Tidal volume reduction in patients with acute lung injury when plateau pressures are not high

Use of a volume- and pressure-limited mechanical ventilation strategy improves clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS). However, the extent to which tidal volumes and inspiratory airway pressures should be reduced to optimize clinical outcomes is a controversial topic. This article addresses the question, "Is there a safe upper limit to inspiratory plateau pressure in patients with ALI/ARDS?" We reviewed data from animal models with and without preexisting lung injury, studies of normal human respiratory system mechanics, and the results of five clinical trials of lung-protective mechanical ventilation strategies. We also present an original analysis of data from the largest of the five clinical trials. The available data from each of these assessments do not support the commonly held view that inspiratory plateau pressures of 30 to 35 cm H2O are safe. We could not identify a safe upper limit for plateau pressures in patients with ALI/ARDS.     

New modalities of mechanical ventilation: high-frequency oscillatory ventilation and airway pressure release ventilation

Management of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) is largely supportive, with the use of mechanical ventilation being a central feature. Recent advances in the understanding of ALI/ARDS and mechanical ventilation have revealed that lung-protective ventilation strategies may attenuate ventilator-associated lung injury and improve patient morbidity/mortality. High-frequency oscillatory ventilation and airway pressure release ventilation are two novel alternative modes of ventilation that theoretically fulfill the principles of lung protection and may offer an advantage over conventional ventilation for ALI/ARDS.     

Microarray-based analysis of ventilator-induced lung injury

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are a frequent cause of intensive care unit admission, affecting over 200,000 patients in the United States each year. Mechanical ventilation is a life-saving intervention in the setting of ARDS and ALI, but clinical trials have demonstrated that mechanical ventilation with excessive tidal volumes plays a role in promoting and perpetuating lung injury and leads to excess mortality. This process has been labeled ventilator-induced lung injury (VILI), but the molecular mechanisms driving this process and its interactions with predisposing risk factors such as sepsis and chemical injury remain incompletely understood. Genome-wide measurements of gene expression using microarray technology represent a powerful tool to examine the pathophysiology of VILI. Several recent studies have used this approach to study VILI in isolation and associated with endotoxin instillation or saline lavage. These studies and others examining gene expression profiles in epithelial cells subjected to cyclic stretch have provided novel insights on the molecular mechanisms underlying VILI. This review will summarize these findings and discuss implications for future studies.     

Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome.

In patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), a recent ARDS Network randomized controlled trial demonstrated that a low tidal volume (VT) mechanical ventilation strategy (6 ml/kg) reduced mortality by 22% compared with traditional mechanical ventilation (12 ml/kg). In this study, we examined the relative efficacy of low VT mechanical ventilation among 902 patients with different clinical risk factors for ALI/ARDS who participated in ARDS Network randomized controlled trials. The clinical risk factor for ALI/ARDS was associated with substantial variation in mortality. The risk of death (before discharge home with unassisted breathing) was highest in patients with sepsis (43%); intermediate in subjects with pneumonia (36%), aspiration (37%), and other risk factors (35%); and lowest in those with trauma (11%) (p < 0.0001). Despite these differences in mortality, there was no evidence that the efficacy of the low VT strategy varied by clinical risk factor (p = 0.76, for interaction between ventilator group and risk factor). There was also no evidence of differential efficacy of low VT ventilation in the other study outcomes: proportion of patients achieving unassisted breathing (p = 0.59), ventilator-free days (p = 0.58), or development of nonpulmonary organ failure (p = 0.44). Controlling for demographic and clinical covariates did not appreciably affect these results. After reclassifying the clinical risk factors as pulmonary versus nonpulmonary predisposing conditions and infection-related versus non-infection-related conditions, there was still no evidence that the efficacy of low VT ventilation differed among clinical risk factor subgroups. In conclusion, we found no evidence that the efficacy of the low VT ventilation strategy differed among clinical risk factor subgroups for ALI/ARDS.     

