【作者】 喻文亮；

【导师】 孙波； 陆铸今； 王莹； 施丽萍； 钱素云；

【作者基本信息】 复旦大学 ， 儿科学， 2006， 博士

【摘要】 前言急性呼吸窘迫综合征（ARDS）是严重威胁各年龄层人群的临床危重症。它集呼吸、循环、血液、代谢、炎症等方面的严重障碍于一身，与呼吸机技术的进步紧密相连，被称为临床危重症的“典型范例”。ARDS是儿科重症监护病房（PICU）最为棘手的疾病之一，也是急性严重呼吸综合征（SARS）及禽流感患儿主要死因，近年已成为欧美发达国家小儿危重病的主攻内容。1994年ARDS欧美联席会议（AECC），颁布了ARDS新定义：1、急性起病；2、PaO₂／FiO₂≤200 mmHg（不论PEEP水平如何）；3、前后位胸片两侧浸润影；4、肺动脉楔压≤18mmHg或临床无左房压增高证据。小儿ARDS为PICU的少见病症，攻克这一临床医学重症必然期待多中心协作以获取具有统计学力度的样本。我国在世界上拥有最丰富的病儿资源，构建全国小儿ARDS协作组，整合PICU病儿资源，开展临床多中心研究，应能提高我国小儿危重医学临床研究水平，并使之在国际儿科研究中占有一席之地。我们组织全国25家省市级儿童医院及综合医院儿科的PICU，成功组建全国小儿ARDS协作组，开展了一项多中心临床流行病学调查；同时结合临床流行病学获得的启示，针对国际肺保护性通气策略中新兴但尚有争议的超常规机械通气治疗手段—ARDS开放肺技术（OLC），开展了一项动物实验。我们希望通过前项研究，获得我国关于小儿ARDS较为全面的资料及数据，并为进一步组织实施小儿危重病多中心、前瞻性临床协作研究和构建我国小儿危重病协作网进行一些尝试；而动物实验的研究则进一步寻求有效的小儿重症ARDS救治措施，如果安全且有效，则可以为下一步开展合理的临床干预研究提供前期实验依据。第一部分小儿ARDS急性呼吸窘迫综合征前瞻性多中心临床流行病学调查背景ARDS是儿科临床危重症，伴有低发病率、高病死率和高医疗费用。1994年ARDS AECC，颁布了ARDS新定义：1、急性起病；2、PaO₂／FiO₂≤200 mmHg（不论PEEP水平如何）；3、前后位胸片两侧浸润影；4、肺动脉楔压≤18 mmHg或临床无左房压增高证据。临床流行病学调查可提供疾病发病情况和发病规律的第一手资料，为进一步开展临床研究、诊断治疗的标准化及临床资源的合理配置提供可靠依据。国际上既往关于小儿ARDS的临床流行病学调查资料显示，PICU中ARDS的患病率为0.7-4.2％，病死率为30-70％。但大多研究为回顾性单中心研究。国际尚未见以94年欧美联席会议ARDS新定义为基础的小儿多中心临床流行病学研究，而国外既往的流行病学调查结果并不能反映我国的发病情况和发病规律，因此，有必要获取我们自己的临床流行病学资料。目的前瞻性调查我国儿科重症监护病房收治小儿ARDS的状况，探讨其在我国PICU中的患病率、病死率、原发病、诊断特点、疾病负担、及病死相关因素等。方法组织全国25家拥有PICU建制的儿童医院组建小儿ARDS协作组，对2004．1．1-2005．6．30期间（各家医院均为12个月）收入参加医院PICU的所有年龄在生后29天-14周岁的危重患儿进行前瞻性调查。PICU危重病儿收治数按国内小儿危重评分及美国PICU入出院指南进行筛选后确定，作为同期小儿ARDS在PICU中患病率的基数。ARDS按94年欧美联席会议标准进行诊断。患儿入选ARDS后，前五天每12小时，五天后每天收集一次数据，大于21天者每周收集两次数据，数据包括：人口学特征、呼吸机参数、气体交换、肺力学及血液动力学指标、器官功能、病人预后和疾病负担等。指定复旦大学附属儿科医院为调查协调中心，负责管理调查工作和数据质量的监控；建立中心数据库和协作组自己的网站及基于网页的数据录入方式，以实现数据的及时呈递和信息的快捷沟通。所有资料应用软件SPSS 11.0进行统计分析。结果25家PICU12个月总收治病人数为12 018例，符合危重病例标准者7 269例，PICU危重病儿病死率为6.7％（485／7 269），ARDS 105例，病死64例，患病率为1.44％（105／7 269），病死率为61.0％（64／105）。ARDS病死率为PICU危重病例的9.0倍。ARDS起病后24小时病死者为23例，占ARDS病死者35.9％（23／64）。ARDS主要原发病为肺炎（55.2％）及脓毒症（22.9％）。并存慢性疾病者32.4％（34例），ARDS起病时平均年龄为54.1±54.7（中位数24）月。ARDS起病距原发病起病时间为77.8±55.7小时，其第25，50，75，90，95百分位分别为24、72、120、144及168小时。ARDS行机械通气者97例，行压力控制通气者61.9％（60／97），机械通气初始参数吸气峰压、平均气道压、呼气末正压及潮气量分别为27.5±6.1cmH₂O、13.9±4.1 cmH₂O、7.1±3.4 cmH₂O及8.0±3.7 ml／kg，生存者及病死者平均机械通气时间分别为10.5±10.8天及6.2±6.8天。生存者平均住院日为18.8天，为危重病例中非ARDS患者平均住院日的2.8倍，ARDS生存者PICU费用为38 986元，为PICU中非ARDS病例的4.3倍。结论小儿ARDS在我国PICU中是一患病率低、病死率高、疾病负担重的疾病，病死率高于欧美国家水平。本研究资料提供了小儿ARDS在我国PICU的收治状况，可以作为现阶段与发达国家平均医疗水平横向对比的依据，为将来针对小儿危重呼吸疾病进行多中心随机对照试验，提供基础治疗和实验设计的参考。第二部分开放肺技术救治油酸致ARDS幼猪的实验研究背景机械通气一直是ARDS最重要的救治手段。小潮气量肺保护性通气策略尽管显著降低了ARDS病人的病死率，但仍有30％的病人无法存活。开放肺技术（OLC）是一项新兴的、仍存争议的超常规呼吸机救治手段，其基本方法是突破传统机械通气的禁区，逐步抬高吸气峰压（PIP）和呼气末正压（PEEP）至极高水平（PIP 50-60 cmH₂O，PEEP 20-30 cmH₂O），完全打开ARDS不张的肺组织，从而达到改善氧合，挽救生命的目的。成人研究显示其对一些重症ARDS病人效果明显。但小儿重症ARDS是否能够应用，是否安全有效值得探讨，为此，我们建立油酸致ARDS幼猪模型，应用OLC，探讨其安全性及有效性；同时比较不同模式机械通气维持肺开放的效果，试图寻找出小儿重症ARDS的救治新途径，探讨出OLC安全有效的新流程。目的在ARDS幼猪模型上建立OLC，探讨其安全性及有效性。比较不同通气模式维持肺开放的效果。方法25头5-6周龄8-10kg健康雄性幼猪，经镇静麻醉后给予气管插管、常规机械通气，稳定30分钟后应用油酸经中心静脉诱导产生ARDS模型。