhalation injury. They also had decreased PaO₂:FiO₂ ratios. There was an increase in extra vascular lung water and a decrease in compliance measures though not to the same extent as in the ARDS group. White blood cell counts dropped from (mean) 21.4 × 10⁹ l⁻¹ (95% CI 15.3–27.5) in day 1 to 4.3 × 10⁹ l⁻¹ (2.2–6.5) on day 3, and lower values tended to correlate with the development of ARDS. Sepsis occurred before onset of ARDS in only three cases. One patient fulfilled the criteria for VAP, but none was thought to have VILI.

We found that respiratory dysfunction after burns is multifactorial, and ARDS and inhalation injury are most important. The early onset of ARDS, together with the changes in white blood cell count and organ dysfunction, favours a syndrome in which respiratory distress is induced by an inflammatory process mediated by the effect of the burn rather than being secondary to sepsis. The power of these conclusions is, however, hampered by the small number of patients in this study.     

Soluble tumor necrosis factor receptor prevents post-pump syndrome.

Post-pump syndrome is an acute lung injury following cardiopulmonary bypass (CPB) which is indistinguishable from the adult respiratory distress syndrome (ARDS). Tumor necrosis factor (TNF) is central to the inflammatory process and is capable of triggering the entire pathophysiologic response leading to ARDS. We hypothesized that treatment with a soluble TNF receptor-binding protein (TNFbp) would reduce the increase in serum TNF and prevent acute lung injury in our sequential insult model of ARDS following CPB. Anesthetized pigs were randomized to one of three groups: Control (n = 3), surgical preparation only; CPB + LPS (n = 6), femoral-femoral hypothermic bypass for 1 h followed by infusion of low dose Escherichia coli lipopolysaccharide (LPS; 1 microg/kg); and TNFbp + CPB + LPS (n = 4), pretreatment with intravenous TNFbp (2 mg/kg) followed immediately by both insults. CPB + LPS caused severe lung injury demonstrated by a significant fall in PaO2 and an increase in both intrapulmonary shunt and peak airway pressure as compared to all groups (P < 0.05). These changes were associated with a significant increase in plasma TNF level and pulmonary neutrophil sequestration. TNFbp significantly reduced plasma levels of TNF and prevented the lung injury typically observed with this ARDS model, but did not reduce pulmonary neutrophil sequestration. Thus, elevated serum TNF is not responsible for neutrophil sequestration but does play a role in neutrophil activation which causes lung injury. Prophylactic use of TNFbp in CPB patients may prevent neutrophil activation and reduce the incidence of post-pump ARDS.     

Molecular basis of lung tissue regeneration

Recent advances have expanded our understanding of lung endogenous stem cells, and this knowledge provides us with new ideas for future regenerative therapy for lung diseases. In studies using animal models for lung regeneration, compensatory lung growth, and lung repair, promising reagents for lung regeneration have been discovered. Stem or progenitor cells are needed for alveolar regeneration, lung growth, and lung repair after injury. Endogenous progenitor cells mainly participate in alveologenesis. However, human lung endogenous progenitor cells have not yet been clearly defined. Recently discovered human alveolar epithelial progenitor cells may give us a new perspective for understanding the pathogenesis of lung diseases. In parallel with such basic research, projects geared toward clinical application are proceeding. Cell therapy using mesenchymal stem cells to treat acute lung injury is one of the promising areas for this research. The creation of bioartificial lungs, which are based on decellularized lungs, is another interesting approach for future clinical applications. Although lungs are the most challenging organ for regenerative medicine, our cumulative knowledge of lung regeneration and of endogenous progenitor cells makes clear the possibilities and limitations of regenerative medicine for lung diseases.     

Pharmacogenetic treatment of acute respiratory distress syndrome

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) occur due to systemic inflammatory disorders or direct injury to the lung. The occurrence of ALI/ARDS is sporadic and is not reliably predicted by the type or severity of injury. A combination of patient characteristics and mechanism of injury are responsible for the sporadic nature of ALI/ARDS and its observed phenotypic variability. Research on the pathophysiology and genetics of ALI/ARDS continues to advance, revealing critical molecular pathways in disease development and specific genetic factors that alter the expression of disease. Despite these advances, pharmacologic therapies have yet to be developed for the prevention or treatment of disease. We anticipate that continued improvement of our understanding of the genetic and pathophysiologic mechanisms underlying ALI/ARDS combined with future clinical trials will allow pharmacogenetic therapies for ALI/ARDS to be developed.     

Role of the neutrophil in septic shock and the adult respiratory distress syndrome.

The adult respiratory distress syndrome (ARDS) is a serious complication of many medical and surgical conditions, most of which do not involve direct pulmonary injury. In surgical practice, septic shock has long been recognised as an important cause of ARDS and it presents many management challenges. Endotoxin released from dead and dying Gram-negative bacteria induces a generalised inflammatory response that results in multiple organ dysfunction, the lung being just one target of this injurious process. In recent years, with the discovery of several key inflammatory mediators, many aspects of this complex condition have been elucidated. The neutrophil has emerged as the central effector cell and possesses a formidable armamentarium of cytokines, enzymes, and oxygen radicals that are capable of inflicting damage to cells. In this review I examine the mechanisms underlying the recruitment and activation of neutrophils in ARDS.     

Acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a heterogeneous lung disease that is triggered by pulmonary and non-pulmonary pathologies. It predominantly causes hypoxaemic respiratory failure and can lead to significant morbidity and mortality. Although ARDS remains underdiagnosed, 24% of mechanically ventilated patients in intensive care units and 33% of coronavirus disease (COVID-19) patients admitted to the hospital are reported to have ARDS. Despite recent advances in treatment, mortality remains at more than 30% for all ARDS patients and 43% for severe ARDS.The pathophysiology is complex and involves acute pulmonary and systemic inflammation, alveolar oedema, and de-recruitment which lead to ventilation-perfusion mismatch, reduced lung compliance and hypoxaemia. Similarities in the pathophysiology of COVID-19 ARDS outnumber differences from non-COVID-19 ARDS. Inhomogeneous distribution of transpulmonary pressure variation throughout the lungs in ARDS increases the risk of patient self-inflicted lung injury and ventilator-associated lung injury.Stratifying ARDS patients as per Berlin definition can help to recognize ARDS early, identify resource requirements and plan appropriate management. Treating the underlying cause, lung-protective ventilation and supportive care are the mainstays of clinical management. Multiple rescue therapies, novel treatments, and methods of facilitating individualized ventilation have been described but many require further validation; and appropriate patient selection is warranted.     

Neutrophil function in a rat model of endotoxin-induced lung injury

Polymorphonuclear neutrophil leukocytes (PMNs) are known to cross the alveolar-capillary barrier and enter the alveolus in acute adult respiratory distress syndrome (ARDS). The pathogenic role of PMNs in both the acute lung injury and subsequent infectious susceptibility in ARDS is not clear. In the present study we investigated the functional status of various neutrophil populations using a chronic, endotoxemia-induced ARDS model. Rats infused with Escherichia coli endotoxin for three days develop an acute lung injury with a histologic picture closely resembling human ARDS. The PMNs recovered from the circulation and by bronchoalveolar lavage were compared with normal rat PMNs. In endotoxemic animals, superoxide production was markedly enhanced in circulating PMNs, indicating production of high levels of potentially cytotoxic oxygen intermediates, while myeloperoxidase activity was decreased in both circulating and lavage PMNs, indicating depressed myeloperoxidase-dependent antimicrobial activity.     

高频振荡通气在成年人急性呼吸窘迫综合征的临床应用

背景 高频振荡通气(high-frequency oscillatory ventilation,HFOV)作为一种新的通气模式,具有高频率、小潮气量、高平均气道压的特点,近年来被成功应用于成年人急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)的治疗.研究表明,HFOV在改善氧合、减少呼吸机相关性肺损伤(ventilator associated lung injury,VILI)方面较常规机械通气(conventional mechanical ventilation,CMV)具有优势.但其对ARDS病死率的影响尚不明确. 目的 通过归纳HFOV在成年人ARDS中的临床应用揭示HFOV的优势和缺陷. 内容 HFOV能够高效改善氧合、减少VILI,但不能减少ARDS的病死率.HFOV技术的最适患者的筛选、最佳使用时机、最佳参数的设定以及与其他治疗手段联用等问题有待进一步探索. 趋向 HFOV应用于ARDS的治疗需要更加深入的研究和探索.     

急性呼吸窘迫综合征患者机械通气相关肺纤维化机制及治疗新进展

背景 机械通气在急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)患者的救治过程中发挥着重要作用,然而机械通气使用不当,可诱发或加重肺损伤,即呼吸机相关性肺损伤,更关键的是机械通气可显著增加ARDS患者肺纤维化的发病率和病死率,有研究报道在ARDS的致死原因中,难以控制的肺纤维化占40％ ～60％. 目的 就ARDS患者机械通气相关肺纤维化的发生机制、防治策略等方面的研究新进展予以综述. 内容 机械通气产生的机械牵张可激活细胞信号通路最终导致肺纤维化的发生发展. 趋向 机械通气导致的肺纤维化已成为ARDS患者预后不良及肺功能下降的重要原因之一,我们应当予以高度重视.随着对其发病机制的不断探索,将为研发有效的防治措施提供更好的理论基础.     

Paracrine factors from mesenchymal stem cells: a proposed therapeutic tool for acute lung injury and acute respiratory distress syndrome

Despite extensive researches in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), current pharmacological therapies and respiratory support are still the main methods to treat patients with ALI and ARDS and the effects remain limited. Hence, innovative therapies are needed to decrease the morbidity and mortality. Because of the proven therapeutic effects in other fields, mesenchymal stem cells (MSCs) might be considered as a promising alternative to treat ALI and ARDS. Numerous documents demonstrate that MSCs can exert multiple functions, such as engraftment, differentiation and immunoregulation, but now the key researches are concentrated on paracrine factors secreted by MSCs that can mediate endothelial and epithelial permeability, increase alveolar fluid clearance and other potential mechanisms. This review aimed to review the current researches in terms of the effects of MSCs on ALI and ARDS and to analyse these paracrine factors, as well as to predict the potential directions and challenges of the application in this field.     

Nephrogenic acute respiratory distress syndrome: A narrative review on pathophysiology and treatment on pathophysiology and treatment

The kidneys have a close functional relationship with other organs especially the lungs. This connection makes the kidney and the lungs as the most organs involved in the multi-organ failure syndrome. The combination of acute lung injury (ALI) and renal failure results a great clinical significance of 80% mortality rate. Acute kidney injury (AKI) leads to an increase in circulating cytokines, chemokines, activated innate immune cells and diffuse of these agents to other organs such as the lungs. These factors initiate pathological cascade that ultimately leads to ALI and acute respiratory distress syndrome (ARDS). We comprehensively searched the English medical literature focusing on AKI, ALI, organs cross talk, renal failure, multi organ failure and ARDS using the databases of PubMed, Embase, Scopus and directory of open access journals. In this narrative review, we summarized the pathophysiology and treatment of respiratory distress syndrome following AKI. This review promotes knowledge of the link between kidney and lung with mechanisms, diagnostic biomarkers, and treatment involved ARDS induced by AKI.