随机对照研究：呼吸末正压通气用于成人急性肺损伤和急性呼吸窘迫综合征

心超

Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.
呼吸末正压通气用于成人急性肺损伤和急性呼吸窘迫综合征：一个随机对照研究
出处：   2008    299(6) :646-55
作者：Mercat A;Richard JC;Vielle B;Jaber S;Osman D;Diehl JL;Lefrant JY;Prat G;Richecoeur J;Nieszkowska A;Gervais C;Baudot J;Bouadma L;Brochard L


摘自 医脉互通 Pubmed 译讯

摘要：
CONTEXT: The need for lung protection is universally accepted, but the optimal level of positive end-expiratory pressure (PEEP) in patients with acute lung injury (ALI) or acute respiratory distress syndrome remains debated. OBJECTIVE: To compare the effect on outcome of a strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation to one aimed at minimizing alveolar distension in patients with ALI. DESIGN, SETTING, AND PATIENTS: A multicenter randomized controlled trial of 767 adults (mean [SD] age, 59.9 [15.4] years) with ALI conducted in 37 intensive care units in France from September 2002 to December 2005. INTERVENTION: Tidal volume was set at 6 mL/kg of predicted body weight in both strategies. Patients were randomly assigned to a moderate PEEP strategy (5-9 cm H(2)O) (minimal distension strategy; n = 382) or to a level of PEEP set to reach a plateau pressure of 28 to 30 cm H(2)O (increased recruitment strategy; n = 385). MAIN OUTCOME MEASURES: The primary end point was mortality at 28 days. Secondary end points were hospital mortality at 60 days, ventilator-free days, and organ failure-free days at 28 days. RESULTS: The 28-day mortality rate in the minimal distension group was 31.2% (n = 119) vs 27.8% (n = 107) in the increased recruitment group (relative risk, 1.12 [95% confidence interval, 0.90-1.40]; P = .31). The hospital mortality rate in the minimal distension group was 39.0% (n = 149) vs 35.4% (n = 136) in the increased recruitment group (relative risk, 1.10 [95% confidence interval, 0.92-1.32]; P = .30). The increased recruitment group compared with the minimal distension group had a higher median number of ventilator-free days (7 [interquartile range {IQR}, 0-19] vs 3 [IQR, 0-17]; P = .04) and organ failure-free days (6 [IQR, 0-18] vs 2 [IQR, 0-16]; P = .04). This strategy also was associated with higher compliance values, better oxygenation, less use of adjunctive therapies, and larger fluid requirements. CONCLUSIONS: A strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation did not significantly reduce mortality. However, it did improve lung function and reduced the duration of mechanical ventilation and the duration of organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00188058.