Ventilator-associated lung injury: a search for better therapeutic targets.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a continuum of injury that may arise from a number of primary insults. Localised injury may progress due to trauma from mechanical ventilation, a finding that has led to intense debate in the clinical and experimental literature over optimal ventilator management. The implementation of low tidal volume strategies has led to an improvement in outcomes; however, mortality remains unacceptably high. In the current review, ventilator-associated lung injury is examined, as it relates to the pathophysiological changes beyond direct airway trauma in ALI and ARDS, and an attempt is made to provide a historical perspective to outline potential current and future pitfalls in the use of surrogate end-points and the discovery of potential biomarkers. The systemic responses that lead to multi-organ dysfunction, the leading causes of morbidity and mortality in ALI and ARDS, are caused by pro-inflammatory signalling cascades and the activation of such diverse mediators as reactive oxygen species, immune response elements, apoptotic constituents and coagulation proteins. These areas are examined, including key mediators, and possible future areas of interest are discussed, including the potential of an "acute lung injury chip" to integrate measured surrogate biomarkers with real-time clinical information to improve patient outcomes.     

Respiratory failure

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common causes of hypoxemic respiratory failure. Multiple etiologies lead to direct and indirect pulmonary injury that progresses through an acute exudative phase, fibroproliferative phase, and recovery phase. Inflammatory mechanisms are thought to play a predominant role in the pathophysiology of ALI/ARDS. Mechanical ventilation with a lower tidal volume and an inspiratory plateau pressure of < or = 30 cm H2O is one intervention that has demonstrated a reduction in mortality. A clinical trial to determine the role of restrictive versus liberal fluid management is underway. Inhaled nitric oxide has been used to improve oxygenation but has not resulted in any outcome benefit. Glucocorticoids may be beneficial in the fibroproliferative phase of lung injury by suppressing chronic inflammation. Rigorous clinical trials of new and established interventions are required to determine optimum therapy and reduce mortality in ALI/ARDS.     

High-frequency ventilation for acute lung injury and ARDS

In patients with acute lung injury (ALI) and ARDS, conventional mechanical ventilation (CV) may cause additional lung injury from overdistention of the lung during inspiration, repeated opening and closing of small bronchioles and alveoli, or from excessive stress at the margins between aerated and atelectatic lung regions. Increasing evidence suggests that smaller tidal volumes (VTs) and higher end-expiratory lung volumes (EELVs) may be protective from these forms of ventilator-associated lung injury and may improve outcomes from ALI/ARDS. High-frequency ventilation (HFV)-based ventilatory strategies offer two potential advantages over CV for pateints with ALI/ARDS. First, HFV uses very small VTs, allowing higher EELVs with less overdistention than is possible with CV. Second, despite the small VTs, high respiratory rates during HFV allow the maintenance of normal or near-normal PaCO(2) levels. In this review, the use of HFV as a lung protective strategy for patients with ALI/ARDS is discussed.     

Future research directions in acute lung injury: summary of a National Heart,Lung, and Blood Institute working group

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are syndromes of acute respiratory failure that result from acute pulmonary edema and inflammation. The development of ALI/ARDS is associated with several clinical disorders including direct pulmonary injury from pneumonia and aspiration as well as indirect pulmonary injury from trauma, sepsis, and other disorders such as acute pancreatitis and drug overdose. Although mortality from ALI/ARDS has decreased in the last decade, it remains high. Despite two major advances in treatment, low VT ventilation for ALI/ARDS and activated protein C for severe sepsis (the leading cause of ALI/ARDS), additional research is needed to develop specific treatments and improve understanding of the pathogenesis of these syndromes. The NHLBI convened a working group to develop specific recommendations for future ALI/ARDS research. Improved understanding of disease heterogeneity through use of evolving biologic, genomic, and genetic approaches should provide major new insights into pathogenesis of ALI. Cellular and molecular methods combined with animal and clinical studies should lead to further progress in the detection and treatment of this complex disease.     

