摘要
目的：ALI/ARDS是临床常见危重症，目前缺乏有效的治疗方法。动物实验及体外研究表明全氟化碳汽化吸入对ALI/ARDS具有治疗作用。本研究通过随机对照临床试验评价全氟化碳汽化吸入对ALI/ARDS的临床疗效和安全性并对其生物学机制进行初步研究。
方法：（1）应用无创正压通气的ALI/ARDS患者随机分入治疗组和对照组，治疗组连续汽化吸入全氟化碳3天，200ml/次，1次/12小时，对照组汽化吸入注射用水，观察治疗后两组患者氧合指数、气管插管率、28天ICU病死率及并发症差异；（2）应用有创正压通气的ALI/ARDS患者随机分入治疗组和对照组，治疗组连续汽化吸入全氟化碳5天，100ml/次，1次/8小时，对照组汽化吸入注射用水，观察治疗后两组患者氧合指数、28天ICU病死率、28天内无机械通气时间及并发症差异；（3）检测全氟化碳汽化吸入前后ALI/ARDS患者血标本白细胞计数、TNF-a和IL-1β水平变化并应用microRNA芯片和基因表达谱芯片高通量研究全氟化碳吸入前后差异表达的microRNA和基因。
结果：（1）应用无创正压通气ALI/ARDS患者19例入选治疗组，20例入选对照组。与对照组比较，治疗组患者氧合指数(P>0.05)、气管插管需求率（P=0.73）、28天ICU病死率(P=0.71)未见统计学差异，未发现与PFC汽化吸入相关的并发症；（2）应用有创正压通气ALI/ARDS患者12例入选治疗组，10例入选对照组。与对照组比较，治疗组患者氧合指数(P>0.05)、28天内无机械通气时间（P=0.39）、28天ICU病死率(P=0.67)未见统计学差异，治疗组第3天平均动脉压升高（99.57vs.82.44,P=0.02）；（3）全氟化碳汽化吸入后C反应蛋白出现下降趋势，但与对照组比较未达到统计学差异（P>0.05），对白细胞计数、TNF-a、IL-1β水平无影响。全氟化碳汽化吸入导致miR-30C-1-3p、 miR-3178、 miR-4534、hsa-miR-4725-3p、miR-92b-5p共5个miRNA和255条基因表达出现变化。
结论：（1）应用无创正压通气汽化吸入全氟化碳治疗ALI/ARDS临床患者与常规无创正压通气治疗比较疗效无差异且安全；（2）应用有创正压通气汽化吸入全氟化碳治疗ALI/ARDS临床患者与常规有创正压通气治疗比较疗效无差异但可能造成血流动力学改变；（3）全氟化碳汽化吸入可能通过影响多个miRNA和基因的表达发挥生物学作用。
Objective：Acute lung injury (ALI)/Acute Respiratory Distress Syndrome (ARDS)is a serious and common condition for which there are currently no specific strategiesfor treatment. It has been proved that perfluorocarbon vaporization inhalation hastherapeutic effects on ALI/ARDS in animal models and vitro studies. The study aimedto evaluate the clinical effects, mechanism and safety of perfluorocarbon vaporizationinhalation through randomized controlled trial.
Methods:（1）The ALI/ARDS patients who received noninvasive positive pressureventilation (NPPV) were randomly divided into treatment or control group. Patients intreatment group received200ml perfluorocarbon vaporization inhalation every12hoursfor3days successively, patients in control group received sterile water inhalation. Aftertreatment, a comparison was made in oxygenation index, the proportion of patientsrequiring intubation, mortality in ICU within28days and the incidence ofcomplications between the two groups;（2）The ALI/ARDS patients who receivedinvasive positive pressure ventilation (IPPV) were randomly divided into treatment orcontrol group. Patients in treatment group received100ml perfluorocarbon vaporizationinhalation every8hours for5days successively, patients in control group receivedsterile water inhalation. After treatment, a comparison was made in oxygenation index,mortality in ICU within28days, the numbers of ventilator-free days between day1andday28, the incidence of complications between the two groups;（3）The level of whiteblood cell count, TNF-a and IL-1βwere detected before and after the therapy.ThemicroRNAs and genes differently expressed before and after the inhalation of theperfluorocarbon were detected by the application of microRNA and cDNA microarrays.