专家评价：
John Kress
with David R Brush
University of Chicago, Chicago, IL, United States of America
CRITICAL CARE & EMERGENCY MEDICINE
This study demonstrates that a ventilator strategy for patients with acute lung injury (ALI) or adult respiratory distress syndrome (ARDS) combining higher levels of positive end-expiratory pressure (PEEP) with low-tidal volume ventilation does not decrease mortality, but is associated with more days free of the ventilator and days free from end-organ dysfunction. This large multicenter study had a well-designed protocol with adequate power to detect a 10% difference in mortality. The authors randomized patients with ARDS/ALI to either a minimal alveolar distension strategy that maintained PEEP and plateau pressure as low as possible, or to an increased alveolar recruitment strategy where PEEP was as high as possible while maintaining the maximal inspiratory plateau pressure between 28 and 30cmH20. All patients were ventilated using low tidal volume ventilation of 6cc/kg ideal body weight. Patients with elevated plateau pressures or refractory hypoxemia underwent protocolized ventilatory strategies designed to maintain the difference in PEEP between the two groups. There was no difference in 28 day, in-hospital or 60 day mortality between the two groups; however, patients in the increased recruitment group had significantly greater ventilator free days and organ-failure free days compared to the minimal distension group. Patients in the increased recruitment group (mean PEEP values 12.0 to 15.8cmH20) had higher PaO2s and were less likely to receive rescue therapies for refractory hypoxemia such as inhaled nitric oxide, recruitment manoeuvres and prone positioning. Higher levels of PEEP were not associated with an increased incidence of pneumothorax or vasopressor requirement, but these patients did require greater fluid loading for hemodynamic support in the first 72 hours. While low-tidal volume ventilation has been widely adopted as a ventilator strategy for patients with ALI or ARDS, there remains considerable equipoise regarding the optimal setting of PEEP. This study suggests that using a ventilator strategy combining low tidal volume ventilation while increasing PEEP to maintain a plateau pressure no greater than 30cmH20 is relatively safe, increases Pa02 and may decrease the need for rescue therapy.
Claude Guerin
hospices civils de Lyon, France
ANESTHESIOLOGY & PAIN MANAGEMENT
In my practice, the use of positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome (ARDS) is still an open and not yet solved question. Here, the authors explore a hypothesis, which is difficult to validate. This study is about the use of PEEP during mechanical ventilation in patients with acute lung injury (ALI) and ARDS. The current objective of mechanical ventilation in ALI/ARDS, apart from keeping safe oxygenation, is to prevent ventilator-induced lung injury (VILI). One large RCT has already shown that use of low tidal volume (6ml/kg predicted by the height or ideal body weight) is able to reduce mortality by 22% as compared to high tidal volume (12ml/kg ideal body weight), at the same level of PEEP in both groups (N Engl J Med 2000, 342:1301-1308 [PMID:10793162]). This result published in 2000 changed the practice of mechanical ventilation in the way of lowering tidal volume in patients with ARDS and of keeping the plateau pressure (a measurement of end-inspiratory alveolar pressure) below 30cm H20. In this study, the authors investigate the possibility that high PEEP would be more efficient than low PEEP to stabilize the airways and, hence, to minimize VILI. Indeed, to date, three large RCTs having included more than 2000 patients compared low versus high PEEP and failed to show an increase in patient survival. This study is one of them. This high quality RCT studied 767 patients over three years. It has been carried out in 37 ICUs in France. Two levels of PEEP were studied; the low level corresponded to that leading to minimal distension (PEEP between 5cm H20 and 9cm H20), while the high level to maximal recruitment (plateau pressure between 28cm H20 and 30cm H20). In both arms the tidal volume was fixed at 6ml/kg ideal body weight. At day one, the PEEP level amounted to 7.1cm H20 versus 14.6cm H20 and plateau pressures of 21.1cm H20 versus 27.5cm H2O in the low and high PEEP groups, respectively, values which were significantly different. The study showed that there was no statistical difference in patient survival between the two groups, however, there were significantly less ventilatory-free days in the low PEEP group. The strengths of this study include the following: (1) Large scale study; (2) It is not a prematurely interrupted multicenter RCT; (3) Original fashion to select PEEP. One weakness was that even though the authors based the study on difference in lung recruitability, this was not assessed and patients with high potential of recruitment may have received low PEEP as patients with low potential of recruitment may have received high PEEP. I think the next steps would be to assess the lung recruitability and to stratify high versus low PEEP in patients according to their potential of recruitment. I don't think we have to change our practice of selecting the right level of PEEP from the results of this study. It reinforces the idea that ARDS is a complex situation and that it is a syndrome, not a disease, and that efforts have to be done to better define this situation.
Jacob Sznajder
with Manu Jain
Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, United States of America
CRITICAL CARE & EMERGENCY MEDICINE
This study adds to the literature that using a protocol to titrate positive-end expiratory pressure (PEEP) in a lung with heterogenous acute respiratory distress syndrome (ARDS) doesn't improve mortality. The study does provide a rationale for testing higher PEEP in a subgroup of patients with ARDS who may benefit. This study attempted to address the issue of hyperinflation by comparing the high and low PEEP levels while limiting hyperinflation in the high PEEP group by keeping the plateau pressure between 28-30cmH2O. The higher PEEP group had lower 28-day mortality (27.8% versus 31.2%), though this difference was not statistically different. Subgroup analysis revealed that the quartile of patients with the least oxygenation impairment (PaO2/FiO2 ratio >181) had greater mortality with higher PEEP, in contrast to the other three quartiles that had lower mortality with higher PEEP. This may be a chance finding or may reflect that, in patients with mild lung injury, there may be less benefit and more cost associated with higher PEEP. Patients with more severe derangements of oxygenation have more recruitable lung and are, thus, more likely to benefit from higher PEEP. Also of interest from this study was the observation that the higher PEEP group required rescue therapy (i.e. prone positioning, nitric oxide inhalation, almitrine infusion) less frequently than the low PEEP group. The mortality of those that required rescue therapy was nearly 50%. Ventilator-induced lung injury (VILI) contributes to morbidity and mortality in acute lung injury (ALI)/ARDS. Animal models suggest that it can be caused by alveolar overdistention and by repetitive opening and closing of alveoli. Low tidal volume ventilation has been shown to improve outcomes in patients with ALI/ARDS presumably by limiting alveolar overdistention. It has been postulated that optimizing ventilator PEEPS may limit injury due to repetitive opening and closing of alveoli. Previous clinical studies evaluating optimal levels of PEEP have failed to resolve this question. One postulated reason for the failure of previous PEEP studies to show benefit is that many of them titrated PEEP based on a predefined algorithm rather than on an individual's lung mechanics. Thus, the putative benefit of optimizing PEEP in a given patient may have been negated by alveolar overdistention. This view is supported by data obtained by CT scanning of patients with ALI/ARDS, which show heterogenous effects of PEEP in a lung with ALI/ARDS. Some patients had significant lung recruitment with PEEP while others developed hyperinflation in already ventilated areas. The next step in research should be to compare the effect on the outcome of a strategy for setting PEEP aimed at increasing alveolar recruitment while limiting hyperinflation to one aimed at minimizing alveolar distension in patients with ALI. A trial in which PEEP is titrated to lung recruitment (as assessed by pressure-volume curves of lung or CT scanning) would provide the best evidence for the putative beneficial effects of high PEEP in ARDS.
摘要：
背景：肺保护是全球都非常关注的问题，但呼吸末正压通气（PEEP）用于治疗成人急性肺损伤(ALI)和急性呼吸窘迫综合征的最佳模式仍有争议。
目的：对ALI的患者设置两种PEEP模式，一种是限制充气过度，增加肺泡复原。另一种是将肺泡膨胀最小化。比较这两种模式的优缺点。
设计，设置和患者： 一个多中心、随机、对照实验，共有767名成年ALI患者（平均年龄59.9±15.4年），分别住院于37个加强监护病房，数据采集从2002年12月到2005年12月。
介入：两组患者的潮气量均设为6ml/kg理想体重。患者随机分为中度PEEP（5-9 cm H2O）（限制膨胀组，n=382），或将PEEP设置到一个平台压力为28-30cm H2O（增加肺泡复原组，n＝385）。
主要指标：第一个指标点为第28天的死亡率；第二个指标点为60天的住院死亡率；停用机械通气时间，和第28天的非器官衰竭情况。
结果：限制膨胀组的第28天死亡率为31.2%（n=119），增加肺泡复原组为27.8%（n=107）(相对危险度，1.12[95%可信区间，0.9-1.4]；P=0.31)。住院死亡率，限制膨胀组的为39%（n=149），增加肺泡复原组为35.4%（n=136）(相对危险度，1.10[95%可信区间，0.92-1.32]；P=0.3)。增加肺泡复原组和限制膨胀组相比，其停用呼吸机时间较长（分别为，7[四分位数间距为｛IQR｝，0-19]；3〔IQR〕，0-17；P = .04). 无器官衰竭时间分别为(6 [IQR, 0-18] vs 2 [IQR, 0-16]; P = 0.04)。这种方法患者顺应性高，氧合好，辅助治疗少，液体流量增加。
结论：限制充气过度，增加肺泡复原这种方法并不能明显减少死亡率。但是它可以改善肺功能和减少机械通气持续时间并增加无器官衰竭的时间。