ARDS模型判断标准：（1）动脉血氧分压／吸入氧浓度（PaO₂／FiO₂）≤200 mmHg；（2）呼吸系统动态顺应性（Cdyn）较基础状态下降50％以上；（3）肺动脉楔压（PAWP）≤18mmHg；（4）出现上述指标后，有4头动物立刻处死，观察病理符合急性肺损伤。肺开放标准为PaO₂／FiO₂≥400mmHg，21头ARDS幼猪在PCV机械通气状态下逐步抬高PIP及PEEP直至PaO₂／FiO₂≥400 mmHg，再将PIP及PEEP逐步下调至最佳值。然后将18头成功建立肺开放技术的幼猪随机分为三组：PCV组，应用压力控制通气，PIP及PEEP分别设定为PIP最佳值、PEEP最佳值；PSV组，应用压力支持通气，PIP及PEEP分别设定为PIP最佳值及PEEP最佳值；APRV组，PIP设定为最佳值，PEEP设定为0。每组通气6小时。在基础状态、ARDS成模时、肺开放时、观察6小时的每一时点监测气体交换、血液动力学、呼吸力学等指标以评估开放肺技术的安全性及有效性。实验结束后行一侧肺灌洗、另一侧肺灌流固定和组织形态学检查。支气管肺泡灌洗液（BALF）中白细胞计数（WCC）、总蛋白（TP）、总磷脂（TPL）和饱和磷脂（DSPC），总磷脂表面张力测定；肺组织湿／干重比（W／D）；肺病理形态学检查，对肺泡扩张、肺损伤特点评分。肺组织中分析测定髓过氧化物酶（MPO）、丙二醛（MDA）以评估炎症反应状况。结果1．ALI模型的建立在3-5小时内可诱导出ARDS模型，表现为弥漫性肺水肿及严重肺泡萎陷、出血等病理表现。模型时PaO₂／FiO₂、Cdyn均显著低于基础状态时（P均＜0.01）。2．开放肺技术的建立21头动物有18头动物成功建立开放肺技术，PaO₂／FiO₂均≥400mmHg。PaO₂／FiO₂、Cdyn均显著高于模型时（P均＜0.01）。无气胸出现。3．气体交换指标三组动物肺开放后（R）各项氧合指标差异无统计学意义。观察6小时（O6）后，APRV组PaO₂／FiO₂显著高于R时点（P＜0.01），PCV组及PSV肺开放后氧合则无显著变化。O6时点APRV组显著高于PCV组（P＜0.05）及PSV组（P＜0.05）。其他氧合指标变化与PaO₂／FiO₂类似。4．肺力学指标三组动物R时点各项肺力学指标均无显著差异。O6时点，APRV组PIP显著低于R时点（P＜0.01），Cdyn显著高于R时点（P＜0.01）。PSV组及PCV组均未见显著差异。三组之间差异无统计学意义。其他肺力学指标变化差异无统计学意义。5．血液动力学指标三组动物R时点心输出量（CO）差异无统计学意义。O6时点CO与成模时点及R时点各组差异无统计学意义。APRV组和PCV组R时点及其后所有时点CO均显著低于基础状态时点（P＜0.01），但PSV组仅R时点CO显著低于基础状态（P＜0.05）。O6时点APRV组及PCV组CO均显著低于PSV组（P＜0.05）。其它血液动力学指标与CO相似。相关分析提示PIP（r=-0.500，P=0.000）及MAP（r=-0.571，P=0.000）与CO存在相关。6．炎症指标基础状态、成模时及处死前白细胞计数三组差异无统计学意义，R时点APRV组白细胞计数显著低于PCV及PSV组（P均＜0.05）。三组各时点白细胞计数差异无统计学意义。肺湿／干重比（W／D）三组差异无统计学意义。肺泡灌洗液（BALF）中白细胞计数差异无统计学意义。MDA APRV组显著高于PCV组（P＜0.05）及PSV组（P＜0.01），MPO三组间差异无统计学意义。7．总磷脂（TPL）含量及饱和磷脂（DSPC）含量APRV组、PSV组量显著高于PCV组（P＜0.05），但其它指标差异无统计学意义。结论在ARDS幼年动物模型上建立开放肺技术安全且有效，证实气道压力释放通气维持开放肺效果方面相对于压力控制通气及压力支持通气具有改善气体交换的优势，而压力支持通气可能具有改善血液动力学状况的优势。该研究为开放肺技术在小儿重症ARDS的救治上提供实验依据。更多还原

【Abstract】 Acute respiratory distress syndrome （ARDS） is a rare but intractable disease in intensive care unit （ICU） leading to a high mortality in patients with pulmonary and extrapulmonary causes. There is an uniform criteria for diagnosis of ARDS in 1994 by American-European Consensus Conference （AECC） definition, but no conmvincing therapeutic guideline has ever been established except for small tidal volume ventilation strategy. Derangements of respiration, circulation, metabolism, coagulation, and inflammation are all present in this syndrome, which is then a perfect paradigm to study the underlying physiology, the complex interations between organ systems, and their interaction with treatment especially mechanical ventilation. ARDS is the main death cause of severe acute respiratory syndrome and avian influenza. It is also one of the most troublesome diseases in pediatric ICU （PICU）.In 1994 AECC, ARDS was defined as co-existance of acute onset of bilateral infiltrates on chest radiograph without evidence of left atrial hypertension, and PaO₂/ FiO₂ ≤200 mmHg, irrespective of ventilatory support, type and settings. In recent years, investigations of various interventions through randomized, controlled clinical trial tend to include patient response towards mandatory mechanical