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.     

Frequency and mortality of acute lung injury and acute respiratory distress syndrome after pulmonary resection for bronchogenic carcinoma.

OBJECTIVE: We reviewed the frequency and mortality of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in our population of patients submitted to pulmonary resection for primary bronchogenic carcinoma. METHODS: From January 1993 to December 1999, a total of 1221 patients received pulmonary resection for primary bronchogenic carcinoma. Of these, 27 met the criteria of post-operative ALI/ARDS. There were 24 men and three women with a mean age of 64 years (range 45--79). Pre-operatively, predicted mean of PaO(2), PaCO(2) and %FEV1 were 72 mmHg (57--86), 37 mmHg (33--42) and 80% (37--114), respectively. Associated cardiac risk factors were present in eight patients. Three patients (11%) had pre-operative radiotherapy. Surgical-pathologic staging included 14 patients at Stage I, 8 patients at Stage II, four patients at Stage IIIa and one patient at Stage IIIb. RESULTS: ALI/ARDS occurred in 2.2% of our operated lung cancer patients. ALI was diagnosed in 10 patients and ARDS in 17 patients. The mean time of presentation following surgery was 4 days (range 1--10) and 6 days (1--13) for ALI and ARDS, respectively. According to the type of operation, the frequency was highest following right pneumonectomy (4.5%), followed by sublobar resection (3.2%), left pneumonectomy (3%), bilobectomy (2.4%), and lobectomy (2%). The frequency following extended operations was 4%. No differences were found between the ALI/ARDS group and the total population of resected lung cancer patients (control group) with respect to sex, mean age, pre-operative blood gases, %FEV1, surgical--pathologic staging and the use of pre-operative radiotherapy. Four patients with ALI (40%) and 10 patients with ARDS (59%) died. Mortality was highest following right pneumonectomy, extended operations and sublobar resections. Hospital mortality of the total population of operated lung cancer patients in the same period was 2.8% (34 patients). ALI/ARDS accounted for 41% of our hospital mortality. CONCLUSIONS: (1) ALI/ARDS is a severe complication following resection for primary bronchogenic carcinoma. (2) We did not detect any significant difference between the ALI/ARDS group and the control group regarding age, pre-operative lung function, staging and pre-operative radiotherapy. (3) ALI/ARDS is associated with high mortality, the highest mortality rates having been observed following right pneumonectomy and extended operation; it currently represents our leading cause of death following pulmonary resection for lung carcinoma. (4) ALI/ARDS may also occur after sublobar resections with an associated high mortality rate.     

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。     

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

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.     

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.     

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.     

Pulmonary function in adult survivors of severe acute lung injury treated with inhaled nitric oxide

Background : Following an episode of acute respiratory distress syndrome (ARDS), some degree of measurable pulmonary impairment may be anticipated. ARDS is thought to be the more severe form of acute lung injury (ALI) and a recently proposed addition to conventional therapy in ALI/ARDS is inhaled nitric oxide (INO). We carried out a non-randomised follow-up study with pulmonary function tests on survivors of severe ALI/ARDS treated with INO.
Methods : Sixteen previously healthy pulmonary patients, survivors of severe ALI/ARDS, were evaluated with pulmonary function tests >8 months after the acute event. The tests included static and dynamic spirometry, diffusion capacity for carbon monoxide (DLCO), blood gas analysis and evaluation of a chest radiograph.
Results : The most common abnormality seen was a low DLCO in 69% of the patients. Abnormally low values were seen in forced vital capacity in 31%, in forced expiratory volume in 1 s in 13%, and in residual volume and total lung capacity in 6%. Blood gas data were within normal limits in 15/16 patients. All chest radiographs showed resolution of the interstitial and alveolar changes present during the acute event.
Conclusion : In this non-randomised follow-up study we conclude that a degree of measurable pulmonary impairment after INO treatment in severe ALI/ARDS was common, but did not differ markedly from other published studies on pulmonary function in similar patient material. No late unexpected major abnormalities due to the inhaled nitric oxide treatment could be identified in these survivors.     

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.     

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.     

重症胰腺炎合并肺损伤36例临床治疗体会

目的 探讨重症胰腺炎合并肺损伤的治疗方法.方法 回顾性分析我院2002年1月～2006年1月收治的重症胰腺炎36例的临床资料.结果 本组病人均合并有不同程度的呼吸功能障碍.其中,急性肺损伤29例,急性呼吸窘迫综合征7例.治愈35例,死亡1例.结论 急性肺损伤和/或急性呼吸窘迫综合征是重症胰腺炎病人较早发生的严重并发症.严密监测、及时治疗可改善其预后.     

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.     

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.     

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.     

Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury

BACKGROUND: Because injury to the alveolar epithelial barrier is a characteristic feature of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), plasma surfactant protein levels may have prognostic value. To test this hypothesis plasma surfactant proteins A and D (SP-A and SP-D) levels were measured in patients with ALI or ARDS enrolled in the NHLBI sponsored multicentre ARDS Network randomised controlled trial of a 6 ml/kg v 12 ml/kg tidal volume strategy. METHODS: Data from 565 participants in the clinical trial were used. Plasma levels of SP-A and SP-D were measured at baseline and on day 3 after the start of the mechanical ventilation protocol. The longitudinal impact of baseline plasma surfactant protein levels on clinical outcomes was examined by multivariate analysis, controlling for mechanical ventilation group, APACHE III score, and other clinical covariates. The effect of 6 ml/kg tidal volume ventilation on plasma SP-A and SP-D levels was evaluated using analysis of covariance. RESULTS: Baseline plasma SP-A levels were not related to any clinical outcome. In contrast, higher baseline plasma SP-D levels were associated with a greater risk of death (OR 1.21 per 100 ng/ml increment; 95% CI 1.08 to 1.35), fewer ventilator-free days (mean decrease -0.88 days; p=0.001), and fewer organ failure-free days (mean decrease -1.06 days; p<0.0001). The 6 ml/kg tidal volume strategy had no effect on the rise in plasma SP-A levels (p=0.91) but attenuated the rise in plasma SP-D levels (p=0.0006). CONCLUSIONS: Early in the course of ALI/ARDS an increased level of plasma SP-D is associated with a worse clinical outcome. The 6 ml/kg tidal volume strategy attenuated the rise of SP-D early in the clinical course. Taken together, these observations indicate that plasma SP-D, a product of alveolar type II cells, is a valuable biomarker in ALI/ARDS.     

特布他林防治急性肺损伤后肺水肿的研究现状

急性肺损伤(acute lung inury,ALI)后渗透性肺水肿是导致损伤后呼吸功能衰竭的主要病理基础,其发生机制错综复杂,至今仍无完善的治疗方案.研究结果显示,β2-受体激动剂特布他林在一定程度上恢复或改善了肺微血管内皮、肺泡上皮的通透性,对肺泡Ⅱ型细胞的钠-钾-ATP酶和上皮细胞的肺泡侧钠通道活性均有上调作用,增强肺泡液体清除功能,对肺损伤后肺水肿具有良好的防治作用,是一种有前景的治疗措施.但是其临床效果尚需要进一步证实,而且其给药途径及药物用量有待进一步的临床实验研究.     

The influence of race on the development of acute lung injury in trauma patients

Background

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are sequelae of severe trauma. It is unknown if certain races are at greater risk of developing ALI/ARDS, and once established, if there are racial differences in the severity of lung injury or mortality.

Methods

Retrospective cohort study of 4,397 trauma patients (1,831 Caucasians, 871 African-Americans, 886 Hispanics, and 809 Asian/Pacific Islanders) requiring intensive care unit (ICU) admission between 1996 and 2007 at an urban Level I trauma center.

Results

African-American patients were most likely to present in shock with penetrating trauma and receive a massive transfusion. The incidence of ALI/ARDS was similar by race (P = .99). Among patients who developed ALI/ARDS, there was no evidence to support a difference in partial pressure of oxygen in arterial blood to fraction of inspired oxygen (Pao₂/Fio₂) (P = .33), lung injury score (P = .67), or mortality (P = .78) by race.

Conclusions

Despite differences in baseline characteristics, the incidence of ALI/ARDS, severity of lung injury, and mortality were similar by race.     

Extracellular thioredoxin levels are increased in patients with acute lung injury

BACKGROUND: Acute lung injury (ALI) and its extreme manifestation the acute respiratory distress syndrome (ARDS) complicate a wide variety of serious medical and surgical conditions. Thioredoxin is a small ubiquitous thiol protein with redox/inflammation modulatory properties relevant to the pathogenesis of ALI. We therefore investigated whether thioredoxin is raised extracellulary in patients with ALI and whether the extent of any increase is dependent upon the nature of the precipitating insult. METHODS: Bronchoalveolar lavage (BAL) fluid and plasma samples were collected from patients with ALI (n=30) and healthy controls (n=18, plasma; n=14, BAL fluid). Lung tissue was harvested from a separate group of patients and controls (n=10). Thioredoxin was measured by ELISA in fluids and by immunohistochemistry in tissue. Interleukin (IL)-8 levels were determined by ELISA. Disease severity was assessed as APACHE II and SOFA scores. RESULTS: BAL fluid levels of thioredoxin were higher in patients with ALI than in controls (median 61.6 ng/ml (IQR 34.9-132.9) v 16.0 ng/ml (IQR 8.9-25.1), p<0.0001); plasma levels were also significantly higher. When compared with controls, sections of wax embedded lung tissue from patients with ALI showed greater positive staining for thioredoxin in alveolar macrophages and type II epithelial cells. BAL fluid levels of thioredoxin correlated with IL-8 levels in BAL fluid but not with severity of illness scores or mortality. BAL fluid levels of thioredoxin, IL-8, and neutrophils were significantly greater in patients with ALI of pulmonary origin. CONCLUSIONS: Extracellular thioredoxin levels are raised in patients with ALI, particularly of pulmonary origin, and have a significant positive association with IL-8. Extracellular thioredoxin levels could provide a useful indication of inflammation in ALI.