Adult respiratory distress syndrome: do selective anticoagulants help?

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung. Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.     

Adult Respiratory Distress Syndrome

The adult respiratory distress syndrome (ARDS) is a form of acute lung injury that is characterized by florid extravascular fibrin deposition. Thrombosis in the pulmonary vasculature and disseminated intravascular coagulation have also been observed in association with ARDS. Fibrin deposition does not occur in the normal lung but is virtually universal in acute lung injury induced by disparate insults. A large body of basic and preclinical evidence further implicates abnormalities of pathways of fibrin turnover in the pathogenesis of acute inflammation and fibrotic repair. Coagulation is locally upregulated in the injured lung, while fibrinolytic activity is depressed. These abnormalities occur concurrently and favor alveolar fibrin deposition. The systemic derangements of fibrin turnover in sepsis are similar to those that occur in the injured lung.Recent clinical trials demonstrate that interventions using selective anticoagulation can provide a mortality advantage and that selective anticoagulants differ in their ability to provide clinical benefit. Preclinical trials in primates with sepsis-induced ARDS now indicate that anticoagulant interventions that block the extrinsic coagulation pathway can protect against the development of pulmonary fibrin deposition as well as lung dysfunction and acute inflammation. These observations provide proof of principle that key steps in the coagulation cascade are appropriate therapeutic targets to prevent the development of acute lung injury in ARDS. Ongoing studies and prior publications also support the hypothesis that reversal of the fibrinolytic defect in ARDS could protect against the development of acute lung injury. In all, these studies suggest that fibrin deposition in the injured lung as well as abnormalities of coagulation and fibrinolysis are integral to the pathogenesis of ARDS. The ability of selective anticoagulants to effectively and safely alter clinical outcome in ARDS remains to be determined.     

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.     

Permeability pulmonary edema. Diagnosis and management

The adult respiratory distress syndrome (ARDS) is a common syndrome of diffuse lung injury with high mortality. An underlying mechanism is pulmonary microvascular injury leading to increased permeability, pulmonary edema and impaired gas exchange. Currently ARDS can only be diagnosed as a constellation of symptoms and signs. The development of an accurate clinical marker of pulmonary microvascular injury or a technique to measure pulmonary microvascular permeability may allow earlier and more specific diagnosis. We review ARDS with emphasis on recent work concerning the mechanisms of lung injury, diagnosis, and therapy.     

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.     

氧合导向最佳呼气末正压对急性呼吸窘迫综合征犬肺局部气体分布和炎症反应的影响

目的 探讨氧合导向最佳呼气末正压(PEEP)对急性呼吸窘迫综合征(ARDS)犬肺组织局部气体分布和炎症反应的影响.方法 静脉注射油酸(油酸组,8只)、肺泡灌洗生理盐水(生理盐水组,8只)复制犬ARDS模型.模型成功后给予氧合导向最佳PEEP进行机械通气,基础状态、模型复制成功及机械通气4 h后均行肺部CT扫描,观察肺局部气体分布.4 h后处死犬,留取肺组织观察病理改变,凝胶迁移率改变电泳(EMSA)测肺组织NF-κB活性,比色法测肺组织髓过氧化物酶(MPO)和丙二醛(MDA)含量,ELISA测肺组织IL-6、IL-10含量.结果 (1)与基础状态比,2组犬模型复制成功后,总肺容积均显著减少,不通气区肺容积明显增加;与模型复制成功时比,2组犬在最佳氧合法确定PEEP水平,CT扫描显示低通气区及不通气区肺容积明显减少,正常通气肺组织增加,但过度膨胀区肺容积也显著增加,以腹侧(非重力依赖区)肺泡过度膨胀明显.与油酸组比,在最佳氧合法确定PEEP水平,生理盐水组过度膨胀区肺容积增多更显著.(2)2组犬肺右下叶腹侧组织损伤评分均明显高于右上叶,肺右下叶背侧组织损伤评分均明显高于右上叶、右下叶腹侧;肺右下叶背侧组织NF-κB活性均明显高于右上叶;肺右下叶背侧、右下叶腹侧组织MPO和MDA含量均明显高于右上叶;肺右下叶背侧组织IL-6、IL-10含量均明显高于右上叶、右下叶腹侧.结论 以氧合导向最佳PEEP致ARDS肺非重力依赖区过度膨胀,加重局部肺损伤.生理盐水组犬肺过度膨胀更显著.     

