Acute Lung Injury Review

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1 REVIEW ARTICLE Acute Lung Injury Review Kenji Tsushima 1,2, Landon S. King 1, Neil R. Aggarwal 1, Antonio De Gorordo 1, Franco R. D Alessio 1 and Keishi Kubo 2 Abstract The first report of acute respiratory distress syndrome (ARDS) was published in 1967, and even now acute lung injury (ALI) and ARDS are severe forms of diffuse lung disease that impose a substantial health burden all over the world. Recent estimates indicate approximately 190,000 cases per year of ALI in the United States each year, with an associated 74,500 deaths per year. Common causes of ALI/ARDS are sepsis, pneumonia, trauma, aspiration pneumonia, pancreatitis, and so on. Several pathologic stages of ALI/ARDS have been described: acute inflammation with neutrophil infiltration, fibroproliferative phase with hyaline membranes, with varying degrees of interstitial fibrosis, and resolution phase. There has been intense investigation into the pathophysiologic events relevant to each stage of ALI/ARDS, and much has been learned in the alveolar epithelial, endobronchial homeostasis, and alveolar cell immune responses, especially neutrophils and alveolar macrophages in an animal model. However, these effective results in the animal models are not equally adoptive to those in randomized, controlled trials. The clinical course of ALI/ARDS is variable with the likely pathophysiologic complexity of human ALI/ARDS. In 1994, the definition was recommended by the American-European Consensus Conference Committee, which facilitated easy nomination of patients with ALI/ARDS for a randomized, clinical trial. Here, we review the recent randomized, clinical trials of ALI/ ARDS. Key words: ALI/ARDS, low-tidal volume strategy, glucocorticoids, nitric oxide, FACTT (Inter Med 48: , 2009) () Definition The first description of acute respiratory distress syndrome (ARDS) appeared in 1967, in a paper by Ashbaugh et al which described 12 patients with acute respiratory distress, cyanosis refractory to oxygen therapy, decrease lung compliance, and diffuse infiltrates on chest radiography (1). In 1988, an expanded definition was proposed based on the level of positive end-expiratory pressure (PEEP), the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, the static lung compliance, and the degree of infiltration evident on chest radiography (2). Another measurement, the lung injury score (3), has been widely used to quantify the disease severity in clinical trials, although it has not been shown to accurately predict outcome during the first 24 to 72 hours after the onset of ARDS (4). In 1994, a new definition was recommended by the American-European Consensus Conference Committee (Table 1) (5), which recognized the variability in severity of lung injury, and separated patients into two groups: those with less severe hypoxemia were categorized as having acute lung injury (ALI), and those with more severe hypoxemia were defined as having ARDS. However, factors such as the underlying cause and involvement of other organ systems are not a part of the existing definition (6). Incidence and Outcome ALI and ARDS are severe forms of diffuse lung disease that impose a substantial health burden in the United States each year. Data from several population-based studies reveals a fairly consistent picture for the age, mortality, severity of illness, ratio of ARDS to ALI, and ratio of ALI to acute respiratory failure, yet there is almost a four-fold difference in the reported incidence of ALI/ARDS between Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, U.S.A. and The First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto Correspondence to Dr. Kenji Tsushima, tsushima@shinshu-u.ac.jp 621

