小儿急性低氧性呼吸衰竭治疗策略前瞻性多中心临床流行病学研究
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摘要
背景
小儿急性低氧性呼吸衰竭(AHRF)是儿童重症监护室(PICU)病儿常见的住院及病死原因,多演变为急性呼吸窘迫综合征(ARDS),是PICU中最为棘手的危重症之一。国外小儿ARDS在PICU的患病率在0.7-4.2%左右,病死率在20-75%左右,国内PICU中ARDS发病率1.44-2.7%、病死率46.4-60.3%,AHRF发病率4%、病死率41.8%。以往AHRF多由于呼吸道细菌感染形成肺炎,缺乏有效呼吸支持演变而成。由于二十多年来逐渐开始在省市级医院普及呼吸机为中心的呼吸支持与危重监护技术应用,可以使大量致死性病例得以存活。但是近年来各种病毒性呼吸系统感染,如手足口病及甲型H1N1,其突发性的流行以及相对复杂的肺及肺外脏器损害为特征的AHRF病例及其高致死性比例,对普及以呼吸机为中心的呼吸支持与危重监护技术提出新挑战。
上世纪90年代围绕呼吸机治疗成人ARDS,提出了肺保护性通气策略的概念,包括小潮气量通气、允许性高碳酸血症、俯卧位通气、开放肺技术及高频通气等。小潮气量通气的目的在于防止由于肺泡的过度膨胀及肺泡内压力过高造成的呼吸机相关性肺损伤,并能够相对减弱机械牵张带来肺促炎症介质合成释放导致的炎症性损害。目前,由美国ARDS协作网完成的小潮气量通气随机对照研究,是唯一明确能降低病人死亡率的策略,小潮气量通气策略(容量控制模式下潮气量6ml/kg、平台压小于30cmH2O)可将ARDS病人的死亡率从38.9%(对照组12ml/kg)降到31%。该研究为小潮气量肺保护性通气策略在成人ARDS呼吸支持治疗中的有效性和安全提供了有力的证据。但小潮气量通气策略在临床常规治疗中的效果尚不及临床对照研究报道那么显著,而且缺乏在小儿ARDS病例中的比较研究报道。按体表面积小儿的潮气量较成人相对较小：2月-1岁(120ml/m2),1-3岁(144ml/m2),成人(294ml/m2)。小潮气量机械通气在实际操作中小儿与成人在通气模式、潮气量的等参数应该是不完全相同的,其是否普遍的适用于儿科仍有疑问。目前国内外尚未有儿科肺保护性通气策略多中心随机对照研究的数据。国内2004年起本实验室组织开展了全国性小儿ARDS前瞻性临床流行病学研究,纳入病例中位年龄2.0岁,小于6岁者63.8%(69/105),机械通气病人86.6%采用压力控制模式通气,纳入后1-3天所测得Vte10.4±5.4ml/kg.2006-2007年本实验室再组织全国26家PICU参与的小儿AHRF多中心研究中,纳入病例中位年龄11个月,AHRF病死率降为41.8%,ARDS病死率降为约46.4%,压力控制模式是主要的通气模式占93%,纳入后1-3天所测得Vte8.8ml/kg(8.0-12),小于6岁小儿占所有收治AHRF的80%以上。此外,该研究也发现纳入初期1-7天的液体负平衡与存活有关联。为此,我们于2008年设计了专门针对该年龄层小儿(29天≤年龄<6岁)限制潮气量和控制液体平衡的机械通气治疗AHRF前瞻性、多中心非对照性临床干预研究。
目的
评估小潮气量肺保护性通气策略治疗小儿低氧性呼吸衰竭的疗效及安全性。了解继2次AHRF的多中心研究后,小儿AHFR在我国PICU中的发生率、原发病、病死率、死亡风险因素及疾病负担等情况有无改变。了解和评估各协作单位在AHRF治疗中对小潮气量肺保护性通气和液体控制策略的实施情况,进一步提高协作单位对多中心研究的方案执行依从性及质量控制能力,为将来开展高标准的小儿多中心随机对照的肺保护性通气策略干预研究奠定基础。
方法
本研究为带有干预性质的非对照的前瞻性多中心临床流行病学研究。在原有小儿AHRF协作组的基础上,共有全国24家单位的PICU参加。参加单位按所在省、市2009年全国人均GDP及全国城镇居民人均可支配收入作了排名,前11家作为经济发达地区医院,其余13家为欠发达地区医院。另外,24家单位中有12家为大学医院。研究时间从2009年1月1日至2009年12月31日(各家医院均为12个月),对所有入住PICU、重点人群(29天≤年龄<6岁)进行病例筛查并对其中的AHRF病人进行前瞻性的调查。PICU危重病儿收治数按国内小儿危重病例评分及美国PICU入出院指南进行筛选后确定,作为计算小儿AHRF发生率的基数。AHRF的诊断标准：急性起病(≤2周),PaO2≤50mmHg或PaO2/FiO2≤250mmHg,气管插管机械通气(Fi02≥30%、PEEP≥2cmH2O方能维持PaO2≥60mmHg或经皮脉冲血氧饱和度(SpO2)≥90%)12小时以上,且通气12小后仍存在呼吸衰竭,PaO2/FiO2≤250mmHg。ALI/ARDS按1994年北美-欧洲(AECC)议定标准进行诊断,其中包括：1)急性起病(≤2周)；2)PaO2/FiO2≤300mmHg(ALI)或PaO2/FiO2≤200mmHg (ARDS);3)胸片示两肺渗出影；4)无左心房高压的临床证据(肺动脉楔压≤18mmHg或用床旁彩超诊断)。
AHRF患儿入选后,每天收集一次数据。数据包括：人口学特征、呼吸机参数、血气、肺力学及血流动力学指标、病人预后和疾病负担等。数据记录到纳入后28天、出院或病死,以先发生者为准。各单位每个月上报PICU收治病人的总体数据。由复旦大学附属儿科医院小儿呼吸与危重病实验室为调查协调中心,负责管理调查工作和数据质量的监控。所有资料应用统计软件SPSS13.0进行统计分析。计量资料中连续变量呈正态分布者表示为x(SD),均数比较采用单因素方差分析；偏态分布者表示为中位数(P25-P75),均数比较采用秩和检验分析。对死亡风险因素进行归入二元logistic回归模型进行逐步回归分析,结果用比值比(OR)及95%可信限(CI)来表示。
结果
1全年24家PICU共收治病人15,462例,其中危重病例12,176例(78.7%),机械通气病例数3,689(30.3%),总病死1,244例(包括放弃出院3天内死亡546例),全年PICU平均病死率10.2%,另有放弃治疗出院1,786例(14.7%)。实际纳入AHRF病人401例,所有的病例都进行了机械通气治疗。符合ALI的诊断标准396例(98.75%),ALI病人中有320例(80.8%)符合ARDS诊断标准。纳入后又有28例ALI病例最后发展为ARDS,最后诊断ARDS病例348例,AHRF.ALI及ARDS病例数占PICU危重病例总数的比例分别为3.29%、3.25%、2.86%。
2AHRF病例中,汉族占绝大部分98.75%,男女之比为2.1：1。中位年龄0.8岁(0.2-2.3)。小于1岁者(未过第1个生日)占53.9%(216例),小于2岁者占70.6%(283例)。AHRF纳入病例数及与PICU危重病例的比例在12个月中分布冬春多于夏秋。
3AHRF以肺内疾病原发者占97.5%,肺炎95.0%,脓毒症143例35.6%(其中肺炎同时符合脓毒症标准的有141例占35.2%)。甲型H1N1流感共9例,死亡2例；麻疹合并肺炎5例,死亡2例；手足口病5例,死亡3例
4AHRF病儿总住院病死率30.2%(121／401),纳入后90天总计死亡124例,90天病死率30.9%(124／401),与住院病死率基本相同,低于2006年国内小儿AHRF多中心研究AHRF病死率41.8%(P<0.001)。
5AHRF病死病人纳入后中位生存时间6.6天(P25-P753.4-12.2),纳入28天平均无机械通气日(VDF)为13.6天,中位值18.7(0-23.0)。存活组VFD中位值21.8天(17.8-23.7),长于死亡组0天(0-0)。
6AHRF死亡病例中脓毒症组纳入后生存中位时间是8.5天(4.8-13.2)多于非脓毒症组5.0天(2.5-11.4)(P=0.038),脓毒症组的通气时间为8.8天(5.1-14.1)明显长于非脓毒症组5.2天(2.9-9.0),(P=0.005),两组各自死亡病例生存时间和通气时间非常接近,机械通气可延长脓毒症病例的生存时间,但不能改善预后。
7AHRF的首要病死原因是原发病(56.1%,69/23),其次是MODS(18.7%,23/123)及呼吸衰竭(15.4%,19/123)。其它为脑死亡(4.1%,5/123),经济原因(4.1%,5/123),其他(脑出血1、肺出血1)(1.6%,2/123)。
8AHRF病人中位PICU住院日11.0天(7.0-17.5),AHRF病人中位费用22,452元,日中位费用1,896元/天,是PICU平均水平的2倍左右；存活的AHRF病人住PICU时间要明显长于病死者,但日均费用则明显要低于病死病人。AHRF病人的中位PICU费用超过1个城镇居民1年的全部可支配收入、1个农村居民4年的收入。
9AHRF401例病例行机械通气治疗的过程中,压力控制模式是主要的通气模式,有90.0%,中位通气时间6.0天(0.6-47.6天)。纳入后7天Pa02呈上升趋势,FiO2则呈逐渐下降趋势,但到了40%后就基本不再下降；PIP一直在20cmH20左右；PEEP随时间的变化不大,同时MAP一直保持在较低的水平；Vte均在7.6ml/kg左右；OI(氧合指数)逐渐降低；呼吸系统动态顺应性纳入时低于0.5,予通气治疗后逐渐好转上升。FiO2纳入第1-7天生存组均低于死亡组,；PEEP生存组低于死亡组,但只有纳入第4、6天有差异；MAP生存组低于死亡组；OI生存组低于死亡组；P/F生存组高于死亡组；Pa02除纳入时生存组略低于死亡组,纳入第1-7天均高于死亡组；PaCO2除纳入时生存组略高于死亡组,纳入第1-7天均低于死亡组,Vte、PIP、MV、Crs纳入7天生存组与死亡组无显著差异。年龄<1y组的Vte在纳入后的前7天都高于≥1y组,在年龄小于1岁(肺损伤偏轻)的AHRF病例VDF<14天的发生率随着Vte水平的升高逐渐降低。
10AHRF纳入后前3天的液体入量中位值为121ml.kg-1.d-1(90-162),前7天128ml.kg-1.d-1(96-172)；而前3天及7天平衡量的中位值分别为31ml.kg-1. d-1(9-75)及33ml.kg-1.d-1(12-74)。病死与存活病人的液体出、入量均无明显差别,除纳入后第6天死亡组中位平衡量略高于存活组,其他纳入点均低于存活组,且在纳入第7天及纳入后前7天差异均有统计学意义。
11在AHRF死亡风险单因素分析中P值小于0.1的参数中有年龄<1岁、合并先心、纳入时心血管系统、肾脏、肝脏、有2个以上肺外脏器功能障碍、PRISMIII、LIS、Crs0.5ml.kg-1.cmH2O-1OI和P/F共12个指标,纳入二元Logistic模型中进行逐步回归分析,年龄(<1岁)合并心血管系统功能障碍、PEEP升高、Pa02降低会增加AHRF死亡风险。单因素分析P值小于0.1的参数中VFD<14d的相关因素在二元Logistic分析后,最终结果是PRISMⅢ评分升高、Pa02降低、PEEP升高、PIP降低及年龄(<1岁)合并心血管系统功能障碍会增加VFD<14d发生率。
12ARDS的原发病、12个月的发生病例分布及呼吸支持及液体控制治疗等情况基本同AHRF。最终二元Logistic回归分析结果：MV降低、PEEP升高、Pa02降低及心血管系统功能障碍会增加ARDS的死亡风险；Crs<0.5ml.kg-1cmH20-1的发生增多、Pa02降低、PEEP升高、PIP降低及年龄(<1岁)同时合并心血管系统功能障碍会增加VFD<14d发生率。
13各PICU危重病例比例中位值86.3%(63.3%-91.2%),低于50%的共有3家。总体上看AHRF及ARDS病例占PICU危重病例比例与AHRF及ARDS病例占机械通气病例比例中位值趋势很相近,各单位相差比较大。发达地区医院的AHRF发生率低于欠发达地区,放弃率及病死率都无统计学意义；但相对的疾病负担反而要轻一些。