Results（:1）19patients who received NPPV were divided into treatment group and20patients were divided into control group. There was no significant difference inoxygenation index(P>0.05), the proportion of patients requiring intubation（P=0.73）,mortality in ICU within28days (P=0.71) and the incidence of complications betweenthe two groups;
（2）12patients who received IPPV were divided into treatment group and10patients were divided into control group. There was no significant difference inoxygenation index(P>0.05), the numbers of ventilator-free days between day1and day28（P=0.39），mortality in ICU within28days (P=0.67) between the two groups. But onthe third days, the mean arterial blood pressure in treatment group was higher than thatin the control group（99.57vs.82.44, P=0.02）;
（3）The level of C-reactive protein of treatment group declined but was notsignificantly different from that of the control group (P>0.05). There was nosignificant difference in the level of white blood cell count, TNF-a and IL-1βbetweenthe two groups. Different expressions were detected in5miRNAs (miR-30C-1-3p,miR-3178, miR-4534, hsa-miR-4725-3p, miR-92b-5p) and255genes before and afterthe inhalation of the perfluorocarbon.
Conclusions:（1）The efficacy of perfluorocarbon vaporization inhalation throughNPPV is not different from NPPV and is safe for ALI/ARDS patients;（2）The efficacyof perfluorocarbon vaporization inhalation through IPPV is not different from IPPV forALI/ARDS patients, but it may result in hemodynamic changes;（3）Perfluorocarbonvaporization inhalation may play a biological role by affecting the expression in anumber of miRNAs and genes.
引文
[1] Blank R, Napolitano LM. Epidemiology of ARDS and ALI. Crit Care Clin.2011,27(3):439-58.
[2] Tawfic QA, Kausalya R. Liquid ventilation. Oman Med J.2011,26(1):4-9.
[3] Chang LP, Lai YS, Wu CJ,et al. Liquid perfluorochemical inhibits inducible nitricoxide synthase expression and nitric oxide formation in lipopolysaccharide-treatedRAW264.7macrophages. J Pharmacol Sci.2009,111(2):147-54.
[4] Angelova M, Nakazawa K, Yokoyama K, et al. Effects of partial liquid ventilationon lipopolysaccharide-induced inflammatory responses in rats. Resuscitation.2004Jul;62(1):89-96.
[5] Hirschl RB, Croce M, Gore D,et al. Prospective, randomized, controlled pilot studyof partial liquid ventilation in adult acute respiratory distress syndrome.Am J RespirCrit Care Med.2002,165(6):781-7.
[6] Kacmarek RM, Wiedemann HP, Lavin PT,et al. Partial liquid ventilation in adultpatients with acute respiratory distress syndrome.Am J Respir Crit Care Med.2006,173(8):882-9.
[7] Bleyl JU, Ragaller M, Tsch U, et al. Vaporized perfluorocarbon improvesoxygenation and pulmonary function in an ovine model of acute respiratory distresssyndrome. Anesthesiology.1999Aug;91(2):461-9.
[8]赵晓巍，张健鹏，黄贤，等.全氟化碳汽化吸入治疗兔海水淹溺型呼吸窘迫综合征的实验研究.中华结核和呼吸杂志.2010,33(3):169-173.
[9]秦鑫，刘又宁.汽化吸入全氟化碳对急性肺损伤小猪小肠黏膜上皮细胞凋亡的影响.中华医学杂志.2007,87(7):493-496.
[10] Zhan Q, Sun B, Liang L, et al. Early use of noninvasive positive pressureventilation for acute lung injury: a multicenter randomized controlled trial.Crit CareMed.2012,40(2):455-60.
