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.     

Low vs high positive end-expiratory pressure in the ventilatory management of acute lung injury

Positive end-expiratory pressure (PEEP) has become an essential component of the care of many critically ill patients who require ventilatory support. The application of PEEP is expected to improve lung mechanics and gas exchange as it recruits lung volume. In the last 3 decades, research of the effects of PEEP in animal models of lung injury and in patients with acute respiratory failure has produced a plethora of information. Support for the use of PEEP comes from historical comparisons and a few randomized controlled studies. Although the data from those animal studies and clinical trials could be seen as very convincing, there are insufficient data to propose an universal approach for the use of PEEP in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In this article I will review the basic mechanisms of PEEP and the current knowledge of the effects of PEEP on the evolution and outcome of ALI/ARDS.     

血管内皮细胞生长因子在急性肺损伤中的作用

急性肺损伤(acute lurg injury,ALI)和急性呼吸窘迫综合征(acute respiratory distressyndrome,ARDS)的特征性病理改变为肺毛细血管通透性增高所致的肺水肿,血管内皮细胞生长因子能抗血管内皮细胞凋亡并增加血管通透性,可能在ALI和ARDS的病理过程中起到重要作用.现对血管内皮细胞生长因子在ALI中的作用进行综述,旨在为ALI和ARDS的治疗提供新的思路.     

Acute lung injury and acute respiratory distress syndrome after pulmonary resection

The occurrence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after thoracic surgery are perplexing and persistent problems. Variously described as postpneumonectomy pulmonary edema, noncardiogenic pulmonary edema, and postlung resection pulmonary edema, ALI and ARDS may be considered a single entity, with ALI being the less severe form of ARDS. It is characterized by the acute onset of hypoxemia with radiographic infiltrates consistent with pulmonary edema, without elevations in the pulmonary capillary wedge pressure. Although this syndrome does not occur frequently and is usually without identifiable cause, the mortality is high. However, the phenomenon has not been rigorously studied owing to the low incidence, with primarily retrospective case series reported. Thus, the nomenclature, risks, and pathogenesis are not well defined. Interest in this syndrome has recently been renewed as the rate of other perioperative complications has declined. ALI/ARDS is reviewed with a focus on potential etiologies and the spectrum of available interventions.     

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.     

中、西医对急性肺损伤/急性呼吸窘迫综合征的认识及展望

背景 急性肺损伤/急性呼吸窘迫综合征(acute lung injury/acute respiratory distress syndrome,ALI/ARDS)由肺内外多种病因引起,其发病机制复杂,病死率高. 目的 文章拟将中、西医两方面对ALI/ARDS的研究作一浅显的对比回顾c内容 综合相关文献,西医和中医无论在病理机制还是治疗方面都各有研究,其中既有相通之处又各成体系. 趋向 为中西医结合治疗ALI/ARDS提供新的线索.     

限制补液在胸外伤继发急性肺损伤或急性呼吸窘迫综合征治疗中的应用

目的总结限制补液在胸外伤合并急性肺损伤(ALI)或急性呼吸窘迫综合征(ARDS)治疗中的应用效果。方法单纯胸外伤合并ALI或ARDS患者132例,采用限制补液技术,适当减少补液,加控制性降压技术,收缩压控制在95~110mmHg之间,早期以维持一个满足基本灌注的偏低血压作为目标血压,减少输液量和速度。通过单纯胸部外伤(排除其他部位重症损伤的干扰)的救治,总结呼吸窘迫防治特点。结果 ALL/ARDS气管插管率为17.4%(23/132),气管切开的发生率为3.8%(5/132),死亡率为2.3%(3/132)。结论 ALI时不恰当的补液过多引发肺水肿是单纯胸外伤并发ARDS主因,而不是反常呼吸所致。适当控制输液,辅以控制性降压技术能大大降低重症胸外伤死亡率。     