2 Table1. DefinitionsoftheAcuteRespiratoryDistresSyndrome(NEnglJMed342: ,2000) Reference year Definition of criteria Advantages Disadvantages Petty and Ashbaugh (1) 1971 Severe dyspnea, tachypnea Cyanosis refractory to oxygen therapy Decreased pulmonary compliance Diffuse alveolar infiltrates on chest radiography Atelectasis, vascular congestion, hemorrhage, pulmonary edema, and hyaline membranes at autopsy First description Summarizes clinical features well Lacks specific criteria to identify patients systematically Murray et al. (2) 1988 Preexisting direct or indirect lung injury Mild-to-moderate or severe lung injury Nonpulmonary organ dysfunction Includes 4-point lung injury scoring system Specifies clinical cause of lung injury Includes consideration of the presence or absence of systemic disease Lung-injury score not predictive of outcome Lacks specific criteria to exclude a diagnosis of cardiogenic pulmonary edema Bernard et al. (3) 1994 Acute onset Bilateral infiltrates on chest radiography Pulmonary-artery wedge pressure <18mmHg or the absence of clinical evidence of left atrial hypertension Acute lung injury considered to be present if PaO 2 :FiO 2 <300 Acute respiratory distress syndrome considered to be present if PaO 2 :FiO 2 <200 PaO 2 denotes partial pressure of arterial oxygen, and FiO 2 fraction of inspired oxygen. Simple, easy to use, especially in clinical trials Recognizes the spectrum of the clinical disorder Does not specify cause Does not consider the presence or absence of multiorgan dysfunction Radiographic findings not specific studies. Recent estimates indicate approximately 190,000 cases per year of ALI in the United States each year, with an associated 74,500 deaths per year (7). In-hospital mortality was 38.5% for ALI, and 41.1% for ARDS (7). Most studies of ALI/ARDS have reported a mortality of 40 to 60%, however, low-tidal volume ventilation has been shown to reduce mortality to 31% in a defined study group (8, 9). The majority of deaths are attributable to sepsis or multiple organ dysfunction syndrome (MODS) rather than primary respiratory failure. Compared with mortality rates of 55-65% reported in the reports in the 1980s and early 1990s, the overall mortality appears to have decreased somewhat in the past twenty years, perhaps related to changes in the method of mechanical ventilation, and improvement in the supportive care of critically ill patients. Pathogenesis Common causes of ALI/ARDS are sepsis (the most common cause is severe sepsis from a pulmonary source), trauma, aspiration, multiple blood transfusion, acute pancreatitis, inhalation injury, and certain types of drug toxicity. While systemic or direct lung injury may be the inciting agent, in those patients susceptible to lung injury, the inflammatory response propagates lung injury especially when coupled with other insults to the lung such as high-tidal volume mechanical ventilation or hyperoxia. Several pathologic stages of ARDS have been described (Fig. 1): acute inflammation with neutrophil infiltration of the alveolar space; fibroproliferative phase with alveolar hyaline membranes, with varying degrees of interstitial fibrosis, and finally, resolution. There has been intense investigation into the pathophysiologic events relevant to the earliest stages of disease, and much has been learned, particularly in animal models, about the changes in endothelial and epithelial homeostasis in the lung in the first hours after initial lung injury (10). Intervention based on interruption of pathways identified in the acute phase has been effective when provided as pre-treatment in animal models, but the requirement for early delivery, coupled with the likely pathophysiologic complexity of human ARDS, has markedly limited clinical utility. The clinical course of ALI/ARDS is variable. Some patients recover within a period of 1-2 weeks, while others suffer a more protracted course with prolonged mechanical ventilation. Death from primary respiratory failure is relatively uncommon, however with prolonged critical illness and mechanical ventilation the risk of superimposed infection or multi-organ failure rises, leading to increased mortality. It is recognized that resolution from lung injury is not simply relief from injurious agents or factors, but rather reflects an actively regulated program involving removal of apoptotic neutrophils, remodeling of matrix, resolution of protein rich alveolar fluid, and engagement of numerous signaling pathways distinct from those involved in acute injury (Fig. 2). Alveolar edema is resolved by the active transport from the distal air spaces into the lung interstitum. Water moves passively through transcellular water channels such as aquaporins (11, 12). Soluble protein appears to be re- 622