Sepsis syndrome, the adult respiratory distress syndrome, and nosocomial pneumonia. A common clinical sequence

Systemic sepsis and pneumonia are common predisposing factors for ARDS, which can serve as the initial manifestation of the multisystem organ failure syndrome. Primary pneumonia that necessitates ICU admission leads to ARDS in approximately 10% of patients. Systemic infection can also lead to ARDS, but when bacteremia alone is present, the risk is low (probably less than 5%). If the septic syndrome with a hemodynamic and end-organ response develops, the ARDS may follow in as many as 40% of patients. When multiple risk factors for acute lung injury are present, the risk of developing ARDS rises dramatically. The septic syndrome, acute lung injury, and multiorgan failure are closely tied to one another because bacterial cell walls can activate inflammatory mediators, such as interleukin-1 and tumor necrosis factor, which can in turn lead to the septic syndrome and inflammatory injury to the lung. Clinical features, more than serum markers, have been the best predictors of whether lung injury will follow sepsis, indicating that the mere presence of mediators alone cannot cause ARDS and that there are individual susceptibility factors in the effects of these mediators. With the advent of monoclonal antibodies and new anti-inflammatory drugs, prevention of progression from sepsis to multiorgan failure may become possible. Pneumonia is the most common infection that complicates ARDS once it is established, and the mortality rate may approach 90%. The existence of acute lung injury, its predisposing conditions, coexisting illnesses, and the therapeutic interventions used for patients with lung injury all can interfere with lung host defenses and set the stage for bacterial infection of the already-injured lung. This infection appears to add to the propagation of the multiple system organ failure that has already begun. In the future, it may become possible to prevent this infection, which would be a welcome development, because currently, we are stymied in our efforts to diagnose and treat pneumonia in the setting of acute lung injury. Preventive efforts will follow from an understanding of the pathogenesis of pneumonia and in the future may include topical antibiotics, selective digestive decontamination, and prophylactic passive immunotherapy.     

Reducing acute respiratory distress syndrome occurrence using mechanical ventilation

The standard treatment for acute respiratory distress syndrome (ARDS) is supportive in the form of low tidal volume ventilation applied after significant lung injury has already developed. Nevertheless, ARDS mortality remains unacceptably high (> 40%). Indeed, once ARDS is established it becomes refractory to treatment, and therefore avoidance is key. However, preventive techniques and therapeutics to reduce the incidence of ARDS in patients at high-risk have not been validated clinically. This review discusses the current data suggesting that preemptive application of the properly adjusted mechanical breath can block progressive acute lung injury and significantly reduce the occurrence of ARDS.     

Elevated plasma surfactant protein-B predicts development of acute respiratory distress syndrome in patients with acute respiratory failure

Surfactant protein-B is a lung specific protein secreted into the air spaces by pulmonary epithelial type II cells that leaks into the bloodstream in increased amounts in patients with ARDS. To test whether elevated plasma levels of surfactant protein-B would predict the development of ARDS in patients with acute hypoxemic respiratory failure, plasma and lung injury scores were collected at study entry and daily thereafter for 3 d from 54 patients admitted to our intensive care unit. ARDS was defined as a new bilateral infiltrate on chest radiograph and a lung injury score > or = 2.5. Twenty patients developed ARDS, of whom seven died. Although the initial lung injury score was not predictive of ARDS, the initial plasma surfactant protein-B was predictive (area under the curve = 0.77 [0.63 to 0.90], nonparametric receiver-operating characteristic analysis). In this cohort, plasma surfactant protein-B was particularly predictive of ARDS when applied to patients suffering a direct lung insult (area under the curve = 0.87 [0.72 to 1.02]), with a sensitivity of 85% (95% CI: 55 to 98%) and specificity of 78% (40 to 97%) at a cutoff of 4,994 ng/ml.     

Existence of leukotoxin 9,10-epoxy-12-octadecenoate in lung lavages from rats breathing pure oxygen and from patients with the adult respiratory distress syndrome