Genetics of acute lung injury: past, present and future

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major health problems worldwide. Critical care physicians have long recognized that there are patients who progress poorly despite therapy while others do unexpectedly better than it might be predicted. It is now well accepted that these responses might be related to variations in the genome. However, little is known about the genes that are responsible for susceptibility and outcome in ALI and ARDS. The search for genetic variants determining susceptibility and predicting outcome is still a developing field. The identification of important associations between genotype and clinical outcomes will have an impact on the development of more efficient genotype- or phenotype-guided therapies for patients with ALI/ARDS. Using this point of view, we will discuss some of the advances in genetic association studies in relation to the occurrence and severity of ALI/ARDS. In addition, we will also discuss the strategic and medical implications of using genetic testing to detect or predict the occurrence and prognosis of ALI/ARDS.     

重症急性胰腺炎相关肺损伤机制与治疗的研究进展

重症急性胰腺炎（SAP）是指因胰酶异常激活对胰腺自身及周围器官产生消化作用而引起的、以胰腺局部炎性反应为主要特征,甚至可导致器官功能障碍的临床常见急腹症。SAP常并发急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）,是目前导致SAP病死率较高的主要原因之一。SAP相关ALI的发生率从15%~55%不等,其临床表现也从轻度低氧血症到ARDS各有不同。并且,ALI和ARDS是SAP腹外功能障碍最显著的表现,发病第1周病死率高达60%。近年来众多研究发现,一方面,SAP相关ALI与多种信号通路的激活密不可分;另一方面,各种炎症因子的刺激、氧化应激、细胞焦亡等也是导致SAP相关ALI的重要原因。笔者就有关SAP相关ALI的机制及治疗的最新研究进展作一综述。     

高迁移率族蛋白1和急性肺损伤

背景 高迁移率族蛋白1(high mobility group box protein 1,HMGB1)是一种非组蛋白染色体结合蛋白,进化上高度保守.HMGB1广泛存在于细胞核内,在核内作为DNA分子伴侣,被释放至细胞外将发挥促炎作用.急性肺损伤(acute lung injury,ALI)和急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)是全身性炎症的肺部表现,特征为血管通透性增高致组织水肿、器官功能障碍.越来越多的研究证实细胞外的HMGB1能够通过促进NF-κB核转位和显著增加促炎因子释放引起ALI和致死性的炎症反应.目的 阐述HMGB1和ALI之间的关系以及HMGB1在治疗ALI中的研究现况,为临床治疗ALI提供新的靶点.内容 重点回顾有关HMGB1在ALI发病中的作用、HMGB1抑制剂在改善ALI中作用的研究.趋向 HMGB1抑制剂可以改善ALI结局,在治疗ALI中具有广阔前景.     

Protective ventilation strategy in the acute respiratory distress syndrome

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) contribute to progressive hypoxemia in critically ill patients. It has been proved that conventional mechanical ventilation with physiological respiratory volume contributes to further lung damage. In this respect, application of protective ventilatory strategy--pulmonary ventilation with limited volume and pressure can avoid mentioned consequences. The aim of this paper is to discuss mechanims by which elements contained in protective mechanical ventilation of patients with ALI/ARDS prevent further progrssive lung injury, to argue the effects of positive end--expiratory pressure and present insturctions for its application.     

Acute lung injury and acute respiratory distress syndrome after pulmonary resection

BACKGROUND: In this study we investigate the frequency and mortality of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after pulmonary resection. METHODS: Patients that underwent pulmonary resection at the Royal Brompton Hospital between 1991 and 1997 were included. The case notes of all patients developing postoperative complications were retrospectively reviewed. RESULTS: The overall combined frequency of ALI and ARDS was 3.9%. The frequency was higher in patients over 60 years of age, males and those undergoing resection for lung cancer. ALI/ARDS caused 72.5% of the total mortality after resection in this series. CONCLUSIONS: In our experience ALI and ARDS are major causes of mortality after lung resection.     