[11]中华医学会重症医学分会.急性肺损伤/急性呼吸窘迫综合征诊断和治疗指南.中国实用外科杂志.2007,27(1):1-6.
[12] Cortes I, Penuelas O, Esteban,A. Acute respiratory distress syndrome: evaluationand management. Minerva Anestesiol.2012,78(3):343-357.
[13] Ventilation with lower tidal volumes as compared with traditional tidalvolumes for acute lung injury and the acute respiratory distress syndrome. TheAcute Respiratory Distress Syndrome Network. N Engl J Med.2000,342(18):1301-8.
[14] Bleyl JU, Ragaller M, Tsch U, et al. Changes in pulmonary function andoxygenation during application of perfluorocarbon vapor in healthy and oleicacid-injured animals. Crit Care Med.2002,30(6):1340-7.
[15] de Abreu MG, Quelhas AD, Spieth P, et al. Comparative effects of vaporizedperfluorohexane and partial liquid ventilation in oleic acid-induced lung injury.Anesthesiology.2006,104(2):278-89.
[16] Spieth PM, Knels L, Kasper M, et al. Effects of vaporized perfluorohexane andpartial liquid ventilation on regional distribution of alveolar damage in experimentallung injury. Intensive Care Med.2007Feb;33(2):308-14.
[17] Goodman RB, Pugin J, Lee JS, et al.Cytokine-mediated inflammation in acutelung injury. Cytokine Growth Factor Rev.2003,14(6):523-35.
[18] Oglesby IK, McElvaney NG, Greene CM. et al. MicroRNAs in inflammatory lungdisease--master regulators or target practice? Respir Res.2010,28;11:148.
[19] Nana-Sinkam SP, Karsies T, Riscili B, et al. Lung microRNA: from developmentto disease. Expert Rev Respir Med.2009,3(4):373-85.
[20] Zhou T, Garcia JG, Zhang W. Integrating microRNAs into a system biologyapproach to acute lung injury.Transl Res.2011,157(4):180-90.
[1] Reynolds HN, McCunn M, Borg U, et al. Acute respiratory distress syndrome:estimated incidence and mortality rate in a5million-person population base. Crit Care.1998,2(1):29–34.
[2] Luhr OR, Antonsen K, Karlsson M, et al. Incidence and mortality after acuterespiratory failure and acute respiratory distress syndrome in Sweden, Denmark, andIceland. The ARF Study Group. Am J Respir Crit Care Med.1999,159(6):1849–61.
[3] Bersten AD, Edibam C, Hunt T, et al. Incidence and mortality of acute lung injuryand the acute respiratory distress syndrome in three Australian States. Am J Respir CritCare Med.2002,165(4):443–8.
[4] Goss CH, Brower RG, Hudson LD, et al. Incidence of acute lung injury in theUnited States. Crit Care Med.2003,31(6):1607–11.
[5] Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lunginjury. N Engl J Med.2005,353(16):1685–93.
[6] Webster NR, Cohen AT, Nunn JF. Adult respiratory distress syndrome--how manycases in the UK? Anaesthesia.1988,43(11):923-6.
[7] Hughes M, MacKirdy FN, Ross J, et al. Acute respiratory distress syndrome: anaudit of incidence and outcome in Scottish intensive care units. Anaesthesia.2003,58(9):838-45.
[8] Li G, Malinchoc M, Cartin-Ceba R, et al. Eight-year trend of acute respiratory distress syndrome:a population-based study in Olmsted County, Minnesota. Am J Respir Crit Care Med.2011,183(1):59-66.
[9] Lu Y, Song Z, Zhou X, et al. A12-month clinical survey of incidence and outcome of acuterespiratory distress syndrome in Shanghai intensive care units. Intensive Care Med.2004,30(12):2197-203.