14AHRF、ARDS发生率大学医院较非大学医院要低,两组病死率无统计学意义,但纳入病例危LIS、OI要高一些、PaO2/FiO2比值则相对要低,放弃率及住PICU天数较非大学医院少。从具体的呼吸参数来看,大学医院病人Vte高于非大学医院(纳入前4天都有统计学差异),应用的PEEP、PIP及MAP等通气压力也较非大学医院略高。在液体管理方面大学医院入量和平衡量较非大学医院小,液体控制做得较好。
15各协作单位Vte平均水平：<6ml/kg (2家)、6-8ml/kg(13家)、8-10ml／kg(7家)、>10ml/kg(1家)4组,不同Vte水平医院的AHRF病例的病死率随Vte水平的升高而逐渐降低,但无统计学差异P=0.155；不同Vte水平医院VDF<14天的发生率随着Vte水平的升高逐渐降低,有统计学差异P=0.045。
结论
1.本次研究29天≤年龄<6岁AHRF在我国PICU内的发生率与2006年的水平相当,但AHRF及ARDS的病死率已有明显的下降。此年龄段的疾病谱较大于6岁年龄段的单纯,更适合进行小潮气量通气的研究。Pa02、PEEP是影响AHRF及ARDS预后的非常重要的呼吸参数。
2.在年龄小于1岁(肺损伤偏轻)的AHRF病例VDF<14天的发生率随着Vte水平的升高逐渐降低。控制潮气量对AHRF病例的结局影响不大,但可能改善AHRF的病程。
3. AHRF死亡病例中脓毒症组生存中位时间及通气中位时间均明显多于非脓毒症组,提示机械通气可延长脓毒症病例的生存时间,但不能改善预后。
4.参加本研究的24家单位Vte总体水平在小潮气量通气策略范围内,就各单位Vte水平而言还是有差异的,有13家(54%)单位符合此范围。
5. AHRF及ARDS在发达地区医院与欠发达地区比较,放弃率及病死率都无统计学差异,总医疗费用相差不明显,但相对的疾病负担要轻一些。
6.大学医院较非大学医院在AHRF、ARDS病死率无统计学显著差异,但纳入病例危重程度较高,放弃率及住PICU天数较少。在呼吸机治疗及液体管理方面大学医院比非大学医院做得好。
BACKGROUND
Acute hypoxemic respiratory failure (AHRF) causes significant morbidity and mortality in pediatric intensive care unit (PICU), often develops to acute respiratory distress syndrome (ARDS). Incidences of AHRF and ARDS in developed countries are0.7-4.2%of total PICU admissions and its death rate varies at20-30%, but in developing countries its death rate is50-75%. Corresponding incidence and death rate of AHRF in the Chinese PICU are4%and41.8%, respectively, whileas ARDS was at1.44-2.7%and46.4-60.3%, respectively. AHRF is commonly caused by pneumonia from upper and lower respiratory tract bacteria or viruses and inadequate treatment. With advanced technology of cardiopulmonary resuscitation, respiratory support and life sign monitoring in modern emergency and PICU facilities, most AHRF may be prevented or cured without compromise with long term adverse outcome. This is especially becoming true in the domestic hospitals of municipal, provincial and sub-provincial cities in the past two decades, and even extending to county level pediatric services in coastal provinces. There is an increasingly new challenge for the attending staffs to use ventilator support technique at daily intensive care service to combat AHRF in ranges from common lung infection to non-typical pneumonia caused by new type of viral respiratory infection, such as hand-foot-mouth disease syndrome, avian and swine influenza which often prevail paroxysmally and cause complex multiple organ failure.
Lung protective ventilation strategy includes restricted tidal volume settings, permissive hypercapnia, ventilation with prone position, high frequency oscillatory ventilation and open lung manouvre, etc., aiming at preventing non-physiological, periodical stretching induced lung injury and facilitating ventilation-perfusion matching at the lower risk of adverse cardiovascular dysfunction. A large multicenter clinical trial in adult ARDS (American ARDS-Net trial) reveals that ventilation with tidal volume at6ml/kg in volume-controlled mode and a plateau pressure<30cm H2O were associated with nearly9%decrease in mortality (number-needed-to-treat,11) compared with higher tidal volume ventilation controls (12ml/kg). When it comes to the clinically conventional ventilation therapy, the result is not notable. There is no multicenter randomly controlled trial on lung protective ventilation strategy in PICU patients with ARDS yet. The fact that physiological parameters of mechanical ventilation between adult and children are different casts an uncertain question as to whether ventilation with lower tidal volume be regarded as a solution in children for lung protective ventilation. This collaborative study group completed a clinical epidemiologic study of incidence, management and outcome of ARDS in25PICUs in2004-2005, and found that ARDS occurred in children at a median age of2years old, and63.8%were below6years old; pressure-control mode was dominant (86.6%), and measured expiratory tidal volume (Vte) at3days after enrollment was10.4±5.4ml/kg. In2006-2007, this collaborative study group perfomed another study in AHRF and ARDS in26PICUs and found that AHRF occurred in children at a median age of11months old, and83%were below6years old, pressure-controlled mode was still used in93%, Vte at3days after enrollment was8.8(8-12) ml/kg. Another finding in this study was that a higher positive fluid balance value at7days after enrollment was associated with increased mortality. In these regards, we designed current multicenter, prospective clinic study targeting to AHRF with ages between29d to less than6years old (5y), with a special protocol for restricted tidal volume ventilation and fluid intake (balance) as non-controlled intervention.
OBJECTIVES
1To evaluate effect and safety of respiratory support protocol with restricted tidal volume and fluid intake for AHRF.
2To observe trend and spectra of the incidence, causes, mortality and its risk factors, and costs in AHRF and ARDS in comparison with two previous multicenter clinic studies in infants and children in PICUs of major cities in China.
3To estimate difference in the participating centers with regard to AHRF patient enrollment and therapeutic strategies.
4To improve compliance among the collaborative PICUs in conducting multicenter non-randomised study that may lead to randomised, controlled trial.