实验注册：临床试验，注册号：NCT00188058.

专家评价：
John Kress with David R Brush
University of Chicago, Chicago, IL, United States of America
美国芝加哥大学
CRITICAL CARE & EMERGENCY MEDICINE
病危护理和急救医学
这个实验研究了ALI患者和ARDS患者的通气治疗方法。较高值的呼气末正压通气配以低容量通气并不能明显减少患者的死亡率，但是减少了呼吸机使用时间和器官衰竭时间。这个大型多中心临床研究进行了精心设计，有足够的数据来说明10％的死亡率的差异。作者随机将患有ARDS/ALI分为两组，一组是用持续PEEP和尽可能低的平台压力，尽可能最低限制肺泡膨胀的策略，另一种以较高的PEEP维持最大吸入平台压在28-39cmH2O以增加肺泡恢复。所有的患者均采用低容量通气6cc/kg体重。两组患者均根据实验设计时的通气方法提高平台压力或耐受低氧血症。在第28天,住院期间，第60天的死亡率，两者之间没有差别：但是，增加肺泡恢复组可以明显增加停用呼吸机时间和减少器官衰竭时间。增加肺泡恢复组（平均PEEP值为12.0-15.8 cmH20）有较高的PaO2，不像其他救援方法会导致难治低氧血症，比如：吸入氧化亚氮，复苏手法和俯卧位。较高水平的PEEP没有增加气胸或血管加压药的使用，但是在头72h患者需要更多的液体负荷来进行循环支持。当低容量通气广泛被采用于治疗ALI和ARDS患者，但是合适的最佳PEEP值仍有争议。这个研究证明了使用低容量通气辅以较高PEEP来维持一个平台压力（<30cmH2O）相对安全，增加Pa02和减少了其他的治疗措施。