ventilation, so that only most severe cases are eligible for the trial study, and those with transient respiratory difficulty and insufficiency may be eliminated.In PICU, ARDS should be classified as rare disease. Multicenter collaboration is essential to obtain enough pediatric ARDS samples to achieve sufficient statistical power. Large population in China determines a sufficient cases available to the study endpoint. To this purpose, we established a collaborative study group of pediatric respiratory disease in 25 PICUs in China and exerted a 12-month prospective, multicenter study in ARDS. Furthermore, based on a new, disputable lung protectiveventilation strategy, that is, open lung concept （OLC）, we conducted an experimental study in an oleic acid-induced model of severe ALI in young piglets and compared the effects of OLC with different ventilatory modes. The first study provided clinical epidemiologic data in pediatric ARDS in China, which may promote interventional investigation as multicenter, randomized, controlled trials in pediatric severe hypoxic respiratory failure. The second study should enable a comprehensible experiment for testing of effects and safety of an extraordinary ventilatory means in combating intractable respiratory failure such as ARDS in children.Part I Prospective, Multicenter Clinical Study of Pediatric Acute Respiratory distress in 25 Pediatric Intensive Care Units in ChinaBackground Acute respiratory distress syndrome is a serious clinical problem associated with low incidence, high mortality, morbidity, and cost in PICU. In 1994, the AECC on ARDS was convened to bring clarity and uniformity to the definition of ALI and ARDS. The conference defined ARDS as acute onset of bilateral infiltrates on chest radiograph without evidence of left atrial hypertension and with a PaO₂/FiO₂ ≤200 mmHg. Clinical epidemiologic studies may provide incidence, clinical course and risk factors of underlying diseases leading to pediatric ARDS. This information is essential for planning research, allocating resources, promoting quality improvement of medical care for pediatric critical patients. The published incidence of ARDS in PICU varies from 0.7% to 4.2%, and the mortality of ARDS in PICU varies from 40% to as high as 80%, most of whcih come from single center and/or retrospective studies. No prospective multicenter studies specifically investigated the incidence and outcomes of ARDS in PICU patients since AECC definition was published and before we initiated this study.Objective To determine incidence, management, mortality, risk factors, diagnostic feature, disease burden of pediatric patients who developed ARDS while in PICU.Methods Chinese collaborative study group for pediatric respiratory failure consisted of 25 PICU located in 20 cities of 17 provinces/municipals, we prospectively investigated all the patients between 29 days to 14 years old admitted