3 Figure1. Thenormalalveolus(left-handside)andtheinjuredalveolusintheacutephaseof acutelunginjuryandacuterespiratorydistressyndrome(right-handside).intheacutephaseof thesyndrome(right-handside),thereissloughingofboththebronchialandalveolarepithelial cels,withtheformationofprotein-richhyalinemembranesonthedenudedbasementmembrane. Neutrophilsadheretotheinjuredcapilaryendothelium andmigratingthroughtheinterstitium intotheairspace,whichisfiledwithprotein-richedemafluid.intheairspace,analveloarmacrophagesecretescytokines,interleukin-1,6,8,and10,(il-1,6,8,and10)andtumornecrosisfactor α(tnf-α),whichactlocalytostimulatechemotaxisandactivateneutrophils.macrophagesalso secreteothercytokines,includinginterleukin-1,6,and10.interleukin-1canalsostimulatetheproductionofextracelularmatrixbyfibroblasts.neutrophilscanreleaseoxidants,proteases,leukotrienes,andotherproinflammatorymolecules,suchasplatelet-activatingfactor(paf).anumberof antinflammatorymediatorsarealsopresentinthealveolarmilieu,includinginterleukin-1 receptorantagonist,solubletumornecrosisfactorreceptor,antibodiesagainstinterleukin-8,andcytokinessuchasinterleukin-10and11(notshown).theinfluxofprotein-richedemafluidintothe alveolusleadtotheinactivationofsurfactant.mifdenotesmacrophageinhibitoryfactor(ref.10). moved by diffusion between alveolar epithelial cells. Insoluble protein is thought to be removed by endocytosis and transcytosis by alveolar epithelial cells and phagocytosis by alveolar macrophages (13). Type II alveolar epithelial cells proliferate to cover the injured basement membrane and differentiate into the type I alveolar epithelial cells. Apoptosis is thought to be a major mechanism for the clearance of neutrophils from the injured lung (14). Clinical Evidence High PEEP (15), alveolar recruitment maneuvers, highfrequency oscillatory ventilation (HFOV) (16, 17) and prone positioning (18, 19) may each be useful as rescue therapies in patients with severe hypoxemia due to ALI/ARDS. However, none of these interventions have been shown to improve survival in randomized clinical trials. In comparison, the first randomized clinical trial to demonstrate an improvement in survival utilized low-tidal volume ventilation in patients with ARDS (20). In that study, conventional ventilation was with a tidal volume of 12 ml/kg of body weight with low PEEP, and a goal partial pressure of carbon dioxide of 35 to 38 mmhg. Protective ventilation utilized a goal tidal volume at or below 6 ml/kg with high PEEP, and per- 623

4 Figure2. Mechanismsimportantintheresolutionofacutelunginjuryandacuterespiratorydis tressyndrome.ontheleftsideofthealveolus,thealveolarepithelium isrepopulatedbytheprolif erationanddiferentiationofalveolartype Icels.Resorptionofalveolaredemafluidisshownat thebaseofthealveolus,withsodium andchloridetransportedthroughtheapicalmembraneof type Icels.Sodium istakenupbytheepithelialsodium channel(enac)andthroughthebaso lateralmembraneoftype Icelsbythesodium pump(na + /K + ATPase).Therelevantpathways forchloridetransportareunclear.watermovesthroughwaterchannels,theaquaporins,located primarilyontypeicels.somewatermayalsocrosbyaparacelularroute.solubleproteinis probablyclearedprimarilybyparacelulardifusionandsecondarilybyendocytosisbyalveolar epithelialcels.macrophagesremoveinsolubleproteinandapoptoticneutrophilsbyphagocytosis. Ontherightsideofthealveolus,thegradualremodelingandresolutionofintraalveolarandinter stitialgranulationtisueandfibrosisareshown(ref.10). missive hypercapnia. The mortality rate at 28 days was significantly lower with protective ventilation than with conventional ventilation (38% vs 71%), with less barotrauma and a higher rate of successful weaning from ventilation in the protective ventilation group. On the basis of this study, a larger study was designed by the Acute Respiratory Distress Syndrome Network (ARDSNet), where patients with lung injury were randomly assigned to receive ventilatory support comparing tidal volumes of 12 vs 6 ml/kg (referred to as the low-tidal volume group) of predicted body weight (21) (Table 2), with a goal plateau airway pressure less than 30 cm of water. The initial respiratory rate was set in the range of 18 to 22 breaths per minutes to avoid marked hypercapnia. In the low-tidal, 6 ml/kg, volume group compared to the 12 ml/kg group, the mean tidal volumes on days 1 to 3 were 6.2±0.8 and 11.8± 