SUBJECTS AND METHODS
The study was designed as a descriptive clinical epidemiologic investigation, conducted prospectively from Jan.2009through Dec.2009for12consecutive months. Based on the previous pediatric AHRF collaborative study group, this study included24PICUs in which eleven from economically developed (newly industrilased) and thirteen from developing (underdeveloped) regions. All PICU admissions were screened according to a domestic pediatric critically ill score and American guidelines for admission and discharge policies for PICU that enrolled in all critically ill patients aged from29days to5years old (before6th birth day). AHRF was defined as:acute onset (<2weeks) of respiratory problems; PaO2≤50mmHg or PaO2/FiO2≤250mmHg for≥12h; requiring endotracheal intubation and mechanical ventilation (FiO2>0.3and positive end-expiratory pressure [PEEP]>2cmH2O to maintain PaO2>60mmHg or SpO2>90%); PaO2/FiO2remained≤250mmHg after12h of ventilation. ALI/ARDS was diagnosed according to the1994America-European Consensus Conference definitions (AECC).
Data were recorded daily, including demographic, physiologic, intervention, medication, outcome and cost. Lab of Pediatric Respiratory and Intensive Care at Children's Hospital of Fudan University served as coordinating center and in charge of collection of data and communication among the participating PICUs. All data were analyzed with statistic software SPSS13.0. Continuous data were presented as means and standard deviation (SD) or median and interquartile range (IQR) where appropriate. Differences of stratified/group data were compared by Mann-Whitney test, and categorical differences were compared with chi-square test. A p value<0.05was considered statistically significant. Assessment of individual clinical risk factors associated with mortality was performed according to previously reported methods for uni-and binary logistic regression. Results were reported as odds ratio (OR) or relative risk and95%confidence interval (CI).
RESULTS
During the12-month study period,15,462patients were admitted to these24PICUs, and12,176identified as critically ill. A total of401met the AHRF criteria,396of them fulfilled ALI criteria and348developed ARDS. Thus they accounted for3.29%,3.25%and2.86%, respectively, of critically ill patients in the total PICU admission.
Median age of AHRF patients was0.8year (change to months)(range0.2-2.3y),53.9%(216/401) were less than1year old. Out of401patients,396(98%) were Han ethnic and272(67.8%) were male. More AHRF were diagnosed during the winter-spring season than in the summer-autumn.
Most AHRF had pneumonia (95%) or sepsis (35.6%, sepsis+pneumonia) as underlying diseases, among them there were infectious diseases of type Ⅰ H1N1swine influenza (9,2died), measles (5,2died), and hand-foot-mouth disease (5,3died).
In hospital of AHRF was30.2%(121/401) and the mortality of90days after enrollment was30.9%(124/401). The median of survival days of AHRF was6.6days (3.4-12.2). The median of ventilation free days (VFD) in28days after enrollment was18.7days (0-23.0), and for the survivors,21.8(17.8-23.7) days.
The median of survival days among the non-survivors of AHRF with sepsis was8.5(4.8-13.2) days, in contrast to5days (2.5-11.4) in those without. The median of ventilation days in the non-survivors of AHRF with sepsis was8.8(5.1-14.1) days versus5(2.5-11.4) days in those without.
The predominant cause of death was underlying diseases (56.1%,69/123), followed by multiple organ system dysfunction/failure (18.7%,23/123) and respiratory failure (15.4%,19/123). Median cost of AHRF was22,452yuan, twice that of the average for a critically ill patient, more than the average urban resident's annaul disposable income and4times that of the rural resident's annual disposable income in China in the same period. Median in-patient stay time of AHRF was11days (7-17.5), with the survivors (13.6days,8.9-19.9) longer than the non-survivors (8.1days,4.6-14.8).
All the patients received mechanical ventilation, and93%(346/373) were ventilated on pressure-controlled mode. Median ventilation period was6(0.6-47.6) days. Upon enrollment, median values for Vte were7.5(4.3-12.3) ml/kg, PIP21(12-35) cmH20, MAP12(7-20) cmH20and PEEP (2.2-11.8)5cmH2O. There is no difference in Vte and PIP between the survivors and non-survivors. Median Vte was higher in subgroup with age<1y than those≥1y old. The incidences of VDF<14d in those with age<1y decreases with increasing Vte.
The median fluid intake during the first3days was121ml.kg-1.d-1(90-162), and in the first7days,128ml.kg-1.d-1(96-172), along with a fluid balance (fluid in minus out) of31(9-75) ml.kg-1.d-1and33(12-74) ml.kg-1.d-1, respectively. The fluid balance of the survivors was higher than those of the non-survivors on day7and during the first7days. There were no statistical difference in fluid intake between the survivors and non-survivors.
By binary logistic analyses, age<1y with cardiovascular system dysfunction as well as levels of PEEP and PaO2was independently associated with mortality in AHRF patients. PRIMS Ⅲ as well as PIP, PEEP and PaO2was independently associated with the incidence of VDF<14d.
The incidence, underlying diseases, ventilation settings and fluid management of ARDS were similar to those of AHRF. Cardiovascular system dysfunction, PEEP, PaO2and MV by binary logistic analyses were independently associated with mortality in ARDS patients. And age<1y with cardiovascular system dysfunction as well as PEEP, PIP, Crs and PaO2was independently associated with the incidence of VDF<14d.
The median percentage of critically ill patients in all PICU admissions was86.3%(63.3%-91.2%) among the24PICUs, with3less than50%. The number of enrolled patients, incidence, mortality and ventilation rate in the critically ill patients varied greatly among PICUs. The burden of illness in the hospitals from developed regions seemed lower than that in the hospitals from underdeveloped ones. The incidence of withdraw and PICU stay days in university affiliated hospitals were lower than in the non-university ones. Median Vte in the university hospitals was higher than in the non-university ones druing the first4days, and fluid intake and balance were lower than in the non-university ones too. The incidences of VDF<14d in different level by Vte of24PICUs decreased gradually with increasing Vte (P=0.045).
CONCLUSIONS
1The incidence of AHRF was close to that reported from2006-2007, but the mortality of AHRF and ARDS were lower than that reported in both2004-2005and2006-2007. The patients from29days and below6years old were more suscepteble to the lower tide volume treatment. PEEP and PaO2were the very important facts associated with prognosis in AHRF and ARDS patients.
2The incidences of VDF<14d in those with ages<1y subgroup decreased with increasing Vte levels.Ventilation with restricted tide volume and/or fluid intake did not have substantial impact on survival in AHRF patient, but may shorten the course of clinical pathology.
3The median of survival days and ventilation days in the non-survivors of AHRF with sepsis was longer than those without. Ventilation with lower Vte had impact on prolonged survival days but did not have impact on the mortality of AHRF with sepis.
4Despite an average level of Vte among24PICUs was kept at lower range, there were variations among the participating PICUs with different median levels and ranges of Vte. Only13(54%) PICUs performed mechanical ventilation with Vte in the recommended ranges.
5The burden of illness in hospitals from newly industrialized regions tended to be lower in contrast to the hospitals from developing regions. The incidence of withdrawal and PICU stay days in the university hospitals were lower than in the non-university ones. For the ventilation and fluid management the university hospitals performed better according to the study protocol than the non-university ones.