to these PICU, and entry criteria were used with a Chinese pediatric critical illness severity score and American guidelines for admission and discharge policies for PICU provided by American college of critical care medicine of the society of critical caremedicine and American academy of pediatrics. ARDS was diagnosed according to the 1994 AECC definition. Information of ARDS patients admitted to all participating PICUs was prospectively collected by trained staffs using a standard case report form. In the first 5 days after study entry, data were collected twice daily, and then once daily in the subsequent days until death or discharge. If the survival period was longer than 21 days, data should be collected at least twice a week until discharge or death. The data included demographics, ventilator settings, hemodynamics and lung mechanics, arterial blood gas, liver, renal function test, prognosis, etc. Children’s Hospital of Fudan University coordinated the study. We eastablished a standard central database and the web site for the collaborative study group. With a network assisted by internet techniques, some data were electronically submitted to the center in a timely and convenient way. Data management was conducted using software SPSS version 11.0.Results A total of 7,269 of ICU admissions was enrolled in a 12-month period, of which 105 （1.44%） developed ARDS. Mortality of all the admissions in these ICUs was 6.7% （485/7 269）, and overall mortality for ARDS was 61.0% （64/105）, which accounts for 13.2% of ICU deaths （64/485） and approximately 9.1 times as high as the average death rate of PICU. The constitutive ratio of deaths in the first 24-h period of the onset of ARDS was 35.9% （23/64）. The mean （SD） time course between the disorders as predisposing factor （s） and onset of ARDS was 77.8 + 55.7 h, the 25th, 50th, 75th, 90th, 95th percentile were 24, 72, 120, 144, 168 h respectively. During the treatment period of ARDS in PICU, 97 patients received mechanical ventilation. The most commonly used ventilatory mode was pressure control （60, 61.9%）. The mean （SD） values of initial peak inspiratory pressure, positive end-expiratory pressure, mean airway pressure and tidal volume in ARDS during invasive mechanical ventilation were 27.5 ± 6.1 cmH₂O, 13.9±4.1 cmH₂O, 7.1±3.4 cmH₂O, and 8.0± 3.7 ml/kg, respectively. The mean length of stay for ARDS survivors was 18.8 days which was 2.8 times as high as the average level for those of PICU stay. Costs of clinical care for ARDS survivors were 4.3 times as high as average level for PICU stay.Conclusion The results provided a preliminary profile of pediatric ARDS in China, with low incidence, high mortality and cost, and the mortality was higher than the published data in developed country. These results suggest an importance ofimplementation of advanced respiratory care concept and protocols as well as clinical epidemiology. This also