0.8 ml/kg of predicted body weight (p<0.001), and the mean plateau pressures were 25±6 and 33±8 cm of water (p<0.001), respectively. The low-tidal volume group had a significantly lower mortality rate (31% vs 40%, p=0.007) vs. ventilation at 12 ml/kg of predicted body weight (Table 3). Other positive outcomes included an increased number of ventilator-free days during the first 28 days after randomization in the low-tidal volume group (mean [±SD], 12±11 vs 10±11 days, p=0.007), despite a higher partial pressure of carbon dioxide, otherwise known as permissive hypercapnia. The authors note that given the potentially harmful consequences of permissive hypercapnia including pulmonary vasoconstriction and cerebral vasodilation, permissive hypercapnia should be used with caution in patients with heart disease or signs of elevated intracranial pressure. Glucocorticoids ( GCs ) as end-effectors of the hypothalamic-pituitary-adrenal axis are important natural inhibitors of inflammation (22). However, endogenous GCs are not always effective in suppressing life-threatening systemic inflammation, even though the degree of cortisolemia 624

5 Table2. Base-lineCharacteristicsofthePatients*(NEnglJMed342: ,2000) Characteristics Group receiving lower tidal volumes (n=432) Group receiving traditional tidal volume (n=429) Age (year) 51±17 52±18 Female sex (%) APACHE III score 81±28 84±28 PaO 2 :FiO 2 138±64 134±58 PaO 2 :FiO 2 < Tidal volume (ml) 676± ±125 Minute ventilation (L/min) 13.4± ±4.3 No. of nonpulmonary organ or system 1.8± ±1.0 failures Lung injury (%) Pneumonia Sepsis Aspiration Trauma 13 9 Other causes Multiple transfusions 2 3 * Plus-minus values are mean±sd. Because of rounding, not all percentages total 100. PaO 2 denotes partial pressure of arterial oxygen, and FiO 2 fraction of inspired oxygen. Table3. MainOutcomeVariables*(NEnglJMed342: ,2000) Variables Group receiving lower tidal volumes Group receiving traditional tidal volume p value Death before discharge home and breathing without assistance (%) Breathing without assistance by day 28 (%) <0.001 No. of ventilator-free days, day 1 to day 28 (%) 12±11 10± Barotrauma, day 1 to 28 (%) No. of days without failure of nonpulmonary organs or systems, day 1 to day 28 15±11 12± * Plus-minus values are mean±sd. The number of ventilator-free days is the mean number of days from days from day 1 to day 28 on which the patient had been breathing without assistance for at least 48 consecutive hours. Barotrauma was defined as any new pneumothorax, pneumomediastinum, or subcutaneous emphysema, or a pneumotocele that was more than 2 cm in diameter. correlates with severity of illness and mortality rate (23). Meduri and Chrousor proposed that the failure of endogenous GC to suppress inflammation could be due to tissue resistance, or inadequacy of the level and duration of endogenous GC elevation to suppress a host immune response, or a combination of these two factors (24). Glucocorticoid receptor (GR)-mediated resistance in the presence of systemic inflammation has been studied in experimental models of sepsis and sepsis-induced ARDS (25); the findings suggest that increased levels of exogenous steroids are necessary to activate GR in the setting of systemic inflammation. The patients with ALI/ARDS had persistent elevations in plasma levels of inflammatory cytokines (TNF-α IL-1β and IL-6) and hypothalamic-pituitary-adrenal axis hormones and similar severity of organ dysfunction scores (26). Meduri et al hypothesized that inadequate secretion of cortisol and/or immune tissue resistance to endogenous GCs might explain the observed failure of GR to suppress inflammation in the presence of persistently elevated ACTH and cortisol levels, and they reported that prolonged methylprednisolone administration (2 mg/kg/day) initiated in a patient who had not improved after the onset of ARDS was associated with rapid, progressive, and sustained reductions in plasma and BAL inflammatory cytokines, chemokines, and procollagen levels with parallel significant improvement in lung injury and multiple organ dysfunction syndrome (26). In a randomized, controlled trial by Meduri and colleagues (27), 63 patients received methylprednisolone, and 28 received placebo. The baseline characteristics of each group at study entry were similar, with the exception of a higher proportion of patients with catecholamine-dependent shock in the control group. Although ICU mortality rates were associated with treatment (p=0.03), survival curve for patients randomized to methylprednisolone and placebo for intention-to-treat (n=91) and eligible (n=72) patients at 2, 6, and 12 months were 76% vs 61% (p=0.13), 67% vs 46% (p=0.07), and 63.5% vs 46% (p=0.13), respectively (Fig. 3). There were no significant differences in mortality rates between two groups. The 625