小儿急性低氧性呼吸衰竭(AHRF)是儿童重症监护室(PICU)病儿常见的住院及病死原因,多演变为急性呼吸窘迫综合征(ARDS),是PICU中最为棘手的危重症之一。国外小儿ARDS在PICU的患病率在0.7-4.2%左右,病死率在20-75%左右,国内PICU中ARDS发病率1.44-2.7%、病死率46.4-60.3%,AHRF发病率4%、病死率41.8%。以往AHRF多由于呼吸道细菌感染形成肺炎,缺乏有效呼吸支持演变而成。由于二十多年来逐渐开始在省市级医院普及呼吸机为中心的呼吸支持与危重监护技术应用,可以使大量致死性病例得以存活。但是近年来各种病毒性呼吸系统感染,如手足口病及甲型H1N1,其突发性的流行以及相对复杂的肺及肺外脏器损害为特征的AHRF病例及其高致死性比例,对普及以呼吸机为中心的呼吸支持与危重监护技术提出新挑战。
上世纪90年代围绕呼吸机治疗成人ARDS,提出了肺保护性通气策略的概念,包括小潮气量通气、允许性高碳酸血症、俯卧位通气、开放肺技术及高频通气等。小潮气量通气的目的在于防止由于肺泡的过度膨胀及肺泡内压力过高造成的呼吸机相关性肺损伤,并能够相对减弱机械牵张带来肺促炎症介质合成释放导致的炎症性损害。目前,由美国ARDS协作网完成的小潮气量通气随机对照研究,是唯一明确能降低病人死亡率的策略,小潮气量通气策略(容量控制模式下潮气量6ml/kg、平台压小于30cmH2O)可将ARDS病人的死亡率从38.9%(对照组12ml/kg)降到31%。该研究为小潮气量肺保护性通气策略在成人ARDS呼吸支持治疗中的有效性和安全提供了有力的证据。但小潮气量通气策略在临床常规治疗中的效果尚不及临床对照研究报道那么显著,而且缺乏在小儿ARDS病例中的比较研究报道。按体表面积小儿的潮气量较成人相对较小：2月-1岁(120ml/m2),1-3岁(144ml/m2),成人(294ml/m2)。小潮气量机械通气在实际操作中小儿与成人在通气模式、潮气量的等参数应该是不完全相同的,其是否普遍的适用于儿科仍有疑问。目前国内外尚未有儿科肺保护性通气策略多中心随机对照研究的数据。国内2004年起本实验室组织开展了全国性小儿ARDS前瞻性临床流行病学研究,纳入病例中位年龄2.0岁,小于6岁者63.8%(69/105),机械通气病人86.6%采用压力控制模式通气,纳入后1-3天所测得Vte10.4±5.4ml/kg.2006-2007年本实验室再组织全国26家PICU参与的小儿AHRF多中心研究中,纳入病例中位年龄11个月,AHRF病死率降为41.8%,ARDS病死率降为约46.4%,压力控制模式是主要的通气模式占93%,纳入后1-3天所测得Vte8.8ml/kg(8.0-12),小于6岁小儿占所有收治AHRF的80%以上。此外,该研究也发现纳入初期1-7天的液体负平衡与存活有关联。为此,我们于2008年设计了专门针对该年龄层小儿(29天≤年龄<6岁)限制潮气量和控制液体平衡的机械通气治疗AHRF前瞻性、多中心非对照性临床干预研究。
目的
评估小潮气量肺保护性通气策略治疗小儿低氧性呼吸衰竭的疗效及安全性。了解继2次AHRF的多中心研究后,小儿AHFR在我国PICU中的发生率、原发病、病死率、死亡风险因素及疾病负担等情况有无改变。了解和评估各协作单位在AHRF治疗中对小潮气量肺保护性通气和液体控制策略的实施情况,进一步提高协作单位对多中心研究的方案执行依从性及质量控制能力,为将来开展高标准的小儿多中心随机对照的肺保护性通气策略干预研究奠定基础。
方法
本研究为带有干预性质的非对照的前瞻性多中心临床流行病学研究。在原有小儿AHRF协作组的基础上,共有全国24家单位的PICU参加。参加单位按所在省、市2009年全国人均GDP及全国城镇居民人均可支配收入作了排名,前11家作为经济发达地区医院,其余13家为欠发达地区医院。另外,24家单位中有12家为大学医院。研究时间从2009年1月1日至2009年12月31日(各家医院均为12个月),对所有入住PICU、重点人群(29天≤年龄<6岁)进行病例筛查并对其中的AHRF病人进行前瞻性的调查。PICU危重病儿收治数按国内小儿危重病例评分及美国PICU入出院指南进行筛选后确定,作为计算小儿AHRF发生率的基数。AHRF的诊断标准：急性起病(≤2周),PaO2≤50mmHg或PaO2/FiO2≤250mmHg,气管插管机械通气(Fi02≥30%、PEEP≥2cmH2O方能维持PaO2≥60mmHg或经皮脉冲血氧饱和度(SpO2)≥90%)12小时以上,且通气12小后仍存在呼吸衰竭,PaO2/FiO2≤250mmHg。ALI/ARDS按1994年北美-欧洲(AECC)议定标准进行诊断,其中包括：1)急性起病(≤2周)；2)PaO2/FiO2≤300mmHg(ALI)或PaO2/FiO2≤200mmHg (ARDS);3)胸片示两肺渗出影；4)无左心房高压的临床证据(肺动脉楔压≤18mmHg或用床旁彩超诊断)。
AHRF患儿入选后,每天收集一次数据。数据包括：人口学特征、呼吸机参数、血气、肺力学及血流动力学指标、病人预后和疾病负担等。数据记录到纳入后28天、出院或病死,以先发生者为准。各单位每个月上报PICU收治病人的总体数据。由复旦大学附属儿科医院小儿呼吸与危重病实验室为调查协调中心,负责管理调查工作和数据质量的监控。所有资料应用统计软件SPSS13.0进行统计分析。计量资料中连续变量呈正态分布者表示为x(SD),均数比较采用单因素方差分析；偏态分布者表示为中位数(P25-P75),均数比较采用秩和检验分析。对死亡风险因素进行归入二元logistic回归模型进行逐步回归分析,结果用比值比(OR)及95%可信限(CI)来表示。
结果
1全年24家PICU共收治病人15,462例,其中危重病例12,176例(78.7%),机械通气病例数3,689(30.3%),总病死1,244例(包括放弃出院3天内死亡546例),全年PICU平均病死率10.2%,另有放弃治疗出院1,786例(14.7%)。实际纳入AHRF病人401例,所有的病例都进行了机械通气治疗。符合ALI的诊断标准396例(98.75%),ALI病人中有320例(80.8%)符合ARDS诊断标准。纳入后又有28例ALI病例最后发展为ARDS,最后诊断ARDS病例348例,AHRF.ALI及ARDS病例数占PICU危重病例总数的比例分别为3.29%、3.25%、2.86%。
2AHRF病例中,汉族占绝大部分98.75%,男女之比为2.1：1。中位年龄0.8岁(0.2-2.3)。小于1岁者(未过第1个生日)占53.9%(216例),小于2岁者占70.6%(283例)。AHRF纳入病例数及与PICU危重病例的比例在12个月中分布冬春多于夏秋。
3AHRF以肺内疾病原发者占97.5%,肺炎95.0%,脓毒症143例35.6%(其中肺炎同时符合脓毒症标准的有141例占35.2%)。甲型H1N1流感共9例,死亡2例；麻疹合并肺炎5例,死亡2例；手足口病5例,死亡3例
4AHRF病儿总住院病死率30.2%(121／401),纳入后90天总计死亡124例,90天病死率30.9%(124／401),与住院病死率基本相同,低于2006年国内小儿AHRF多中心研究AHRF病死率41.8%(P<0.001)。
5AHRF病死病人纳入后中位生存时间6.6天(P25-P753.4-12.2),纳入28天平均无机械通气日(VDF)为13.6天,中位值18.7(0-23.0)。存活组VFD中位值21.8天(17.8-23.7),长于死亡组0天(0-0)。
6AHRF死亡病例中脓毒症组纳入后生存中位时间是8.5天(4.8-13.2)多于非脓毒症组5.0天(2.5-11.4)(P=0.038),脓毒症组的通气时间为8.8天(5.1-14.1)明显长于非脓毒症组5.2天(2.9-9.0),(P=0.005),两组各自死亡病例生存时间和通气时间非常接近,机械通气可延长脓毒症病例的生存时间,但不能改善预后。
7AHRF的首要病死原因是原发病(56.1%,69/23),其次是MODS(18.7%,23/123)及呼吸衰竭(15.4%,19/123)。其它为脑死亡(4.1%,5/123),经济原因(4.1%,5/123),其他(脑出血1、肺出血1)(1.6%,2/123)。
8AHRF病人中位PICU住院日11.0天(7.0-17.5),AHRF病人中位费用22,452元,日中位费用1,896元/天,是PICU平均水平的2倍左右；存活的AHRF病人住PICU时间要明显长于病死者,但日均费用则明显要低于病死病人。AHRF病人的中位PICU费用超过1个城镇居民1年的全部可支配收入、1个农村居民4年的收入。
9AHRF401例病例行机械通气治疗的过程中,压力控制模式是主要的通气模式,有90.0%,中位通气时间6.0天(0.6-47.6天)。纳入后7天Pa02呈上升趋势,FiO2则呈逐渐下降趋势,但到了40%后就基本不再下降；PIP一直在20cmH20左右；PEEP随时间的变化不大,同时MAP一直保持在较低的水平；Vte均在7.6ml/kg左右；OI(氧合指数)逐渐降低；呼吸系统动态顺应性纳入时低于0.5,予通气治疗后逐渐好转上升。FiO2纳入第1-7天生存组均低于死亡组,；PEEP生存组低于死亡组,但只有纳入第4、6天有差异；MAP生存组低于死亡组；OI生存组低于死亡组；P/F生存组高于死亡组；Pa02除纳入时生存组略低于死亡组,纳入第1-7天均高于死亡组；PaCO2除纳入时生存组略高于死亡组,纳入第1-7天均低于死亡组,Vte、PIP、MV、Crs纳入7天生存组与死亡组无显著差异。年龄<1y组的Vte在纳入后的前7天都高于≥1y组,在年龄小于1岁(肺损伤偏轻)的AHRF病例VDF<14天的发生率随着Vte水平的升高逐渐降低。
10AHRF纳入后前3天的液体入量中位值为121ml.kg-1.d-1(90-162),前7天128ml.kg-1.d-1(96-172)；而前3天及7天平衡量的中位值分别为31ml.kg-1. d-1(9-75)及33ml.kg-1.d-1(12-74)。病死与存活病人的液体出、入量均无明显差别,除纳入后第6天死亡组中位平衡量略高于存活组,其他纳入点均低于存活组,且在纳入第7天及纳入后前7天差异均有统计学意义。
11在AHRF死亡风险单因素分析中P值小于0.1的参数中有年龄<1岁、合并先心、纳入时心血管系统、肾脏、肝脏、有2个以上肺外脏器功能障碍、PRISMIII、LIS、Crs0.5ml.kg-1.cmH2O-1OI和P/F共12个指标,纳入二元Logistic模型中进行逐步回归分析,年龄(<1岁)合并心血管系统功能障碍、PEEP升高、Pa02降低会增加AHRF死亡风险。单因素分析P值小于0.1的参数中VFD<14d的相关因素在二元Logistic分析后,最终结果是PRISMⅢ评分升高、Pa02降低、PEEP升高、PIP降低及年龄(<1岁)合并心血管系统功能障碍会增加VFD<14d发生率。
12ARDS的原发病、12个月的发生病例分布及呼吸支持及液体控制治疗等情况基本同AHRF。最终二元Logistic回归分析结果：MV降低、PEEP升高、Pa02降低及心血管系统功能障碍会增加ARDS的死亡风险；Crs<0.5ml.kg-1cmH20-1的发生增多、Pa02降低、PEEP升高、PIP降低及年龄(<1岁)同时合并心血管系统功能障碍会增加VFD<14d发生率。
13各PICU危重病例比例中位值86.3%(63.3%-91.2%),低于50%的共有3家。总体上看AHRF及ARDS病例占PICU危重病例比例与AHRF及ARDS病例占机械通气病例比例中位值趋势很相近,各单位相差比较大。发达地区医院的AHRF发生率低于欠发达地区,放弃率及病死率都无统计学意义；但相对的疾病负担反而要轻一些。
14AHRF、ARDS发生率大学医院较非大学医院要低,两组病死率无统计学意义,但纳入病例危LIS、OI要高一些、PaO2/FiO2比值则相对要低,放弃率及住PICU天数较非大学医院少。从具体的呼吸参数来看,大学医院病人Vte高于非大学医院(纳入前4天都有统计学差异),应用的PEEP、PIP及MAP等通气压力也较非大学医院略高。在液体管理方面大学医院入量和平衡量较非大学医院小,液体控制做得较好。
15各协作单位Vte平均水平：<6ml/kg (2家)、6-8ml/kg(13家)、8-10ml／kg(7家)、>10ml/kg(1家)4组,不同Vte水平医院的AHRF病例的病死率随Vte水平的升高而逐渐降低,但无统计学差异P=0.155；不同Vte水平医院VDF<14天的发生率随着Vte水平的升高逐渐降低,有统计学差异P=0.045。
结论
1.本次研究29天≤年龄<6岁AHRF在我国PICU内的发生率与2006年的水平相当,但AHRF及ARDS的病死率已有明显的下降。此年龄段的疾病谱较大于6岁年龄段的单纯,更适合进行小潮气量通气的研究。Pa02、PEEP是影响AHRF及ARDS预后的非常重要的呼吸参数。
2.在年龄小于1岁(肺损伤偏轻)的AHRF病例VDF<14天的发生率随着Vte水平的升高逐渐降低。控制潮气量对AHRF病例的结局影响不大,但可能改善AHRF的病程。
3. AHRF死亡病例中脓毒症组生存中位时间及通气中位时间均明显多于非脓毒症组,提示机械通气可延长脓毒症病例的生存时间,但不能改善预后。
4.参加本研究的24家单位Vte总体水平在小潮气量通气策略范围内,就各单位Vte水平而言还是有差异的,有13家(54%)单位符合此范围。
5. AHRF及ARDS在发达地区医院与欠发达地区比较,放弃率及病死率都无统计学差异,总医疗费用相差不明显,但相对的疾病负担要轻一些。
6.大学医院较非大学医院在AHRF、ARDS病死率无统计学显著差异,但纳入病例危重程度较高,放弃率及住PICU天数较少。在呼吸机治疗及液体管理方面大学医院比非大学医院做得好。
BACKGROUND
Acute hypoxemic respiratory failure (AHRF) causes significant morbidity and mortality in pediatric intensive care unit (PICU), often develops to acute respiratory distress syndrome (ARDS). Incidences of AHRF and ARDS in developed countries are0.7-4.2%of total PICU admissions and its death rate varies at20-30%, but in developing countries its death rate is50-75%. Corresponding incidence and death rate of AHRF in the Chinese PICU are4%and41.8%, respectively, whileas ARDS was at1.44-2.7%and46.4-60.3%, respectively. AHRF is commonly caused by pneumonia from upper and lower respiratory tract bacteria or viruses and inadequate treatment. With advanced technology of cardiopulmonary resuscitation, respiratory support and life sign monitoring in modern emergency and PICU facilities, most AHRF may be prevented or cured without compromise with long term adverse outcome. This is especially becoming true in the domestic hospitals of municipal, provincial and sub-provincial cities in the past two decades, and even extending to county level pediatric services in coastal provinces. There is an increasingly new challenge for the attending staffs to use ventilator support technique at daily intensive care service to combat AHRF in ranges from common lung infection to non-typical pneumonia caused by new type of viral respiratory infection, such as hand-foot-mouth disease syndrome, avian and swine influenza which often prevail paroxysmally and cause complex multiple organ failure.