calls for attention in improvement of service quality, resource and staff competence as well as welfare policies for pediatric intensive care. It also serves as a basis for further multicenter, prospective clinical studies of pediatric ARDS.Part II Experimental Study on Open Lung Concept in Rescuing Treatment of Young Piglets with ARDS Induced by Oleic AcidBackground Mechanical ventilation remains the most important treatment for pediatric ARDS. About 30% adult patients died of ARDS even though lung protective ventilation strategy by lower tidal volume was executed. A new, disputable lung protective ventilation strategy which mainly targets to ARDS, that is, open lung concept （OLC） has currently been the focus of clinical and experimental investigation of the field. Anecdotal reports revealed that it may achieve dramatic oxygenation target by increasing PIP and PEEP to very high levels to open unstable alveoli completely. Whether it is feasible in pediatric ARDS remains unknown. The aim of current study is to investigate efficacy and safety of OLC in severe experimental ALLObjective To establish an ARDS model in young piglets induced by oleic acid. To explore the feasibility of OLC on ARDS piglet and compare effects of mandatory and assist ventilatory modes after OLC was established in the ARDS piglets.Methods The study was performed in 25 male piglets （body weight 8-10 kg）. Anesthesia was induced by ketamine. A tracheotomy was performed with placement of an endotracheal tube connected to the ventilator circuit, followed by mechanical ventilation with a standard tidal volume of 10 ml/kg. Following instrumentation and a 30-min stabilization period, severe lung injury was produced by oleic acid. After establishment of ARDS model, PIP and PEEP were increased step by step every 5 minutes until PaO₂/FiO₂ ≥ 400 mmHg in 21 piglets. Then PIP and PEEP were decreased and titrated step by step every 5 minutes until an optimal level of oxygenation was achieved. In 18 piglets when OLC was established successfully, they then were randomly allocated to three groups （n=6） receiving PCV, PSV and APRV,respectively for another 6 h. The variables for gas exchange, lung mechanics, hemodynamics were measured at baseline （B）, establishment of ALI （M）, accomplishment of OLC （R）, and every 1 h during post-OLC period. Blood cytology was measured at B, M, R, and the 6 h of the post-OLC period. Values for total proteins （TP）, total phospholipids （TPL）, disaturated phosphatidylcholine （DSPC） were measured with biochemical methods, and values of minimum and maximum surface tension ( γ _min, γ _max) of TPL in bronchoalveolar lavage fluid （BALF） were measured using pulsating bubble surfactometer. Wet-to-dry lung weight ratio （W/D）, lung morphology, myeloperoxidase （MPO） and malondialdehyde （MDA） in lung tissue were determined at the end of the experiment.Results1. Twenty-five piglets developed ARDS in 3 to 5 hours