[10] Brochard L, Rouby JJ. Changing mortality in acute respiratory distress syndrome?Yes, we can! Am J Respir Crit Care Med.2009,179(3):177–8.
[11] Milberg JA, Davis DR, Steinberg KP, et al. Improved survival of patients withacute respiratory distress syndrome (ARDS):1983–1993. JAMA.1995,273(4):306–9.
[12] Abel SJ, Finney SJ, Brett SJ, et al. Reduced mortality in association with theacute respiratory distress syndrome (ARDS). Thorax.1998,53(4):292–4.
[13] Stapleton RD, Wang BM, Hudson LD, et al. Causes and timing of death inpatients with ARDS. Chest.2005,128(2):525–32.
[14] Rocco TR Jr, Reinert SE, Cioffi W, et al. A9-year,single-institution, retrospectivereview of death rate and prognostic factors in adult respiratory distress syndrome. AnnSurg.2001,233(3):414–22.
[15] Krafft P, Fridrich P, Pernerstorfer T, et al. The acute respiratory distress syndrome:definitions, severity and clinical outcome. An analysis of101clinical investigations.Intensive Care Med.1996,22(6):519–29.
[16] Erickson SE, Martin GS, Davis JL, et al. Recent trends in acute lung injurymortality:1996–2005. Crit Care Med.2009,37(5):1574–9.
[17] Spragg RG, Bernard GR, Checkley W, et al. Beyond mortality: future clinicalresearch in acute lung injury. Am J Respir Crit Care Med.2010,181(10):1121–7.
[18] Zambon M, Vincent JL. Mortality rates for patients with acute lung injury/ARDShave decreased over time. Chest.2008,133(5):1120–7.
[19] Phua J, Badia JR, Adhikari NK, et al. Has mortality from acute respiratory distresssyndrome decreased over time? A systematic review. Am J Respir Crit Care Med.2009,179(3):220–7.
[20] Montgomery AB, Stager MA, Carrico CJ, et al. Causes of mortality in patientswith the adult respiratory distress syndrome. Am Rev Respir Dis.1985,132(3):485-9.
[21] Garber BG, Hebert PC, Yelle JD, et al. Adult respiratory distress syndrome:a systemic overview of incidence and risk factors. Crit Care Med.1996,24(4):687–95.
[22] Pelosi P, Caironi P, Gattinoni L. Pulmonary and extrapulmonary forms of acuterespiratory distress syndrome. Semin Respir Crit Care Med.2001,22(3):259–68.
[23] Pelosi P, D’Onofrio D, Chiumello D, et al. Pulmonary and extrapulmonary acuterespiratory distress syndrome are different. Eur Respir J Suppl.2003,42:48s–56s.
[24] Agarwal R, Srinivas R, Nath A, et al. Is the mortality higher in the pulmonary vsthe extrapulmonary ARDS? A meta analysis. Chest.2008,133(6):1463–73.
[25] Gao L, Barnes KC. Recent advances in genetic predisposition to clinical acute lunginjury. Am J Physiol Lung Cell Mol Physiol.2009,296(5):L713-25.
[26] Berkowitz DM, Danai PA, Eaton S, et al. Alcohol abuse enhances pulmonaryedema in acute respiratory distress syndrome. Alcohol Clin Exp Res.2009,33(10):1690-6.
[27] Gajic O, Dabbagh O, Park PK, et al. Early identification of patients at risk of acutelung injury: evaluation of lung injury prediction score in a multicenter cohort study. AmJ Respir Crit Care Med.2011,183(4):462-70.
[28] Moss M, Guidot DM, Steinberg KP, et al. Diabetic patients have a decreasedincidence of acute respiratory distress syndrome. Crit Care Med.2000,28(7):2187-92.
[29] Erickson SE, Shlipak MG, Martin GS, et al. Racial and ethnic disparities inmortality from acute lung injury. Crit Care Med.2009,37(1):1-6.
[30] Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors ofthe acute respiratory distress syndrome. N Engl J Med.2003,348(8):683-93.