Prone positioning ventilation for treatment of acute lung injury and acute respiratory distress syndrome

Patients who are diagnosed with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) usually have ventilation-perfusion mismatch, severe decrease in lung capacity, and gas exchange abnormalities. Health care work-ers have implemented various strategies in an attempt to compensate for these pathological alterations. By rotating patients with ALI/ARDS between the supine and prone position, it is possible to achieve a significant improvement in PaO2/FiO2, decrease shunting and therefore improve oxy-genation without use of expensive, invasive and experimen-tal procedures.     

Effects of hypercapnia and hypercapnic acidosis on attenuation of ventilator-associated lung injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with impaired gas exchange, severe inflammation and alveolar damage including cell death. Patients with ALI or ARDS typically experience respiratory failure and thus require mechanical ventilation for support, which itself can aggravate lung injury. Recent developments in this field have revealed several therapeutic strategies that improve gas exchange, increase survival and minimize the deleterious effects of mechanical ventilation. Among those strategies is the reduction in tidal volume and allowing hypercapnia to develop during ventilation, or actively inducing hypercapnia. Here, we provide an overview of hypercapnia and the hypercapnic acidosis that typically follows, as well as the therapeutic effects of hypercapnia and acidosis in clinical studies and experimental models of ALI. Specifically, we review the effects of hypercapnia and acidosis on the attenuation of pulmonary inflammation, reduction of apoptosis in alveolar epithelial cells, improvement in sepsis-induced ALI and the therapeutic effects on other organ systems, as well as the potentially harmful effects of these strategies. The clinical implications of hypercapnia and hypercapnic acidosis are still not entirely clear. However, future research should focus on the intracellular signaling pathways that mediate ALI development, potentially focusing on the role of reactive biological species in ALI pathogenesis. Future research can also elucidate how such pathways may be targeted by hypercapnia and hypercapnic acidosis to attenuate lung injury.     

In vitro and in vivo effects of salbutamol on neutrophil function in acute lung injury

BACKGROUND: Intravenous salbutamol (albuterol) reduces lung water in patients with the acute respiratory distress syndrome (ARDS). Experimental data show that it also reduces pulmonary neutrophil accumulation or activation and inflammation in ARDS. AIM: To investigate the effects of salbutamol on neutrophil function. METHODS: The in vitro effects of salbutamol on neutrophil function were determined. Blood and bronchoalveolar lavage (BAL) fluid were collected from 35 patients with acute lung injury (ALI)/ARDS, 14 patients at risk from ARDS and 7 ventilated controls at baseline and after 4 days' treatment with placebo or salbutamol (ALI/ARDS group). Alveolar-capillary permeability was measured in vivo by thermodilution (PiCCO). Neutrophil activation, adhesion molecule expression and inflammatory cytokines were measured. RESULTS: In vitro, physiological concentrations of salbutamol had no effect on neutrophil chemotaxis, viability or apoptosis. Patients with ALI/ARDS showed increased neutrophil activation and adhesion molecule expression compared with at risk-patients and ventilated controls. There were associations between alveolar-capillary permeability and BAL myeloperoxidase (r = 0.4, p = 0.038) and BAL interleukin 8 (r = 0.38, p = 0.033). In patients with ALI/ARDS, salbutamol increased numbers of circulating neutrophils but had no effect on alveolar neutrophils. CONCLUSION: At the onset of ALI/ARDS, there is increased neutrophil recruitment and activation. Physiological concentrations of salbutamol did not alter neutrophil chemotaxis, viability or apoptosis in vitro. In vivo, salbutamol increased circulating neutrophils, but had no effect on alveolar neutrophils or on neutrophil activation. These data suggest that the beneficial effects of salbutamol in reducing lung water are unrelated to modulation of neutrophil-dependent inflammatory pathways.     