Treatment of acute lung injury: historical perspective and potential future therapies

The acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and colleagues in 1967. However, despite considerable efforts, early progress in treatment was slowed by lack of consistent definitions and appropriately powered clinical trials. In 1994, the American-European Consensus Conference on ARDS established criteria defining ARDS as well as acute lung injury (ALI). Additionally, the conference established research directives and international coordination of clinical studies. Current incidence of ALI in the United States is estimated at 200,000 cases per year with a mortality rate approaching 40%. Mechanical ventilation, using positive end-expiratory pressure and reduced tidal volumes and inspiratory pressures, along with improved supportive care has increased survival rates. However, to date, pharmacological therapies have failed to improve survival in multicenter clinical trials. This article focuses on clinical treatments for ALI that have been tested in phase II and III clinical trials as well as a discussion of potential future therapies.     

Partial liquid ventilation for acute respiratory distress syndrome

PLV represents an intriguing alternative paradigm in the approach to the patient with ALI. Within the past decade, substantial information has become available regarding this technique. Clearly, PLV is feasible in patients with ALI and ARDS, and it appears to be safe with respect to short-term effects on hemodynamics and lung physiology, as well as long-term toxicity (although further research in this area is warranted). Although PLV has not yet been proven to be superior to traditional mechanical ventilation for patients with ALI or ARDS, PLV possesses an intriguing combination of physical, physiologic, and biologic effects: "Liquid PEEP" effect--e.g., more effective recruitment of dependent lung zones than achieved by gas ventilation Anti-inflammatory effects Lavage of alveolar debris Mitigation of ventilator-induced lung injury Direct anti-inflammatory effects--e.g., decreased macrophage release of proinflammatory cytokines, etc. Prevention of nosocomial pneumonia Combination with other modalities--e.g., exogenous surfactant replacement, inhaled NO, prone position Enhanced delivery of drugs or gene vectors into the lung. The results of ongoing and future clinical trials will be necessary to establish whether PLV improves clinical outcomes in patients with ALI or ARDS, or specific subgroups of such patients. Significant work also remains to be done to define the optimum dose level of PLV and the most appropriate ventilatory strategies.     

Pediatric acute lung injury: prospective evaluation of risk factors associated with mortality

RATIONALE: The 1994 American European Consensus Committee definitions of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) have not been applied systematically in the pediatric population. OBJECTIVES: The purpose of this study was to evaluate prospectively the epidemiology and clinical risk factors associated with death and prolonged mechanical ventilation in all pediatric patients admitted to two large, pediatric intensive care units with ALI/ARDS using Consensus criteria. METHODS: All pediatric patients meeting Consensus Committee definitions for ALI were prospectively identified and included in a relational database. MEASUREMENTS AND MAIN RESULTS: There were 328 admissions for ALI/ARDS with a mortality of 22%. Multivariate logistic regression analyses revealed (1) the initial severity of oxygenation defect, as measured by the Pa(O2)/FI(O2) ratio; (2) the presence of nonpulmonary and non-central nervous system (CNS) organ dysfunction; and (3) the presence of CNS dysfunction were independently associated with mortality and prolonged mechanical ventilation. A substantial fraction of patients (28%) did not require mechanical ventilation at the onset of ALI; 46% of these patients eventually required intubation for worsening ALI. CONCLUSIONS: Mortality in pediatric ALI/ARDS is high and several risk factors have major prognostic value. In contrast to ALI/ARDS in adults, the initial severity of arterial hypoxemia in children correlates well with mortality. A significant fraction of patients with pediatric ALI/ARDS can be identified before endotracheal intubation is required. These patients provide a valuable group in whom new therapies can be tested.     