Claude Guerin
hospices civils de Lyon, France
ANESTHESIOLOGY & PAIN MANAGEMENT
麻醉学和疼痛处理
以我的经验，在ARDS患者中使用PEEP仍是一个有争议的问题。这里，这个作者研究了一个非常难以证明的假设。这个研究对ALI和ARDS患者在行机械通气时辅以PEEP。对ALI/ARDS患者中使用机械通气的目的，不仅仅是为了保持安全的氧合，还要防止机械通气所导致的肺损伤（VILI）。一个大型临床随机对照实验已经证实在使用同样的PEEP的情况下，使用低容量通气（6ml/kg根据理想体重或身高）和高容量通气(12ml/kg根据理想体重或身高)可以减少22%的死亡率，(N Engl J Med 2000, 342:1301-1308 [PMID:10793162])。这项研究发表在2000年，改变了以往机械通气的方法，降低ARDS患者的潮气量并保持一个吸气末平台肺泡压力小于30cmH2O。在这篇研究中，作者发现高PEEP比低PEEP可以更有效的稳定气道，因此减少了VILI发生。事实上，有三个大型的临床随机对照实验包括2000多个患者，均发现和低PEEP相比，高PEEP并没有增加患者的生存率。这个研究是其中之一，这个高质量的RCT研究了767名患者，花费了超过3年的时间。病例采集于法国37个ICU。作者研究了两种PEEP方法：一种是是用持续PEEP和平台压力（PEEP维持在5cmH2O－9cmH2O），尽可能最低限制肺泡膨胀的策略，另一种以较高的PEEP维持最大吸入平台压在28-30cmH2O以增加肺泡恢复。两组患者均采用了固定的6ml/kg的理想体重的潮气量的值。在第一天的时候，低PEEP组和高PEEP组的PEEP水平分别为7.1cm H20和14.6cm H20，21.1cm H20 和27.5cm H2O。这项研究显示，两组患者之间的生存差异没有区别，但是用低PEEP组的患者其停机械通气的时间短。这个研究的可信度包括一下几个方面：(1)大规模的实验； (2)不是一个短年期的多中心的RCT实验。 (3)随机方法选择PEEP。唯一的缺点在于作者研究了两组之间的肺恢复情况，但是，在实验前没有估计两组患者的肺的情况，可能接受低PEEP治疗的患者其本身的肺的情况较差，而接受高PEEP的患者其本身可能肺恢复的能力就较强。我认为下一步应该根据患者本身的肺恢复能力来分组，再行低PEEP组和高PEEP组的肺恢复情况的比较。我不认为我们会因为这篇文章而改变我们以往选择的合适的PEEP值。需要强调的是，ARDS是一种复杂的情况，是一种综合症，不是一种疾病，我们必须努力更好的定义这种情况。


Jacob Sznajder
with Manu Jain
Division of Pulmonary and Critical Care Medicine, Northwestern University, Feinberg School of Medicine, United States of America
CRITICAL CARE & EMERGENCY MEDICINE
危重病护理和急救医学

这个研究使用了逐步增加PEEP治疗ARDS，结果发现并没有增加死亡率。这个文章提供了一个治疗ARDS有效的方法，就是用较高的PEEP。本研究比较一种用持续PEEP尽可能最低限制肺泡膨胀的策略，另一种以较高的PEEP维持最大吸入平台压在28-30cmH2O以增加肺泡恢复。较高PEEP组的死亡率低于较低PEEP组(27.8% vs 31.2%)，但这点差异没有统计学意义。亚组分析显示1/4的患者有最小程度的氧损伤(PaO2/FiO2 率 >181)但死亡率高于较高PEEP组，但其他3/4组则比较高PEEP组死亡率低。这个结果可能反映了在轻度肺损伤的患者，用高PEEP无益处而且花费更高。而患者如果有严重的氧合紊乱和肺功能，则用高PEEP比较有利。虽然这个实验的结果很有意思，较高PEEP组比较低PEEP组需要更多的辅助治疗（如：俯卧位，氧化亚氮，阿米三嗪注射）。这些需要辅助治疗的患者的死亡率接近50%，呼吸机诱导的肺损伤（VILI）在ALI/ARDS患者中的发病率和死亡率中也有作用。
动物模型揭示：这个原因可能是由于反复的肺泡打开和关闭导致的肺泡过度膨胀有关。低潮气量通气证实可以通过限制肺泡过度膨胀而改善ALI/ARDS患者的情况。那么可以这样假设合理的通气时候的PEEP可以减少由于肺泡反复闭合所导致的损伤。以前临床上所用的最佳PEEP水平可能不能解决这个问题。另一个对PEEP的研究，显示逐步增加PEEP比较有益的原因可能是基于预定义的算法而不是就个体的肺机制而言。因此，假定最佳PEEP对患者有利，可能可以忽略其肺泡的过度膨胀。对ALI/ARDS 患者行PEEP的肺的CT扫描的结果证实了这一推断。一些行PEEP患者的肺恢复明显，同时另一些则在以有通气的区域形成了充气过度现象。下一步的研究是找到一个使用PEEP的最佳模式，可以增加肺恢复，同时限制肺泡过度充气，减少ALI患者的过度膨胀。逐步增高PEEP有利于肺恢复（通过肺压力容量曲线和CT扫描）这一实验，可能为高PEEP用于ARDS的治疗提供了一个有利的证据。
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