[31] Davydow DS, Desai SV, Needham DM, et al. Psychiatric morbidity in survivors ofthe acute respiratory distress syndrome: a systematic review. PsychosomMed.2008,70(4):512-19.
[32] Hopkins RO, Key CW, Suchyta MR, et al. Risk factors for depression and anxietyin survivors of acute respiratory distress syndrome. Gen Hosp Psychiatry.2010,32(2):147-55.
[33] Hopkins RO, Weaver LK, Collingridge D, et al. Two-year cognitive, emotional,and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir CritCare Med.2005,171(4):340-7.
[34] Bernard GR, Artigas A, Brigham KL, et al. The American-European ConsensusConference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trialcoordination. Am J Respir Crit Care Med.1994,149(3Pt1):818–24.
[35] Esteban A, Fernandez-Segoviano P, Frutos-Vivar F, et al. Comparison of clinicalcriteria for the acute respiratory distress syndrome with autopsy findings. Ann InternMed.2004,141(6):440–5.
[36] Stewart RM, Park PK, Hunt JP, et al. Less is more: improved outcomes in surgicalpatients with conservative fluid administration and central venous catheter monitoring. JAm Coll Surg.2009,208(5):725–35.
[37] Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonary-artery versus centralvenous catheter to guide treatment of acute lung injury. N Engl J Med.2006,354(21):2213–24.
[38] Murray JF, Matthay MA, Luce JM, et al. An expanded definition of the adultrespiratory distress syndrome. Am Rev Respir Dis.1988,138(3):720–3.
[39] Peek GJ, Clemens F, Elbourne D, et al. CESAR: conventional ventilatory supportvs extracorporeal membrane oxygenation for severe adult respiratory failure.BMCHealth Serv Res.2006,6:163.
[40] Ferguson ND, Davis AM, Slutsky AS, et al. Development of a clinical definitionfor acute respiratory distress syndrome using the Delphi technique. J Crit Care.2005,20(2):147–54.
[41] Ferguson ND, Frutos-Vivar F, Esteban A, et al. Acute respiratory distresssyndrome: underrecognition by clinicians and diagnostic accuracy of three clinicaldefinitions. Crit Care Med.2005,33(10):2228–34.
[42] Ventilation with lower tidal volumes as compared with traditional tidalvolumes for acute lung injury and the acute respiratory distress syndrome. TheAcute Respiratory Distress Syndrome Network. N Engl J Med.2000,342(18):1301-8.
[43] Villar J, Kacmarek RM, Perez-Mendez L, et al. A high positive end-expiratorypressure, low tidal volume ventilatory strategy improves outcome in persistent acuterespiratory distress syndrome: a randomized, controlled trial. Crit Care Med.2006,34(5):1311-18.
[44] Determann RM, Royakkers A, Wolthuis EK, et al. Ventilation with lower tidalvolumes as compared with conventional tidal volumes for patients without acute lunginjury: a preventive randomized controlled trial. Crit Care.2010,14(1):R1.
[45] Cheng IW, Eisner MD, Thompson BT, et al. Acute effects of tidal volume strategyon hemodynamics, fluid balance, and sedation in acute lung injury. Crit CareMed.2005,33(1):63-70.
[46] Kahn JM, Andersson L, Karir V, et al. Low tidal volume ventilation does notincrease sedation use in patients with acute lung injury. Crit Care Med.2005,33(4):766-71.
[47] Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positiveend-expiratory pressures in patients with the acute respiratory distress syndrome.N Engl J Med.2004,351(4):327-36.
[48] Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidalvolumes, recruitment maneuvers, and high positive end-expiratory pressure foracute lung injury and acute respiratory distress syndrome: a randomized controlled trial.JAMA.2008,299(6):637-45.
[49] Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting inadults with acute lung injury and acute respiratory distress syndrome: a randomizedcontrolled trial. JAMA.2008,299(6):646-55.