The role of cytokines during the pathogenesis of ventilator-associated and ventilator-induced lung injury

Mortality rates from acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) range from 30 to 65%. Although mechanical ventilation (MV) may delay mortality in critically ill patients with ALI/ARDS, it may also cause a lung injury that further promotes and perpetuates ALI/ARDS and multiorgan dysfunction syndrome (MODS). Recent studies have demonstrated that lung protective strategies of MV, as compared with the injurious strategy of conventional MV (CMV) can reduce absolute mortality rates during ALI/ARDS. The protective strategies limit tidal volumes and peak/plateau pressures while maximizing positive end-expiratory pressure. The injury to the lung by CMV is characterized histologically by edema, leukocyte extravasation, and endothelial and epithelial damage. Both human and animal studies suggest that alveolar cell deformation from CMV leads to the release of cytokines/chemokines which orchestrate the extravasation, activation, and recruitment of leukocytes, causing ventilator-associated lung injury (VALI) and ventilator-induced lung injury (VILI). Moreover, VALI/VILI can perpetuate the chronic inflammatory response during ALI/ARDS and MODS. This article explores the role of cytokines/chemokines during the pathogenesis of VALI/VILI.     

烟雾吸入性急性肺损伤/急性呼吸窘迫综合征的研究进展

目前烟雾吸入性急性肺损伤（ALI）／急性呼吸窘迫综合征（ARDS）的发病机制尚未完全明确,可能与烟雾所致的氧化性损伤、肺表面活性物质变化、细胞因子改变、细胞凋亡的发生有关。与机制相应的治疗方法仍未找到,常见的临床治疗方法（如：机械通气,肺泡灌洗,药物治疗）虽然已被证明有一定疗效,但仍然无法治愈烟雾吸入性ALI／ARDS。体外二氧化碳排除及一氧化氮治疗等新方法的尝试为我们进一步研究烟雾吸入性ALI／ARDS提供了新的思路。     

Evidencias de la posición en decúbito prono para el tratamiento del síndrome de distrés respiratorio agudo: una puesta al día

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) have high incidence and mortality rates. Most of the recently introduced treatments have failed to improve the prognosis of patients with ALI or ARDS or to reduce mortality. Several studies have shown improved oxygenation in the prone position during mechanical ventilation in patients with ARDS. However, current evidence strongly suggests that placing ARDS patients in prone position does not improve survival or reduce the duration of mechanical ventilation. Therefore, though in clinical practice this position may improve refractory hypoxemia in patients with ARDS, there is no evidence to support its systematic use.     

Noninvasive ventilation in Plasmodium vivax related ALI/ARDS

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), complications of P. falciparum malaria are associated with a very high mortality but are rarely seen in P. vivax malaria. Herein, we report a 28-year old woman who developed ARDS after infection with P. vivax. In a systematic review the literature for the use of noninvasive ventilation (NIV) in cases of ALI/ARDS related to P. vivax, from among 45 reports noninvasive positive pressure ventilation (NIPPV) was used in the management of three cases of ALI/ARDS related to P. vivax. The use of NIV in vivax malaria related ALI/ARDS is associated with a good outcome.     

Epidemiology of acute lung injury and acute respiratory distress syndrome in The Netherlands: a survey

BACKGROUND: The characteristics, incidence and risk factors for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) may depend on definitions and geography. METHODS: A prospective, 3-day point-prevalence study was performed by a survey of all intensive care units (ICU) in the Netherlands (n=96). Thirty-six ICU's responded (37%), reporting on 266 patients, of whom 151 were mechanically ventilated. The questionnaire included criteria and potential risk factors for ALI/ARDS, according to the North American-European Consensus Conference (NAECC) or the lung injury score (LIS>or=2.5). RESULTS: Agreement between definitions was fair (kappa 0.31-0.42, P=0.001). ALI/ARDS was characterized, regardless of definition, by radiographic densities, low oxygenation ratios, high inspiratory O(2) and airway pressure requirements. Depending on definitions, ALI and ARDS accounted for about 12-33% and 7-9% of ICU admissions per year, respectively, constituting 21-58% (ALI) and 13-16% (ARDS) of all mechanically ventilated patients. The annual incidences of ALI and ARDS are 29.3 (95%CI 18.4-40.1) and 24.0 (95%CI 14.2-33.8) by NAECC, respectively, and are, respectively, 83.6 (95%CI 65.3-101.9) and 20.9 (95%CI 11.7-30.1) by LIS per 100,000. Risk factors for ALI/ARDS were aspiration, pneumonia, sepsis and chronic alcohol abuse (the latter only by NAECC). CONCLUSION: The effect of definitions of ALI/ARDS on mechanical ventilation in the Netherlands is small. Nevertheless, the incidence of ALI/ARDS may be higher than in other European countries but lower than in the USA, and the incidence of ALI by LIS may overestimate compared to that by NAECC. Aspiration, pneumonia, sepsis and chronic alcohol abuse are major risk factors, largely independent of definitions.     