Lung protective ventilation strategy includes restricted tidal volume settings, permissive hypercapnia, ventilation with prone position, high frequency oscillatory ventilation and open lung manouvre, etc., aiming at preventing non-physiological, periodical stretching induced lung injury and facilitating ventilation-perfusion matching at the lower risk of adverse cardiovascular dysfunction. A large multicenter clinical trial in adult ARDS (American ARDS-Net trial) reveals that ventilation with tidal volume at6ml/kg in volume-controlled mode and a plateau pressure<30cm H2O were associated with nearly9%decrease in mortality (number-needed-to-treat,11) compared with higher tidal volume ventilation controls (12ml/kg). When it comes to the clinically conventional ventilation therapy, the result is not notable. There is no multicenter randomly controlled trial on lung protective ventilation strategy in PICU patients with ARDS yet. The fact that physiological parameters of mechanical ventilation between adult and children are different casts an uncertain question as to whether ventilation with lower tidal volume be regarded as a solution in children for lung protective ventilation. This collaborative study group completed a clinical epidemiologic study of incidence, management and outcome of ARDS in25PICUs in2004-2005, and found that ARDS occurred in children at a median age of2years old, and63.8%were below6years old; pressure-control mode was dominant (86.6%), and measured expiratory tidal volume (Vte) at3days after enrollment was10.4±5.4ml/kg. In2006-2007, this collaborative study group perfomed another study in AHRF and ARDS in26PICUs and found that AHRF occurred in children at a median age of11months old, and83%were below6years old, pressure-controlled mode was still used in93%, Vte at3days after enrollment was8.8(8-12) ml/kg. Another finding in this study was that a higher positive fluid balance value at7days after enrollment was associated with increased mortality. In these regards, we designed current multicenter, prospective clinic study targeting to AHRF with ages between29d to less than6years old (5y), with a special protocol for restricted tidal volume ventilation and fluid intake (balance) as non-controlled intervention.
OBJECTIVES
1To evaluate effect and safety of respiratory support protocol with restricted tidal volume and fluid intake for AHRF.
2To observe trend and spectra of the incidence, causes, mortality and its risk factors, and costs in AHRF and ARDS in comparison with two previous multicenter clinic studies in infants and children in PICUs of major cities in China.
3To estimate difference in the participating centers with regard to AHRF patient enrollment and therapeutic strategies.
4To improve compliance among the collaborative PICUs in conducting multicenter non-randomised study that may lead to randomised, controlled trial.
SUBJECTS AND METHODS
The study was designed as a descriptive clinical epidemiologic investigation, conducted prospectively from Jan.2009through Dec.2009for12consecutive months. Based on the previous pediatric AHRF collaborative study group, this study included24PICUs in which eleven from economically developed (newly industrilased) and thirteen from developing (underdeveloped) regions. All PICU admissions were screened according to a domestic pediatric critically ill score and American guidelines for admission and discharge policies for PICU that enrolled in all critically ill patients aged from29days to5years old (before6th birth day). AHRF was defined as:acute onset (<2weeks) of respiratory problems; PaO2≤50mmHg or PaO2/FiO2≤250mmHg for≥12h; requiring endotracheal intubation and mechanical ventilation (FiO2>0.3and positive end-expiratory pressure [PEEP]>2cmH2O to maintain PaO2>60mmHg or SpO2>90%); PaO2/FiO2remained≤250mmHg after12h of ventilation. ALI/ARDS was diagnosed according to the1994America-European Consensus Conference definitions (AECC).
Data were recorded daily, including demographic, physiologic, intervention, medication, outcome and cost. Lab of Pediatric Respiratory and Intensive Care at Children's Hospital of Fudan University served as coordinating center and in charge of collection of data and communication among the participating PICUs. All data were analyzed with statistic software SPSS13.0. Continuous data were presented as means and standard deviation (SD) or median and interquartile range (IQR) where appropriate. Differences of stratified/group data were compared by Mann-Whitney test, and categorical differences were compared with chi-square test. A p value<0.05was considered statistically significant. Assessment of individual clinical risk factors associated with mortality was performed according to previously reported methods for uni-and binary logistic regression. Results were reported as odds ratio (OR) or relative risk and95%confidence interval (CI).
RESULTS
During the12-month study period,15,462patients were admitted to these24PICUs, and12,176identified as critically ill. A total of401met the AHRF criteria,396of them fulfilled ALI criteria and348developed ARDS. Thus they accounted for3.29%,3.25%and2.86%, respectively, of critically ill patients in the total PICU admission.
Median age of AHRF patients was0.8year (change to months)(range0.2-2.3y),53.9%(216/401) were less than1year old. Out of401patients,396(98%) were Han ethnic and272(67.8%) were male. More AHRF were diagnosed during the winter-spring season than in the summer-autumn.
Most AHRF had pneumonia (95%) or sepsis (35.6%, sepsis+pneumonia) as underlying diseases, among them there were infectious diseases of type Ⅰ H1N1swine influenza (9,2died), measles (5,2died), and hand-foot-mouth disease (5,3died).
In hospital of AHRF was30.2%(121/401) and the mortality of90days after enrollment was30.9%(124/401). The median of survival days of AHRF was6.6days (3.4-12.2). The median of ventilation free days (VFD) in28days after enrollment was18.7days (0-23.0), and for the survivors,21.8(17.8-23.7) days.