[50] Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratorypressure in patients with acute lung injury and acute respiratory distresssyndrome:systematic review and meta-analysis. JAMA.2010,303(9):865-73.
[51] Gattinoni L, Caironi P, Valenza F, et al. The role of CT-scan studies for thediagnosis and therapy of acute respiratory distress syndrome. Clin Chest Med.2006,27(4):559-70.
[52] Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation guided by esophagealpressure in acute lung injury. N Engl J Med.2008,359(20):2095-104.
[53] Bouhemad B, Brisson H, Le-Guen M, et al. Bedside ultrasound assessment ofpositive end-expiratory pressure-induced lung recruitment. Am J Respir Crit CareMed.2011,183(3):341-7.
[54] Fan E, Wilcox ME, Brower RG, et al. Recruitment maneuvers for acute lunginjury:a systematic review. Am J Respir Crit Care Med.2008,178(11):1156-63.
[55] Gattinoni L, Tognoni G, Pesenti A, et al. Effect of prone positioning on thesurvival of patients with acute respiratory failure. N Engl J Med.2001,345(8):568-73.
[56] Guerin C, Gaillard S, Lemasson S, et al. Effects of systematic prone positioning inhypoxemic acute respiratory failure: a randomized controlled trial. JAMA.2004,292(19):2379-87.
[57] Mancebo J, Fernández R, Blanch L, et al. A multicenter trial of prolonged proneventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med.2006,173(11):1233-9.
[58] Taccone P, Pesenti A, Latini R, et al. Prone positioning in patients with moderateand severe acute respiratory distress syndrome: a randomized controlled trial. JAMA.2009,302(18):1977-84.
[59] Gattinoni L, Carlesso E, Taccone P, et al. Prone positioning improves survival insevere ARDS: a pathophysiologic review and individual patient meta-analysis. MinervaAnestesiol.2010,76(6):448-54.
[60] Chan KP, Stewart TE, Mehta S. High-frequency oscillatory ventilation for adultpatients with ARDS. Chest.2007,131(6):1907-16.
[61] Downar J, Mehta S. Bench-to-bedside review: high-frequency oscillatory ventilation in adultswith acute respiratory distress syndrome. Crit Care,2006,10(6):240
[62] Derdak S, Mehta S, Stewart TE, et al. High-frequency oscillatory ventilation for acuterespiratory distress syndrome in adults: a randomized, controlled trial.Am J Respir Crit Care Med.2002,166(6):801-8.
[63] Bollen CW, van Well GT, Sherry T, et al. High frequency oscillatory ventilation comparedwith conventional mechanical ventilation in adult respiratory distress syndrome: a randomizedcontrolled trial [ISRCTN24242669]. Crit Care.2005,9(4):R430-9.
[64] Sud S, Sud M, Friedrich JO, et al. High frequency oscillation in patients with acutelung injury and acute respiratory distress syndrome (ARDS): systematic review andmeta-analysis. BMJ.2010,340:c2327.
[65] Lehmler HJ. Anti-inflammatory effects of perfluorocarbon compounds. Expert RevRespir Med.2008,2(2):273-89.
[66] Hirschl RB, Parent A, Tooley R, et al. Liquid ventilation improves pulmonaryfunction, gas exchange, and lung injury in a model of respiratory failure. Ann Surg.1995;221(1):79-88.
[67] Hirschl RB, Croce M, Gore D,et al. Prospective, randomized, controlled pilot studyof partial liquid ventilation in adult acute respiratory distress syndrome.Am J RespirCrit Care Med.2002,165(6):781-7.
[68] Kacmarek RM, Wiedemann HP, Lavin PT,et al. Partial liquid ventilation in adultpatients with acute respiratory distress syndrome.Am J Respir Crit Care Med.2006,173(8):882-9.
[69] Cortes I, Penuelas O, Esteban,A. Acute respiratory distress syndrome: evaluation andmanagement. Minerva Anestesiol.2012,78(3):343-357.