6 Figure3. Survivalcurvesforpatientsrandomized to methylprednisoloneand placebo for intention-to-treat(n=91)andeligible(n=72)patients.kaplan-meierlog-rankpvaluesforthe intention-to-treatandfulyeligiblecurvesare0.06and0.13,respectively.bluelinesandredlines representmethylprednisoloneandplacebo,respectively.survivaldataupto1yearwithintentionto-treatanalysis(dashedlines)of91patientsrandomizedtomethylprednisolone(n=63)vsplacebo (n=28):7days,88.9% vs78.6% (p=0.20);28days,81% vs64.3% (p=0.09);60days,76.2% vs 60.7% (p=0.13);6months,66.7% vs46.4% (p=0.07);and1year,63.5% vs46.4% (p=0.13).survivaldataupto1yearforthe72fulyeligiblepatients(solidlines)randomizedtomethylprednisolone(n=51)vsplacebo(n=21):7days,96.1% vs81% (p=0.06);28days,88.2% vs76.4% (p=0.20); 60days,86.3% vs71.4% (p=0.14);6months,74.5% vs57.1% (p=0.15);and1year,70.6% vs 57.1% (p=0.27)(ref.27). Table4. AnalysisofNO Reference Main Results/Merit Limitation/Demerit NO end-products in the BAL (31) Detectable for 21 days after onset at risk for ARDS patients The number of patients with sustained ARDS declined with time Detectable for 14 days after onset in ARDS patients Low mortality in higher NO on day 3 and 7 after onset EBC nitrite (33) EBC nitrite identify situation of critical mechanical stress (EBC nitrite correlated with tidal volume and expiratory minute volume) EBC nitrite does not correlate with EBC IL-6 and EBC IL-8 The ratio of EBC nitrite and the size of the tidal volume correlated with lung injury Higher baseline levels of urine NO (32) More ventilator-free day More organ-failure-free day Better outcome The role of urinary tract infection Unknown source of the NO Sample collection error Improved outcome after low-tidal strategy Treatment of inhaled NO Meta-analysis Sokol et al. (35) Improvement in oxygenation in the first 4 days after treatment No effect on mortality, ventilator-free day No advantage of specific dose of inhaled NO Adhikari et al. (36) Increased the ratio of PF ratio and decreased the oxygenation index No effect on hospital mortality, duration of ventilation, ventilation-free day No effect on mean pulmonary arterial pressure NO, nitric oxide; BAL, bronchoalveolar lavage; EBC, exhaled breath condensate; IL, interleukin 626

7 Table5. MainOutcomeVariables(NEngJMed354: ,2006) Variables Conservative strategy Liberal strategy p value Death at 60 days (%) Ventilator-free days from day 1 to day ± ±0.5 <0.001 ICU-free days, days 1 to ± ± Organ-failure-free days Days 1 to 7 Cardiovascular failure 3.9± ± CNS failure 3.4± ± Renal failure 5.5± ± Hepatic failure 5.7± ± Coagulation abnormalities 5.6± ± Days 1 to 28 Cardiovascular failure 19.0± ± CNS failure 18.8± ± Renal failure 21.5± ± Hepatic failure 22.0± ± Coagulation abnormalities 22.0± ± Plus-minus values are mean±sd.cns, central nervous system. For this analysis, cardiovascular failure was defined by a systolic blood pressure of 90mmHg or less or the need for a vasopressor (in contrast, shock was defined by a mean arterial pressure of less than 60mmHg or the need for a vasopressor [except a dose of dopamine of 5µg/kg/minute or less]; a coagulation abnormality was defined by a platelet count of 80000/mm 3 or less; hepatic failure was defined by a serum bilirubin level of a t least 2mg/dL; and renal failure was defined by a serum creatinine levels of at least 2mg/dL. We calculated the number of days without organ or system failure by subtracting the number of days with organ failure from the lesser of 28 days or the number of days to death. methylprednisolone-treated patients had a significantly lower rate of infection, however it was notable that among the 27 infections which developed after day 7, 16 were identified in the absence of fever. Treated patients had significant reduction in C-reactive