The median of survival days among the non-survivors of AHRF with sepsis was8.5(4.8-13.2) days, in contrast to5days (2.5-11.4) in those without. The median of ventilation days in the non-survivors of AHRF with sepsis was8.8(5.1-14.1) days versus5(2.5-11.4) days in those without.
The predominant cause of death was underlying diseases (56.1%,69/123), followed by multiple organ system dysfunction/failure (18.7%,23/123) and respiratory failure (15.4%,19/123). Median cost of AHRF was22,452yuan, twice that of the average for a critically ill patient, more than the average urban resident's annaul disposable income and4times that of the rural resident's annual disposable income in China in the same period. Median in-patient stay time of AHRF was11days (7-17.5), with the survivors (13.6days,8.9-19.9) longer than the non-survivors (8.1days,4.6-14.8).
All the patients received mechanical ventilation, and93%(346/373) were ventilated on pressure-controlled mode. Median ventilation period was6(0.6-47.6) days. Upon enrollment, median values for Vte were7.5(4.3-12.3) ml/kg, PIP21(12-35) cmH20, MAP12(7-20) cmH20and PEEP (2.2-11.8)5cmH2O. There is no difference in Vte and PIP between the survivors and non-survivors. Median Vte was higher in subgroup with age<1y than those≥1y old. The incidences of VDF<14d in those with age<1y decreases with increasing Vte.
The median fluid intake during the first3days was121ml.kg-1.d-1(90-162), and in the first7days,128ml.kg-1.d-1(96-172), along with a fluid balance (fluid in minus out) of31(9-75) ml.kg-1.d-1and33(12-74) ml.kg-1.d-1, respectively. The fluid balance of the survivors was higher than those of the non-survivors on day7and during the first7days. There were no statistical difference in fluid intake between the survivors and non-survivors.
By binary logistic analyses, age<1y with cardiovascular system dysfunction as well as levels of PEEP and PaO2was independently associated with mortality in AHRF patients. PRIMS Ⅲ as well as PIP, PEEP and PaO2was independently associated with the incidence of VDF<14d.
The incidence, underlying diseases, ventilation settings and fluid management of ARDS were similar to those of AHRF. Cardiovascular system dysfunction, PEEP, PaO2and MV by binary logistic analyses were independently associated with mortality in ARDS patients. And age<1y with cardiovascular system dysfunction as well as PEEP, PIP, Crs and PaO2was independently associated with the incidence of VDF<14d.
The median percentage of critically ill patients in all PICU admissions was86.3%(63.3%-91.2%) among the24PICUs, with3less than50%. The number of enrolled patients, incidence, mortality and ventilation rate in the critically ill patients varied greatly among PICUs. The burden of illness in the hospitals from developed regions seemed lower than that in the hospitals from underdeveloped ones. The incidence of withdraw and PICU stay days in university affiliated hospitals were lower than in the non-university ones. Median Vte in the university hospitals was higher than in the non-university ones druing the first4days, and fluid intake and balance were lower than in the non-university ones too. The incidences of VDF<14d in different level by Vte of24PICUs decreased gradually with increasing Vte (P=0.045).
CONCLUSIONS
1The incidence of AHRF was close to that reported from2006-2007, but the mortality of AHRF and ARDS were lower than that reported in both2004-2005and2006-2007. The patients from29days and below6years old were more suscepteble to the lower tide volume treatment. PEEP and PaO2were the very important facts associated with prognosis in AHRF and ARDS patients.
2The incidences of VDF<14d in those with ages<1y subgroup decreased with increasing Vte levels.Ventilation with restricted tide volume and/or fluid intake did not have substantial impact on survival in AHRF patient, but may shorten the course of clinical pathology.
3The median of survival days and ventilation days in the non-survivors of AHRF with sepsis was longer than those without. Ventilation with lower Vte had impact on prolonged survival days but did not have impact on the mortality of AHRF with sepis.
4Despite an average level of Vte among24PICUs was kept at lower range, there were variations among the participating PICUs with different median levels and ranges of Vte. Only13(54%) PICUs performed mechanical ventilation with Vte in the recommended ranges.
5The burden of illness in hospitals from newly industrialized regions tended to be lower in contrast to the hospitals from developing regions. The incidence of withdrawal and PICU stay days in the university hospitals were lower than in the non-university ones. For the ventilation and fluid management the university hospitals performed better according to the study protocol than the non-university ones.
引文
[1]Flori HR, Glidden DV, Rutherford GW, et al. Pediatric acute respiratory injury: prospective evaluation of risk factors associated with mortality [J]. Am J Respir Crit Care Med,2005,171(9):995-1001.
[2]Timmons OD, Dean JM, Vernon DD. Mortality rates and prognostic variables in children with acult respiratory distress syndrome [J]. J Pediatr,1991,119(6): 896-899.
[3]Gof AYT, Chan PWK, Lum LCS, et al. Incidence of acute respiratory distress syndrome:a comparison of two definitions [J]. Arch Dis Child,1998,79(3): 256-259.
[4]Khemani RG, Conti D, Alonzo TA, et al. Effect of tidal volume in children with acute hypoxemic respiratory failure [J]. Intensive Care Med,2009, 35:1428-1437.
[5]Yu WL, Lu ZJ, Wang Y, et al. The epidemiology of acute respiratory distress syndrome in pediatric intensive care units in China [J]. Inetensive Care Med, 2009:136-143.
[6]Hu XG, Qian SY, Xu F, et al. Incidence, management and mortality of acute hypoxemic respiratory failure and acute respiratory distress syndrome from a prospective study of Chinese paediatric intensive care network [J]. Act Paediatr, 2010 (in press)
[7]Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults [J]. Lancet,1967,2(7511):319-323.
[8]Bernard GR, Artiga A, Brigham KL, et al. the Consensus Committee. The American-European Consensus Conference on ARDS definitions, mechanisms, relevant outcomes, and clinical trial coordination [J]. Am J Respir Crit Care Med,1994,149(3):818-824
[9]Hughes M, Mackirdy FN, Ross J, et al. Acute respiratory distress syndrome:an audit of incidence and outcome in Scottish intensive care units [J]. Anaesthesia, 2003,58(9):838-845.
[10]Estenssoro E, Dubin A, Laffaire E, et al. Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome [J]. Crit Care Med,2002,30(11):2450-2456.
[11]The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome [J]. N Engl J Med,2000; 342(18): 1301-1308.
[12]宁寿葆.儿科学[M].上海：上海医科大学出版社,2000：150.
[13]Dahlem P, van Aalderen WMC, Hamaker ME, et al. Incidence and short-term outcome of acute lung injury in mechanically ventilated children [J]. Eur Respir J,2003,22(6):980-985.
[14]Parsons PE, Eisner MD, Thompson BT, et al. Lowertidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury [J]. Crit Care Med,2005,33(1):1-6.
[15]Mancini M, Zavala E, Mancebo J, et al. Mechanisms of pulmonary gas exchange improvement during a protective ventilatory strategy in acute respiratory distress syndrome [J]. Am J Respir Crit Care Med,2001,164: 1448-1453.
[16]王玉,陆铸今.小潮气量机械通气在小儿呼吸衰竭中的应用[J].实用儿科临床杂志,2006,21(22)：1562-1563
[17]Stewart TE, Mende MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotrauma in patienta at high risk for acute respiratory distres syndrome. Presure- and Volume-Limited Ventilation StrategyGroup [J]. N En J Med,1998,338:355-361
[18]Brower RG, Shanholtz CB, Fessler HE, et al. Prospective, randomized, controled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients [J]. Crit Care Med, 1999,27:1492-1498.
[19]Clark RH, Slut sky Gerestman DR. Lung protective st rategies of ventilation in the neoeate what are they[J]. Pediat rics,2000,105 (11):112-114.
[20]施丽萍,孙眉月,杜立中.新生儿呼吸窘迫综合征呼吸治疗肺保护性研究[J].中华儿科杂志,2003,41(2)：95-98.
[21]孙轶、周晓光、刘放云.肺保护性通气策略对呼吸窘迫综合征新生儿肺氧合功能的影响[J].中国小儿急救医学,2007,14(4)：305-308
[22]廖霓,张国英,郑静,等.不同潮气量机械通气对新生儿低氧性呼吸衰竭疗效的影响[J].华西医学,2008,23(6)：1319-1320
[23]Kornecki A, Tsuchida S, Ondiveeran HK, et al. Lung development and susceptibility to ventilator-induced lung injury [J]. Am J Respir Crit Care Med, 2005,171:743-752.
[24]Trachsel D, McCrindle BW, Nakagawa S, et al. Oxygenation Index Predicts Outcome in Children with Acute Hypoxemic Respiratory Failure [J]. Am J Respir Crit Care Med,2005,172(2):206-211.
[25]Erickson S, Schibler A, Numa A, et al.Acute lung injury in pediatric intensive care in Australia and New Zealand-A prospective, multicenter, observational study [J]. Pediatr Crit Care Med,2007,8(4):317-323
[26]喻文亮,陆铸今,王莹,等.小儿急性呼吸窘迫综合征前瞻性多中心临床临床流行病学研究[J].中华急诊医学杂志,2005,14(6)：448-453.
[27]Timmons OD, Dean JM, Vernon DD. Mortality rates and prognostic variables in children with adult respiratory distress syndrome [J]. J Pediatr,1991,119(6): 896-899.