Pulmonary influxed neutrophils have been suggested to be involved in the development of hyperoxia-induced lung injury. We recently revealed that a highly toxic substance, 9,10-epoxy-12-octadecenoate, is biosynthesized by human neutrophils, thus it was named leukotoxin. Because hyperoxia-induced lung injury is a model of adult respiratory distress syndrome (ARDS), this study was designed to investigate whether or not leukotoxin is involved in the genesis of pulmonary oxygen toxicity and ARDS. After exposure to hyperoxia for 60 h, rats showed acute pulmonary edema, which was evidenced by increased lung weight, albumin concentrations, and angiotensin-converting enzyme (ACE) activities in lung lavages. These changes were correlated with an increased number of neutrophils. We detected leukotoxin in lung lavages of rats after exposure to hyperoxia for 60 h by high performance liquid chromatography and gas-chromatography/mass spectrometry. After intravenous injection of leukotoxin (100 mumol/kg) to rats, acute edematous lung injury occurred showing increases in lung weight, lung lavage albumin concentrations, and lung lavage ACE activities. In the lung lavages obtained from 5 patients with ARDS, significant increases in albumin concentrations and ACE activities were observed compared with those from subjects without pulmonary disease. Moreover, considerable amounts of leukotoxin, 38.5 +/- 21.9 nmol/lung lavage, were observed in the lavages from patients with ARDS. These findings suggest that leukotoxin plays an important role in the genesis of acute edematous lung damage in pulmonary oxygen toxicity, and that leukotoxin also links with the development of lung injury observed in patients with ARDS.     

糖皮质激素治疗急性呼吸窘迫综合征的病理生理基础及临床应用

急性肺损伤和急性呼吸窘迫综合征是发生于严重感染、休克、创伤及烧伤等疾病过程中,肺实质细胞损伤导致的临床综合征.各种损伤导致的机体炎症反应失控是急性呼吸窘迫综合征的根本原因.糖皮质激素是临床上重要的抗炎药物,具有抑制炎症反应,减轻细胞因子对组织的损伤和抑制纤维化等作用.但目前糖皮质激素在急性呼吸窘迫综合征中的应用价值褒贬不一.本文将对糖皮质激素治疗急性呼吸窘迫综合征患者的病理生理基础及临床应用进行综述.     

H1N1-associated acute respiratory distress syndrome

The worldwide 2009-2010 pandemic of novel H1N1 influenza reminds us that influenza can still be a lethal disease. Acute lung injury and acute respiratory distress syndrome (ARDS) have been the most devastating complications of this pathogen. We present a case of a previously healthy 40-year-old obese man who succumbed to H1N1-associated ARDS. In this focused review, we discuss the pathophysiologic peculiarities and management of acute lung injury/ARDS related to H1N1 infection.     

Platelet-specific alpha-granule proteins and thrombospondin in bronchoalveolar lavage in the adult respiratory distress syndrome

Levels of platelet-specific alpha-granule proteins, PF, BTG, and TSP were measured in BAL fluids of patients with the ARDS, ILD, and normal healthy subjects, comprising two separate cohorts. In both groups BAL showed elevated levels of BTG and thrombospondin in ARDS patients. Low levels of PF4 were found in BAL and did not differ between ARDS and control patients. The BTG:PF4 ratio was 2:1 or greater in BAL of ARDS patients and of control subjects with other lung diseases, suggesting in vivo release. In ARDS patients, the ratio of TSP to BTG exceeded that usually found in plasma. In ARDS patients in group 2, BAL levels of TSP, BTG, and total protein correlated strongly with the composite injury scores that were used to quantitate their degree of lung injury. Elevated levels of platelet-derived proteins, which modulate chemotaxis of inflammatory cells and promote connective tissue reorganization, occur in the alveolar compartment of ARDS and ILD patients but are usually undetectable in BAL of healthy control subjects. Levels in these patients in BAL fluid are nonspecific indices of the severity of lung injury in patients with ARDS.     

Subpopulation of hyperresponsive polymorphonuclear neutrophils in patients with adult respiratory distress syndrome. Role of cytokine production.

To gain further insight into the pathogenesis of the adult respiratory distress syndrome (ARDS), we studied possible relationships among the activation status of circulating polymorphonuclear neutrophils (PMN), cytokine levels, and the severity of lung injury in 31 patients: 15 with ARDS, nine with severe pneumonia uncomplicated by ARDS, and seven mechanically ventilated with neither ARDS nor pneumonia. Nine healthy subjects served as controls. Using flow cytometry, we identified a subpopulation of PMN with an increased capacity to generate hydrogen peroxide after stimulation ex vivo in all three patient groups; significantly higher values were found in those with ARDS. The PMN stimulation index, a reflection of the degree of hyperresponsiveness, correlated with elevated levels of tumor necrosis factor-alpha (TNF alpha) in plasma, and both spontaneous and lipopolysaccharide-induced TNF alpha production by cultured monocytes. These biologic expressions of PMN activation and cytokine generation both correlated with indices of the severity of lung injury, but not with the overall clinical severity. In contrast, IL-6 and IL-1 beta showed little or no relationship with either the degree of lung injury or PMN hyperresponsiveness. We conclude that TNF-alpha-primed PMN may play a major role in the pathogenesis of ARDS-associated lung injury.     