protein levels. As a conclusion, methylprednisolone-induced down-regulation of systemic inflammation was associated with significant improvement in pulmonary and extra-pulmonary organ dysfunction and a reduction in duration of mechanical ventilation and ICU length of stay. Despite the benefits of GC therapy seen in the study, other studies have not shown a benefit of GC therapy on mortality. The NHLBI Acute Respiratory Distress Syndrome Network published the results of a randomized controlled trial of methylprednisolone in ARDS patients of at least 7 days duration (28). Although treatment with methylprednisolone increased the number of ventilator-free days, shock-free days, and ICU-free days during the first month, the hospital mortality rate was 28.6% in the placebo group and 29.3% in the methylprednisolone group at 60 days, and at 180 days, mortality rate was 31.9% and 31.5%, respectively. If initiated more than 14 days after the onset of ARDS, a significant increase in mortality was observed in the methylprednisolone group. These results do not support the routine use of methylprednisolone in ARDS, especially when administered to patients with ARDS duration greater than 14 days. Meduri et al (27) started prolonged low-dose methylprednisolone to severe ARDS patients at early point after onset, and the NHLBI Acute Respiratory Distress Syndrome Network started prolonged low-dose methylprednisolone to persistent ARDS patients at 7-13 days or days after onset ARDS. We suppose that the latter study showed higher APACHE III compared to the former study. As the result, the efficacy of methylprednisolone was different in the survivors of hospital admission between two studies. In meta-analysis assessed through a Bayesian hierarchical model for comparing the odds of developing ARDS and mortality, a possibility of reduced mortality with steroids started after onset of ARDS was suggested, and preventive steroids possibly increase the incidence of ARDS (29). Therefore, the prolonged low-dose glucocorticoid treatment in early ARDS, not persistent ARDS, after the onset may be associated with the reduction in duration of mechanical ventilation and ICU length of stay. Important markers of oxidative injury in the lung include nitrogen oxide species (NOx) (30). Nitric oxide (NO) reacts with superoxide anion to form a highly reactive intermediate known as peroxynitrite (31). As summarized in Table 4, in a single-center clinical study, higher NOx levels in bronchoalveolar lavage fluid from patients with ALI were associated with increased mortality on day 3 and day 7 after ALI, leading to the conclusion that BAL NOx elevation occurs early and is associated with worse outcomes (32). In another observational study, patients with ALI had higher NOx levels in comparison to patients with hydrostatic pulmonary edema (33). In the before-mentioned NHLBI ARDS Network study using low tidal volume ventilation, urine NO levels were collected in a subgroup of 566 excluding 14 grossly contaminated urine samples of the 861 patients, revealing that higher baseline levels of urine NO to urine creatinine (NO/ Cr) were associated with lower mortality, more ventilatorfree days (mean increase, 1.9 days), and more organ-failurefree days (mean increase, 2.3 days) on multivariate analysis. Similar results were shown using urine NO alone. NO/Cr levels were higher on day 3 in the low tidal volume strategy than in the high tidal volume strategy group (p=0.04) (34). 627

8 The presence of higher levels of NO may reflect a greater percentage of intact lung endothelium and epithelium as a result of a less severe initial insult. And endogenous NO may be protective during ALI or endogenous NO may serve as a marker of less severe organ injury or both. Both explanations may be valid in patients with ALI. NO has been shown to be involved in various cell-cell interactions and injury models in the lung, and is produced by alveolar epithelial cells, alveolar macrophages, and endothelial cells of the lung. It has been shown to protect type II pneumocytes from stretch injury (35). It is known to vasodilate the microcirculation, which allows for increased perfusion of tissue beds, improved ventilation-to-perfusion matching, and improved oxygenation (36). Higher NO levels could help prevent further tissue