[70] Bleyl JU, Heller AR, Heintz M, et al. Effects of perfluorohexane vapor in the treatment ofexperimental lung injury. Pulm Pharmacol Ther.2010,23(5):450-5.
[71] Bleyl JU, Ragaller M, Tsch U, et al. Vaporized perfluorocarbon improvesoxygenation and pulmonary function in an ovine model of acute respiratory distresssyndrome. Anesthesiology.1999,91(2):461-9.
[72] Peter JV, John P, Graham PL, et al. Corticosteroids in the prevention and treatmentof acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ.2008,336(7651):1006-9.
[73] Bernard GR, Luce JM, Sprung CL, et al. High-dose corticosteroids in patients withthe adult respiratory distress syndrome. N Engl J Med.1987,317(25):1565-70.
[74] Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety ofcorticosteroids for persistent acute respiratory distress syndrome. N Engl J Med.2006,354(16):1671-84.
[75] Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in earlysevere ARDS: results of a randomized controlled trial. Chest.2007,131(4):954-63.
[76] Lamontagne F, Briel M, Guyatt GH,et al. Corticosteroid therapy for acute lunginjury, acute respiratory distress syndrome, and severe pneumonia: a meta-analysis ofrandomized controlled trials. J Crit Care,2010,25(3):420-435
[77] Rossaint R, Falke KJ, Lopez F, et al. Inhaled nitric oxide for the adult respiratorydistress syndrome. N Engl J Med.1993,328(6):399-405.
[78] Hsu CW, Lee DL, Lin SL, et al. The initial response to inhaled nitric oxidetreatment for intensive care unit patients with acute respiratory distress syndrome.Respiration.2008,75(3):288-95.
[79] Adhikari NK, Burns KE, Friedrich JO, et al. Effect of nitric oxide on oxygenationand mortality in acute lung injury: systematic review and meta-analysis. BMJ.2007,334(7597):779
[80] Afshari A, Brok J, Moller AM, et al. Inhaled nitric oxide for acute respiratorydistress syndrome (ARDS) and acute lung injury in children and adults. CochraneDatabase Syst Rev.2010,(7):CD002787.
[81] Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral feeding witheicosapentaenoic acid, gamma-linolenic acid, and antioxidants in patients withacute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group.Crit Care Med.1999,27(8):1409-20.
[82] Marik PE, Zaloga GP. Immunonutrition in critically ill patients: a systematicreview and analysis of the literature. Intensive Care Med.2008,34(11):1980-90.
[83] Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3fatty acid,gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA,2011,306(14):1574-1581
[84] Groeneveld AB. Vascular pharmacology of acute lung injury and acute respiratorydistress syndrome. Vascul Pharmacol.2002,39(4-5):247-56.
[85] Sakr Y, Vincent JL, Reinhart K, et al. High tidal volume and positive fluid balanceare associated with worse outcome in acute lung injury. Chest.2005,128(5):3098-108.
[86] Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of twofluid-management strategies in acute lung injury. N Engl J Med.2006,354(24):2564-75.
[87] Wheeler AP, Bernard GR, Thompson BT, et al. Pulmonary-artery versus centralvenous catheter to guide treatment of acute lung injury. N Engl J Med,2006,354(21):2213-2224
[88] Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority ofpatients with acute lung injury and the acute respiratory distress syndrome. Am J RespirCrit Care Med.2001,163(6):1376-83.
[89] Matthay MA. Alveolar fluid clearance in patients with ARDS: does it make adifference? Chest.2002,122(6Suppl):340S-343S.
[90] Perkins GD, McAuley DF, Thickett DR, et al. The beta-agonist lung injury trial(BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med.2006,173(3):281-7.
[91] National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome(ARDS) Clinical Trials Network, Matthay MA, Brower RG, Carson S, etal.Randomized, placebo-controlled clinical trial of an aerosolized β-agonist fortreatment of acute lung injury. Am J Respir Crit Care Med.2011,184(5):561-8.