[28]Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury [J]. N Engl J Med,2005,353(16):1865-1693.
[29]National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Wiedemann HP. Wheeler AP. Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury [J]. N Engl J Med,2006,354(24):2564-2575
[30]Cunliffe M. Fluid and electrolyte management in children [J]. Br J Anaesth, 2003,3(1):1-4.
[31]Karimova A, Pinsky DJ. The endothelial response to oxygen deprivation: biology and clinical implications [J]. Intensive Care Med,2001,27(1):19-31.
[32]Estenssoro E, Gonzalez F, Laffaire E, et al. Shock on admission day is the best predictor of prolonged mechanical ventilation in the ICU [J]. Chest,2005, 127(2):598-603.
[33]Rivers E. Fluid managemen strategies in acute lung injury-Liberal, Conservative, or both? [J] N Engl J Med,2006,354(24):2598-2599.
[34]Thompson Bt. Glucocorticoids and acute lung injury [J]. Crit Care Med,2003, 31(4 Suppl):s253-257.
[35]Martinot A, Fourier C, Cremer R, et al. Short-course, high-dose corticosteroid treatment in six children with late ARDS [J]. Pediatr pulmonol,1997,23(4): 314-316.
[36]Goh AY, Sekaran D, Roziah M, et al. Corticosteroid rescue in late paediatric acute respiratory distress syndrome [J]. Respirology,1999,4(3):295-297.
[37]Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock [J]. JAMA,2002,288(7):862-871.
[38]National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome [J]. N Engl J Med,2006,354(16):1671-1684.
[39]Wheeler AP, Bernard GR. Acute lung injury and ther acute respiratory distress syndrome:a clinical review [J]. Lancet,2007,369(9572):1553-1565.
[40]Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS:results of a randomized controlled trial [J]. Chest,2007,131(4): 954-63.
[41]Meduri GU, Marik PE, Pastores SM, et al. Acute lung injury and ther acute respiratory distress syndrome:a clinical review [J]. Lancet,2007,370(9585): 384-385.
[42]胡晓光,钱素云,李昌崇,等.小儿急性低氧性呼吸衰竭支持相关预后及差异及影响因素[J].中华急诊医学杂志,2010,19(2)：190-194.
[43]Kahn JM, Goss CH, Heagerty PJ, et al. Hospital volume and the outcomes of Mechnical Ventilation[J]. N Engl J Med,2006,34(9):2349-2354.
[44]Ferguson ND, Kacmarek RM, Chiche JD, et al. Screening of ARDS patients using standardized ventilator settings:influence on enrolment in a clinical trial [J]. Intensive Care Med,2004,30(6):1111-1116.
[45]Villar J, Perez-Mendez L, Lopez J, et al. An early PEEP/FiO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome [J]. Am J Respir Crit Care Med,2007,176(8):795-804.
[1]Flori HR, Glidden DV, Rutherford GW, et al. Pediatric acute respiratory injury: prospective evaluation of risk factors associated with mortality [J]. Am J Respir Crit Care Med,2005,171(9):995-1001.
[2]Timmons OD, Dean JM, Vernon DD. Mortality rates and prognostic variables in children with acult respiratory distress syndrome [J]. J Pediatr,1991,119(6):896-899.
[3]Gof AYT, Chan PWK, Lum LCS, et al. Incidence of acute respiratory distress syndrome:a comparison of two definitions [J]. Arch Dis Child,1998,79(3): 256-259.
[4]Khemani RG, Conti D, Alonzo TA, et al. Effect of tidal volume in children with acute hypoxemic respiratory failure [J]. Intensive Care Med,2009, 35:1428-1437.
[5]Yu WL, Lu ZJ, Wang Y, et al. The epidemiology of acute respiratory distress syndrome in pediatric intensive care units in China [J]. Inetensive Care Med, 2009:136-143.
[6]Hu XG, Qian SY, Xu F, et al. Incidence, management and mortality of acute hypoxemic respiratory failure and acute respiratory distress syndrome from a prospective study of Chinese paediatric intensive care network [J]. Act Paediatr, 2010 (in press)
[7]Belperio JA, Keane MP, Burdick MD, et al. Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury [J]. J Clin Invest,2002,110:1703-1716.
[8]The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome [J]. N Engl J Med,2000; 342(18): 1301-1308.
[9]Amato MB, Barbas CS, M edeiros DM, et al. Effect of aprotective-ventilation strategy on mortality in the acute respiratory distress syndrome [J]. N Engl J Med, 1998,338:347-354.
[10]Parsons PE, Eisner MD, Thompson BT, et al. Lowertidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury [J]. Crit Care Med,2005,33(1):1-6.
[11]Boker A, Graham M R, W alley KR, et al. Improved arterial oxygenation with biologically variable or fractal ventilation using low tidal volumes in a porcine model of acute respiratory distress syndrome [J]. Am J Respir Crit Care M ed, 2002,165:456-462.
[12]Parsons PE, Eisner M D, Thompson BT, et al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury [J]. Crit Care Med,2005,33:1-6.
[13]Mancini M, Zavala E, Mancebo J, et al. Mechanisms of pulmonary gas exchange improvement during a protective ventilatory strategy in acute respiratory distress syndrome [J]. Am J Respir Crit Care Med,2001,164: 1448-1453.
[14]Durante GD, Turco MD, Rustichini L, et al. ARDSNet lower tidal volume ventilatory strategy may generate intrinsic positive end-expiratory distress syndrome [J]. Am J Respir Crit Care Med 2002; 165(159):1271-1274.
[15]王玉,陆铸今.小潮气量机械通气在小儿呼吸衰竭中的应用[J].实用儿科临床杂志,2006,21(22)：1562-1563
[16]施丽萍,孙眉月,杜立中.新生儿呼吸窘迫综合征呼吸治疗肺保护性研究[J].中华儿科杂志,2003,41(2)：95-98.
[17]孙轶、周晓光、刘放云.肺保护性通气策略对呼吸窘迫综合征新生儿肺氧合功能的影响[J].中国小儿急救医学,2007,14(4)：305-308
[18]廖霓,张国英,郑静,等.不同潮气量机械通气对新生儿低氧性呼吸衰竭疗效的影响[J].华西医学,2008,23(6)：1319-1320
[19]Albuali WH, Singh RN, DD Fraser, et al. Have changes in ventilation practice improved outcome in children with acute lung injury [J]. Pediatr Crit Care Med 2007,8(4):324-330
[20]Erickson S, Schibler A, Numa A, et al.Acute lung injury in pediatric intensive care in Australia and New Zealand-A prospective, multicenter, observational study [J]. Pediatr Crit Care Med,2007,8(4):317-323
[21]宁寿葆.儿科学[M].上海：上海医科大学出版社,2000：150.
[22]Kornecki A, Tsuchida S, Ondiveeran HK, et al. Lung development and susceptibility to ventilator-induced lung injury [J]. Am J Respir Crit Care Med, 2005,171:743-752.
[2]Timmons OD, Dean JM, Vernon DD. Mortality rates and prognostic variables in children with acult respiratory distress syndrome [J]. J Pediatr,1991,119(6): 896-899.
[3]Gof AYT, Chan PWK, Lum LCS, et al. Incidence of acute respiratory distress syndrome:a comparison of two definitions [J]. Arch Dis Child,1998,79(3): 256-259.
[4]Khemani RG, Conti D, Alonzo TA, et al. Effect of tidal volume in children with acute hypoxemic respiratory failure [J]. Intensive Care Med,2009, 35:1428-1437.
[5]Yu WL, Lu ZJ, Wang Y, et al. The epidemiology of acute respiratory distress syndrome in pediatric intensive care units in China [J]. Inetensive Care Med, 2009:136-143.
[6]Hu XG, Qian SY, Xu F, et al. Incidence, management and mortality of acute hypoxemic respiratory failure and acute respiratory distress syndrome from a prospective study of Chinese paediatric intensive care network [J]. Act Paediatr, 2010 (in press)
[7]Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults [J]. Lancet,1967,2(7511):319-323.
[8]Bernard GR, Artiga A, Brigham KL, et al. the Consensus Committee. The American-European Consensus Conference on ARDS definitions, mechanisms, relevant outcomes, and clinical trial coordination [J]. Am J Respir Crit Care Med,1994,149(3):818-824
[9]Hughes M, Mackirdy FN, Ross J, et al. Acute respiratory distress syndrome:an audit of incidence and outcome in Scottish intensive care units [J]. Anaesthesia, 2003,58(9):838-845.
[10]Estenssoro E, Dubin A, Laffaire E, et al. Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome [J]. Crit Care Med,2002,30(11):2450-2456.
[11]The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome [J]. N Engl J Med,2000; 342(18): 1301-1308.
[12]宁寿葆.儿科学[M].上海：上海医科大学出版社,2000：150.
[13]Dahlem P, van Aalderen WMC, Hamaker ME, et al. Incidence and short-term outcome of acute lung injury in mechanically ventilated children [J]. Eur Respir J,2003,22(6):980-985.
[14]Parsons PE, Eisner MD, Thompson BT, et al. Lowertidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury [J]. Crit Care Med,2005,33(1):1-6.
[15]Mancini M, Zavala E, Mancebo J, et al. Mechanisms of pulmonary gas exchange improvement during a protective ventilatory strategy in acute respiratory distress syndrome [J]. Am J Respir Crit Care Med,2001,164: 1448-1453.