Short-term cardiorespiratory effects of proportional assist and pressure-support ventilation in patients with acute lung injury/acute respiratory distress syndrome

BACKGROUND: Recent data indicate that assisted modes of mechanical ventilation improve pulmonary gas exchange in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Proportional assist ventilation (PAV) is a new mode of support that amplifies the ventilatory output of the patient effort and improves patient-ventilator synchrony. It is not known whether this mode may be used in patients with ALI/ARDS. The aim of this study was to compare the effects of PAV and pressure-support ventilation on breathing pattern, hemodynamics, and gas exchange in a homogenous group of patients with ALI/ARDS due to sepsis. METHODS: Twelve mechanically ventilated patients with ALI/ARDS (mean ratio of partial pressure of arterial oxygen to fractional concentration of oxygen 190 +/- 49 mmHg) were prospectively studied. Patients received pressure-support ventilation and PAV in random order for 30 min while maintaining mean airway pressure constant. With both modes, the level of applied positive end-expiratory pressure (7.1 +/- 2.1 cm H2O) was kept unchanged throughout. At the end of each study period, cardiorespiratory data were obtained, and dead space to tidal volume ratio was measured. RESULTS: With both modes, none of the patients exhibited clinical signs of distress. With PAV, breathing frequency and cardiac index were slightly but significantly higher than the corresponding values with pressure-support ventilation (24.5 +/- 6.9 vs. 21.4 +/- 6.9 breaths/min and 4.4 +/- 1.6 vs. 4.1 +/- 1.3 l . min . m, respectively). None of the other parameters differ significantly between modes. CONCLUSIONS: In patients with ALI/ARDS due to sepsis, PAV and pressure-support ventilation both have clinically comparable short-term effects on gas exchange and hemodynamics.     

高CO2血症在急性肺损伤治疗中的相关机制

高CO2血症是肺保护性通气策略的一个重要组成部分。临床证据支持了容许性高CO2血症在急性肺损伤／急性呼吸窘迫综合征（ALI／ARDS）患者中的应用。动物实验也证明治疗性高CO2血症可减轻缺血／再灌注、机械通气、内毒素所致的肺损伤。高CO2血症可在多个方面影响ALI／ARDS的病理生理，免疫功能及细胞分子水平的变化。     

Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): paradox or paradigm?

Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), remains a devastating condition with a high mortality. It is characterised by alveolar injury and increased pulmonary vascular permeability. Vascular endothelial cell growth factor (VEGF) was identified by its properties to increase permeability and act as a cellular growth factor, hence its potential for a key role in the pathogenesis of ALI/ARDS. This review describes the basic biology of VEGF and its receptors as an essential prerequisite to discussing the available and sometimes paradoxical published data, before considering a paradigm for the role of VEGF in the human lung.     

Technical advances in renal replacement therapy

Critically ill patients are subject to several risk factors for organ injury: surgical intervention, trauma, rhabdomyolysis, hemodynamic instability, organ hypoperfusion, bacteremia and endotoxemia, sepsis and septic shock. These conditions may cause acute kidney injury (AKI), myocardial dysfunction, liver failure, coagulation abnormalities, acute lung injury (ALI), adult respiratory distress syndrome (ARDS), bone marrow depression, loss of acid/base homeostasis, and finally, brain dysfunction. The resulting picture of multiple organ dysfunction syndrome (MODS) is a lethal clinical entity that is refractory to all therapies in the majority of cases. According to the "humoral theory of sepsis", soluble substances circulate in blood and participate in the generation of the different disorders of MODS; thus, AKI is not the only clinical disorder observed in intensive care unit (ICU) patients nor is it an isolated syndrome. Current extracorporeal management of such patients focuses mainly on renal replacement therapy (RRT). Nevertheless, in recent years, technical evolution of extracorporeal devices led to the potential creation of multiple organ support therapy (MOST) in order to provide a comprehensive replacement of multiorgan dysfunction: hence, other organs (liver, heart, lungs) and syndromes (abdominal sepsis, septic shock) can today be consistently supported and bridged. The technical advances of extracorporeal equipment, moreover, might allow today the design of a dedicated pediatric RRT device in order to treat patients below 10 kg, with the safety and adequacy standards that are currently granted to the adult population. This review will describe the technical evolution of MOST machines and current literature available on MOST.