[92] Gao SF, Perkins GD, Gates S, et al. Effect of intravenous beta-2agonist treatmenton clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre,randomised controlled trial. Lancet.2012,379(9812):229-235.
[93] Perkins GD, Park D, Alderson D, et al. The Beta Agonist Lung Injury TrIal(BALTI)--prevention trial protocol. Trials.2011,12:79
[94] Gainnier M, Roch A, Forel JM, et al. Effect of neuromuscular blocking agents ongas exchange in patients presenting with acute respiratory distress syndrome.Crit CareMed.2004,32(1):113-19.
[95] Forel JM, Roch A, Marin V, et al. Neuromuscular blocking agents decreaseinflammatory response in patients presenting with acute respiratory distresssyndrome. Crit Care Med.2006,34(11):2749-57.
[96] Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acuterespiratory distress syndrome. N Engl J Med.2010,363(12):1107-16.
[97] Hamm H, Fabel H, Bartsch W. The surfactant system of the adult lung: physiologyand clinical perspectives. Clin Investig.1992,70(8):637-57.
[98] Gunther A, Siebert C, Schmidt R, et al. Surfactant alterations in severe pneumonia,acute respiratory distress syndrome, and cardiogenic lung edema. Am J Respir Crit CareMed.1996,153(1):176-84.
[99] Baker CS, Evans TW, Randle BJ, et al. Damage to surfactant-specific protein inacute respiratory distress syndrome. Lancet.1999,353(9160):1232-7.
[100] Davidson WJ, Dorscheid D, Spragg R, et al. Exogenous pulmonary surfactant forthe treatment of adult patients with acute respiratory distress syndrome: results of ameta-analysis. Crit Care.2006,10(2):R41.
[101] Zeiher BG, Artigas A, Vincent JL, et al. Neutrophil elastase inhibition in acutelung injury: results of the STRIVE study. Crit Care Med.2004,32(8):1695-702.
[102] Lelcuk S, Huval WV, Valeri CR, et al. Inhibition of ischemia-inducedthromboxane synthesis in man. J Trauma.1984,24(5):393-6.
[103] Williams JG, Maier RV. Ketoconazole inhibits alveolar macrophage productionof inflammatory mediators involved in acute lung injury (adult respiratory distresssyndrome). Surgery.1992,112(2):270-7.
[104] Yu M, Tomasa G. A double-blind, prospective, randomized trial of ketoconazole,a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distresssyndrome. Crit Care Med.1993,21(11):1635-42.
[105] Slotman GJ, Burchard KW, D’Arezzo A, et al. Ketoconazole prevents acuterespiratory failure in critically ill surgical patients. J Trauma.1988,28(5):648-54.
[106] Ketoconazole for early treatment of acute lung injury and acute respiratorydistress syndrome: a randomized controlled trial. The ARDS Network. JAMA.2000,283(15):1995-2002.
[107] Randomized, placebo-controlled trial of lisofylline for early treatment of acutelung injury and acute respiratory distress syndrome. The ARDS Network. Crit CareMed.2002,30(1):1-6
[108] Zapol WM, Snider MT, Hill JD, et al. Extracorporeal membrane oxygenation insevere acute respiratory failure. A randomized prospective study.JAMA.1979,242(20):2193-6.
[109] Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment ofconventional ventilatory support versus extracorporeal membrane oxygenation forsevere adult respiratory failure (CESAR): a multicentre randomised controlled trial.Lancet.2009,374(9698):1351-63
[110] Matthay MA, Goolaerts A, Howard JP, et al. Mesenchymal stem cells for acute lung injury:preclinical evidence. Crit Care Med.2010,38(10Suppl): S569-73.
[111] Hayes M, Curley G, Laffey JG. Mesenchymal stem cells-a promising therapy for AcuteRespiratory Distress Syndrome. F1000Med Rep.2012,4:2.