after oleic acid injection as evidenced by marked decrease of PaO₂/FiO₂< 200 mmHg, and reduction of Cdyn by 50% compared to the corresponding time B levels. Four piglets were sacrificed at once for evaluation of lung pathological changes. The pathologic changes in these piglets revealed significant protenaceous alveolar edema and atelactasis, alternative with markedly interstitial hemorrhage.2. OLC was achieved successfully in 18 piglets with ARDS as evidenced by marked increase of PaO₂/FiO₂>400 mmHg, and Cdyn significantly increased compared to that at time M （P<0.01）. No pneumothorax was found in these animals.3. Gas exchange. No significant difference was observed in all gas exchange variables among the three groups at the time R. At time 06 h in the APRV group, PaO₂/FiO₂ increased significantly as compared with that at R （P<0.01）, or compare with PCV （P<0.05） and PSV （P<0.05） at the same time point. The same is true for the difference of other oxygenation variables compared to PaO₂/FiO₂.4. Lung mechanics. No significant difference was observed in all lung mechanics variables among the three groups at the time R. At 06 in the APRV, PIP （P<0.01） decreased and Cdyn （P<0.01） increased significantly as compared with those at R, but no significant difference in PIP and Cdyn was found among the three groups. No significant difference of other lung mechanic variables was observed.5. Hemodynamics. No significant difference was observed in all hemodynamic variables at the time R. No significant difference was found in cardiac output （CO） between 06 and R or M. CO in the APRV （P<0.01） and the PCV （P<0.01） at R and following all time point decreased significantly as compared with that at timeB. CO in the APRV （P<0.01） and the PCV （P<0.05） was lower than that in the PSV. The difference of other hemodynamic variables was similar to CO, whcih was inversely correlated to PIP （r=-0.500, P=0.000） and MAP（r=-0.571, P=0.000）.6. Inflammation. No significant difference was found in white blood cell counts （WCC） among three groups at time B, R and 06. WCC of the APRV was lower than that of the PCV （P<0.05） and the PSV （P<0.05） at R. There was no significant difference in W/D, MPO among the three groups. MDA in the APRV increased significantly as compared with the PCV （P<0.05） and the PSV （P<0.01）. No difference was observed in WCC in BALF among the three groups.7. Phospholipid assay. Significant increase was seen in TPL and DSPC in the APRV and the PSV as compared to the PCV, but no significant difference in DSPC/TPL, TP and DSPC/TP.ConclusionThe achievement of OLC on piglets with ARDS is feasible. To maintain the oxygenation effects of OLC, APRV is superior to PCV and PSV. In contrast, PSV had advantage of hemodynamic stability as compared to APRV and PCV when OLC was performed. These results warrant a design of clinical investigation to assess efficacy of OLC in ARDS in pediatric patients.更多还原