damage by improving oxygen and nutrition delivery to the tissue, and may be protective towards endothelial tissue by decreasing platelet and leukocytes adhesion to the endothelium (36). Given the cellular benefits and studies demonstrating improved outcome with increase NO levels, the possibility of using inhaled NO as a treatment for acute lung injury has generated considerable interest. However, a systemic review and meta-analysis of five randomized, controlled trials evaluating nitric oxide published in 2003 found no benefit on mortality or ventilator-free days; only one trial showed improved oxygenation (37). In another study, Adhikari et al reported using data source of Medline, CINAHL, Embase, and CENTRAL (to October 2006) for ALI/ARDS (38), and the results included 12 trials and a total of 1,237 randomized patients that met inclusion criteria. Inhaled NO did not show a significant effect on hospital mortality (risk ratio 1.10, 95% confidence interval ), duration of ventilation, or ventilator-free days. On the first day of treatment, inhaled NO was associated with small improvements in the ratio of partial pressure of oxygen to fraction of inspired oxygen and the oxygenation index. While it is conceivable that patients who receive inhaled NO will have improved oxygenation, this benefit appears short-lived, disappearing after hours. Therefore, inhaled NO therapy is not recommended as routine management in ALI/ARDS, but can be considered as rescue therapy for refractory hypoxemia on an individual case basis. A well-designed, randomized clinical trial of fluid management (Fluid and Catheter Therapy Trial; FACTT) in ALI/ ARDS was reported in 2006 (39). As discussed previously, pathological changes in ARDS include increased capillary permeability, which worsens as intravascular hydrostatic pressure rises and oncotic pressure falls (11). In terms of fluid management, the conservative approach consists of restricted fluid intake and increased urinary output in an attempt to decrease lung edema and shorten the duration of mechanical ventilation with the potential risk of decreased cardiac output and extra-pulmonary organ dysfunction. In the FACTT trial, a liberal fluid group was compared to a conservative group, and there was a rigorous protocol applied to patients in each group. In terms of overall fluid status, the liberal-strategy group received more fluid (6,992± 502mL) than the conservative-strategy group (-136±491mL) during 7 days (p<0.001) and on day 1 through 4 had a lower urinary output, resulting in a significantly higher cumulative fluid balance. Although indices of end-organ function varied between the 2 groups, most were not significant. Of note, the group managed conservatively had a slightly lower cardiac index which translated to a small increase in the number of cardiovascular-failure free days. In terms of lung function, the conservative-strategy group showed better lung injury scores and oxygenation indices, as well as lower plateau pressures and PEEP. Although there was no significant difference in 60-day mortality between the groups, the conservative-strategy group had more ventilator-free days, days free of central nervous system failure, and ICU-free days during the first 28 days (Table 5). These results were similar to the conclusions of Mitchell et al (40), who conducted a randomized controlled trial contrasting liberal and conservative approaches using pulmonary artery occlusion pressure as a guide, and despite an improvement in ventilator-free days, there was again no mortality benefit in the conservative fluid group. Conclusion The only intervention to achieve mortality benefit has been low-tidal volume ventilation, using a goal tidal volume of 6 ml/kg predicted body weight. Management with a conservative fluid strategy demonstrated consistent benefit in the number of ventilator-free days, shock-free days, and ICU-free days, but this did not translate into a mortality benefit. Based on these results, low-tidal volume ventilation should be the standard of care in an ICU setting, with the added goal of a conservative fluid strategy to reduce time on the ventilator and shorten ICU length of stay. References 1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. 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