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.     

Surfactant Treatment for Congenital Heart Disease Patients with Acute Respiratory Distress Syndrome

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) can be a significant source of morbidity for pediatric cardiac patients in the intensive care unit. Children with unrepaired or palliated congenital heart disease are at increased risk for lower respiratory tract infections, while postoperatively they are at risk for ALI/ARDS precipitated by cardiopulmonary bypass. Surfactant dysfunction and inactivation are key contributors to the pathophysiology of ALI/ARDS, and there is growing evidence that exogenous intratracheal surfactant administration in noncardiac patients may ameliorate the lung injury seen in children with ALI/ARDS, leading to improved outcomes and survival. Evidence for a beneficial effect of exogenous surfactant treatment in congenital heart disease patients with ALI/ARDS is lacking. We present three consecutive children with congenital heart disease and ARDS who had significant and sustained improvement in lung function and oxygenation after treatment with exogenous surfactant, hastening their recovery from life-threatening hypoxemia.     

Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome

Accumulation and activation of inflammatory cells in the lung characterize the acute respiratory distress syndrome (ARDS). However, the precise mechanism for lung epithelial and endothelial cell damage remains unknown. Based on evidence that rapid apoptosis caused by CD8(+) cytolytic T cells can induce pathological cell death, we hypothesized that this mechanism may also participate in the acute lung injury, and attempted to evaluate apoptosis-related factors in bronchoalveolar lavage fluid (BALF) from ARDS patients. Quantitative polymerase chain reaction (PCR) analysis revealed that the messenger ribonucleic acids (mRNAs) for several apoptosis molecules, such as perforin, granzyme A, granzyme B, FasL, and Fas were highly upregulated in the acute phase of ARDS following sepsis. In contrast, low or negligible mRNA expression of these molecules was detected in patients with normal lung function, in septic patients without lung injury (septic non-ARDS), and in patients in the late phase of septic ARDS (late ARDS). While the genes of the classic proinflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-8, and inducible nitric oxide synthase (iNOS) were upregulated in septic non-ARDS or late ARDS patients, expressions of these genes in the acute phase of septic ARDS were most distinct. The immunofluorescence flow cytometry showed that only the lymphocyte population in BALF from acute phase of septic ARDS patients expressed perforin and granzyme. The level of soluble FasL in the BALF increased only in the acute ARDS patients. These results thus suggested that the dual apoptosis pathway, perforin/granzyme and FasL/Fas system, is likely to be another participant for the pathogenesis of acute lung injury.     

Treatment of ARDS

Improved understanding of the pathogenesis of acute lung injury (ALI)/ARDS has led to important advances in the treatment of ALI/ARDS, particularly in the area of ventilator-associated lung injury. Standard supportive care for ALI/ARDS should now include a protective ventilatory strategy with low tidal volume ventilation by the protocol developed by the National Institutes of Health ARDS Network. Further refinements of the protocol for mechanical ventilation will occur as current and future clinical trials are completed. In addition, novel modes of mechanical ventilation are being studied and may augment standard therapy in the future. Although results of anti-inflammatory strategies have been disappointing in clinical trials, further trials are underway to test the efficacy of late corticosteroids and other approaches to modulation of inflammation in ALI/ARDS.     

Decreased VEGF concentration in lung tissue and vascular injury during ARDS.

Endothelial injury is an important prognostic factor in acute respiratory distress syndrome (ARDS). Decreased production of vascular endothelial growth factor (VEGF) in ARDS may favour vascular lesions, since VEGF promotes endothelial survival by inhibiting apoptosis. This study sought to document low VEGF levels in lung tissue from ARDS patients, to determine whether the cause was injury to alveolar type II cells (the main pulmonary source of VEGF) and to evaluate the vascular consequences. Lung specimens were obtained by open biopsy or autopsy from 29 patients with severe ARDS (two survivors) and five controls. As compared with controls, homogenates of lung tissue from ARDS patients contained less VEGF (median (interquartile range) ARDS 8.2 (4.7-12.2) versus controls 28.4 (9.9-47.1) ng x g(-1) protein). Increased immunostaining with surfactant protein B was seen in ARDS lungs. Extensive cellular apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining), including endothelial and alveolar type II cells, was demonstrated, and vascular bed density (CD31 immunostaining) decreased in ARDS lungs as compared with controls. VEGF levels were negatively correlated to apoptotic endothelial cell counts. In conclusion, decreased vascular endothelial growth factor levels in lung tissue may participate in the decrease in lung perfusion in acute respiratory distress syndrome.