[16]王玉,陆铸今.小潮气量机械通气在小儿呼吸衰竭中的应用[J].实用儿科临床杂志,2006,21(22)：1562-1563
[17]Stewart TE, Mende MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotrauma in patienta at high risk for acute respiratory distres syndrome. Presure- and Volume-Limited Ventilation StrategyGroup [J]. N En J Med,1998,338:355-361
[18]Brower RG, Shanholtz CB, Fessler HE, et al. Prospective, randomized, controled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients [J]. Crit Care Med, 1999,27:1492-1498.
[19]Clark RH, Slut sky Gerestman DR. Lung protective st rategies of ventilation in the neoeate what are they[J]. Pediat rics,2000,105 (11):112-114.
[20]施丽萍,孙眉月,杜立中.新生儿呼吸窘迫综合征呼吸治疗肺保护性研究[J].中华儿科杂志,2003,41(2)：95-98.
[21]孙轶、周晓光、刘放云.肺保护性通气策略对呼吸窘迫综合征新生儿肺氧合功能的影响[J].中国小儿急救医学,2007,14(4)：305-308
[22]廖霓,张国英,郑静,等.不同潮气量机械通气对新生儿低氧性呼吸衰竭疗效的影响[J].华西医学,2008,23(6)：1319-1320
[23]Kornecki A, Tsuchida S, Ondiveeran HK, et al. Lung development and susceptibility to ventilator-induced lung injury [J]. Am J Respir Crit Care Med, 2005,171:743-752.
[24]Trachsel D, McCrindle BW, Nakagawa S, et al. Oxygenation Index Predicts Outcome in Children with Acute Hypoxemic Respiratory Failure [J]. Am J Respir Crit Care Med,2005,172(2):206-211.
[25]Erickson S, Schibler A, Numa A, et al.Acute lung injury in pediatric intensive care in Australia and New Zealand-A prospective, multicenter, observational study [J]. Pediatr Crit Care Med,2007,8(4):317-323
[26]喻文亮,陆铸今,王莹,等.小儿急性呼吸窘迫综合征前瞻性多中心临床临床流行病学研究[J].中华急诊医学杂志,2005,14(6)：448-453.
[27]Timmons OD, Dean JM, Vernon DD. Mortality rates and prognostic variables in children with adult respiratory distress syndrome [J]. J Pediatr,1991,119(6): 896-899.
[28]Rubenfeld GD, Caldwell E, Peabody E, et al. Incidence and outcomes of acute lung injury [J]. N Engl J Med,2005,353(16):1865-1693.
[29]National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Wiedemann HP. Wheeler AP. Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury [J]. N Engl J Med,2006,354(24):2564-2575
[30]Cunliffe M. Fluid and electrolyte management in children [J]. Br J Anaesth, 2003,3(1):1-4.
[31]Karimova A, Pinsky DJ. The endothelial response to oxygen deprivation: biology and clinical implications [J]. Intensive Care Med,2001,27(1):19-31.
[32]Estenssoro E, Gonzalez F, Laffaire E, et al. Shock on admission day is the best predictor of prolonged mechanical ventilation in the ICU [J]. Chest,2005, 127(2):598-603.
[33]Rivers E. Fluid managemen strategies in acute lung injury-Liberal, Conservative, or both? [J] N Engl J Med,2006,354(24):2598-2599.
[34]Thompson Bt. Glucocorticoids and acute lung injury [J]. Crit Care Med,2003, 31(4 Suppl):s253-257.
[35]Martinot A, Fourier C, Cremer R, et al. Short-course, high-dose corticosteroid treatment in six children with late ARDS [J]. Pediatr pulmonol,1997,23(4): 314-316.
[36]Goh AY, Sekaran D, Roziah M, et al. Corticosteroid rescue in late paediatric acute respiratory distress syndrome [J]. Respirology,1999,4(3):295-297.
[37]Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock [J]. JAMA,2002,288(7):862-871.
[38]National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome [J]. N Engl J Med,2006,354(16):1671-1684.
[39]Wheeler AP, Bernard GR. Acute lung injury and ther acute respiratory distress syndrome:a clinical review [J]. Lancet,2007,369(9572):1553-1565.
[40]Meduri GU, Golden E, Freire AX, et al. Methylprednisolone infusion in early severe ARDS:results of a randomized controlled trial [J]. Chest,2007,131(4): 954-63.
[41]Meduri GU, Marik PE, Pastores SM, et al. Acute lung injury and ther acute respiratory distress syndrome:a clinical review [J]. Lancet,2007,370(9585): 384-385.
[42]胡晓光,钱素云,李昌崇,等.小儿急性低氧性呼吸衰竭支持相关预后及差异及影响因素[J].中华急诊医学杂志,2010,19(2)：190-194.
[43]Kahn JM, Goss CH, Heagerty PJ, et al. Hospital volume and the outcomes of Mechnical Ventilation[J]. N Engl J Med,2006,34(9):2349-2354.
[44]Ferguson ND, Kacmarek RM, Chiche JD, et al. Screening of ARDS patients using standardized ventilator settings:influence on enrolment in a clinical trial [J]. Intensive Care Med,2004,30(6):1111-1116.
[45]Villar J, Perez-Mendez L, Lopez J, et al. An early PEEP/FiO2 trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome [J]. Am J Respir Crit Care Med,2007,176(8):795-804.
[1]Flori HR, Glidden DV, Rutherford GW, et al. Pediatric acute respiratory injury: prospective evaluation of risk factors associated with mortality [J]. Am J Respir Crit Care Med,2005,171(9):995-1001.
[2]Timmons OD, Dean JM, Vernon DD. Mortality rates and prognostic variables in children with acult respiratory distress syndrome [J]. J Pediatr,1991,119(6):896-899.
[3]Gof AYT, Chan PWK, Lum LCS, et al. Incidence of acute respiratory distress syndrome:a comparison of two definitions [J]. Arch Dis Child,1998,79(3): 256-259.
[4]Khemani RG, Conti D, Alonzo TA, et al. Effect of tidal volume in children with acute hypoxemic respiratory failure [J]. Intensive Care Med,2009, 35:1428-1437.
[5]Yu WL, Lu ZJ, Wang Y, et al. The epidemiology of acute respiratory distress syndrome in pediatric intensive care units in China [J]. Inetensive Care Med, 2009:136-143.
[6]Hu XG, Qian SY, Xu F, et al. Incidence, management and mortality of acute hypoxemic respiratory failure and acute respiratory distress syndrome from a prospective study of Chinese paediatric intensive care network [J]. Act Paediatr, 2010 (in press)
[7]Belperio JA, Keane MP, Burdick MD, et al. Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury [J]. J Clin Invest,2002,110:1703-1716.
[8]The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome [J]. N Engl J Med,2000; 342(18): 1301-1308.
[9]Amato MB, Barbas CS, M edeiros DM, et al. Effect of aprotective-ventilation strategy on mortality in the acute respiratory distress syndrome [J]. N Engl J Med, 1998,338:347-354.
[10]Parsons PE, Eisner MD, Thompson BT, et al. Lowertidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury [J]. Crit Care Med,2005,33(1):1-6.
[11]Boker A, Graham M R, W alley KR, et al. Improved arterial oxygenation with biologically variable or fractal ventilation using low tidal volumes in a porcine model of acute respiratory distress syndrome [J]. Am J Respir Crit Care M ed, 2002,165:456-462.
[12]Parsons PE, Eisner M D, Thompson BT, et al. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury [J]. Crit Care Med,2005,33:1-6.
[13]Mancini M, Zavala E, Mancebo J, et al. Mechanisms of pulmonary gas exchange improvement during a protective ventilatory strategy in acute respiratory distress syndrome [J]. Am J Respir Crit Care Med,2001,164: 1448-1453.
[14]Durante GD, Turco MD, Rustichini L, et al. ARDSNet lower tidal volume ventilatory strategy may generate intrinsic positive end-expiratory distress syndrome [J]. Am J Respir Crit Care Med 2002; 165(159):1271-1274.
[15]王玉,陆铸今.小潮气量机械通气在小儿呼吸衰竭中的应用[J].实用儿科临床杂志,2006,21(22)：1562-1563
[16]施丽萍,孙眉月,杜立中.新生儿呼吸窘迫综合征呼吸治疗肺保护性研究[J].中华儿科杂志,2003,41(2)：95-98.
[17]孙轶、周晓光、刘放云.肺保护性通气策略对呼吸窘迫综合征新生儿肺氧合功能的影响[J].中国小儿急救医学,2007,14(4)：305-308
[18]廖霓,张国英,郑静,等.不同潮气量机械通气对新生儿低氧性呼吸衰竭疗效的影响[J].华西医学,2008,23(6)：1319-1320
[19]Albuali WH, Singh RN, DD Fraser, et al. Have changes in ventilation practice improved outcome in children with acute lung injury [J]. Pediatr Crit Care Med 2007,8(4):324-330
[20]Erickson S, Schibler A, Numa A, et al.Acute lung injury in pediatric intensive care in Australia and New Zealand-A prospective, multicenter, observational study [J]. Pediatr Crit Care Med,2007,8(4):317-323
[21]宁寿葆.儿科学[M].上海：上海医科大学出版社,2000：150.
[22]Kornecki A, Tsuchida S, Ondiveeran HK, et al. Lung development and susceptibility to ventilator-induced lung injury [J]. Am J Respir Crit Care Med, 2005,171:743-752.