Treatment of acute lung injury: clinical and experimental studies

This presentation at the 2007 Aspen Lung Injury and Repair Conference provided a brief historical perspective from the 1998 Aspen Conference on Acute Lung Injury, highlighting the discussion of clinical definitions. There was also a review of the National Heart, Lung, and Blood Institute ARDS Network clinical trials, with an emphasis on the success of the lung-protective ventilation strategy in reducing mortality. In addition, there was a discussion of the recently completed fluid and catheter treatment trial, which demonstrated no benefit for pulmonary arterial catheterization over central venous catheterization for monitoring patients with acute lung injury (ALI). The trial demonstrated an increase in ventilator-free days with a fluid-conservative protocol. Finally, there was a discussion of recent experimental studies that show promise for cell-based therapy with mesenchymal stem cells for the treatment of endotoxin-induced ALI in mice. There were three objectives for this presentation at the 2007 Lung Injury, Repair, and Remodeling Conference: (1) to provide a brief historical perspective from the 1998 Aspen Conference on Acute Lung Injury; (2) to review major National Heart, Lung, and Blood Institute clinical trials conducted in the past 10 years by the ARDS Network; and (3) to review some of our promising work with cell-based therapy for experimental ALI.     

Mortality rates for patients with acute lung injury/ARDS have decreased over time

BACKGROUND: Over the last decade, several studies have suggested that survival rates for patients with acute lung injury (ALI) or ARDS may have improved. We performed a systematic analysis of the ALI/ARDS literature to document possible trends in mortality between 1994 and 2006. METHODS: We used the Medline database to select studies with the key words "acute lung injury," "ARDS," "acute respiratory failure," and "mechanical ventilation." All studies that reported mortality rates for patients with ALI/ARDS defined according to the criteria of the American European Consensus Conference were selected. We excluded studies with < 30 patients and studies limited to specific subgroups of ARDS patients such as sepsis, trauma, burns, or transfusion-related ARDS. RESULTS: Seventy-two studies were included in the analysis. There was a wide variation in mortality rates among the studies (15 to 72%). The overall pooled mortality rate for all studies was 43% (95% confidence interval, 40 to 46%). Metaregression analysis suggested a significant decrease in overall mortality rates of approximately 1.1%/yr over the period analyzed (1994 to 2006). The mortality reduction was also observed for hospital but not for ICU or 28-day mortality rates. CONCLUSIONS: In this literature review, the data are consistent with a reduction in mortality rates in general populations of patients with ALI/ARDS over the last 10 years.     

内毒素导致的急性肺损伤治疗的研究进展

急性肺损伤(ALI)可迅速发展为急性呼吸窘迫综合征(ARDS),内毒素血症是ALI最主要的原因之一,治疗效果不理想,病死率高,一直是临床和基础研究关注的焦点。近年来在抗炎、抗氧化、抗凝治疗等方面进行了大量的实验研究,但尚缺乏临床试验的验证。目前作为治疗ALI/ARDS的主要方法——呼吸机治疗在通气模式的研究方面进展较快...