March 6, 2018
Alexandre Biasi Cavalcanti, Marcelo Britto Passos Amato, Carlos Roberto Ribeiro de Carvalho
In Reply Dr McKown and colleagues suggest that the method used to personalize PEEP might be one explanation for the higher mortality in the recruitment maneuver and PEEP titration group. When multiple PEEP levels had similar compliance, we set the PEEP at 2 cm above the highest of these levels based on observations from a previous case series.1 Mean PEEP levels used in the experimental group were similar to other high-PEEP trials. We also used a tidal volume of 5 mL/kg predicted body weight during PEEP titration, although tidal volume was set at 6 mL/kg during maintenance ventilation (or lower if plateau pressure >30 cm H2O). We acknowledge that using the same tidal volume both during PEEP titration and maintenance ventilation would have been a better choice, although the small differences between tidal volume during PEEP titration and maintenance ventilation were unlikely to substantially change the level of optimal PEEP.
回答：McKown医生及其同事提示，我们使用的个体化设置PEEP方法可能是造成肺复张及PEEP滴定组患者病死率较高的原因之一。基于既往病例系列研究结果，当多个PEEP水平下的顺应性相似时，我们将PEEP设置在上述最高水平之上2 cm。试验组的平均PEEP水平与其他高PEEP研究相似。在PEEP滴定过程中，我们使用的潮气量为5 mL/kg理想体重，尽管在维持通气过程中我们使用的潮气量为6 mL/kg 理想体重（如果平台压>30 cm H2O，潮气量更低）。我们承认在滴定PEEP及维持通气过程中采用相同的潮气量可能是更好的选择，但这两个阶段潮气量的微小差异不太可能显著影响适宜的PEEP水平。
Dr Barbas and colleagues offer 5 potential explanations for the results. First, the recruitment maneuver was abrupt and short. The recruitment maneuver adopted in the trial was based on 2 noncontrolled studies that showed excellent lung recruitability and safety.1,2 We started the recruitment maneuver with the same PEEP level as the study by Borges et al1 and increased PEEP in steps of 10 cm H2O, similarly to Matos et al,2 or in steps of 5 cm H2O in the second half of the trial.
Our recruitment maneuver was shorter (1 minute) based on evidence showing that most lung recruitment occurs in 10 seconds of a sustained inflation, while the risk of hypotension increases after this time.3 Second, Barbas and colleagues suggest that intensivists had little experience with recruitment maneuvers, sometimes not noticing a reversible complication. Adequate implementation of the protocol was pursued zealously in ART using multiple strategies. All sites were visited and received training (except 1 site trained with web conference), used bedside manuals to guide procedures, and were contacted immediately after each patient was enrolled to promote adherence to study procedures. We also conducted periodic teleconferences and sent monthly newsletters. The proposition that inexperience might explain the results is not supported by data: there was no evidence of heterogeneity of treatment effect on mortality across sites, including sites with experienced investigators. Third, Barbas and colleagues state that about 22% of the patients did not receive the second recruitment maneuver after PEEP titration. In fact, the protocol established that whenever complications occurred during the first recruitment maneuver, the second should be omitted. Fourth, it was argued that most patients in the experimental group did not receive a new recruitment maneuver from day 1 to 7, whereas some patients in the control group received a recruitment maneuver. Similar to previous studies,1,2 recruitment was only repeated after day 1 when oxygenation worsened or circuits were disconnected. Most patients continuously improved oxygenation, thus repeating the recruitment maneuver was inappropriate. The control group followed the ARDS Network protocol, which allowed recruitment maneuvers in cases of refractory hypoxemia. Fifth, allowing prone position after evidence of benefit provided by the PROSEVA trial was an ethical imperative but not a confounder because prone positioning was well-balanced between groups.4
Barbas医生及其同事提出了解释研究结果的5种可能原因。首先，肺复张时间较短。试验中采用的肺复张操作基于2项非对照研究，这两项研究均证实了这一操作的效果及安全性。我们开始肺复张时的PEEP水平与Borges的研究相似，且每次增加PEEP 10 cm H2O（与Matos等人的研究相似），或在研究的后半部分每次增加PEEP 5 cm H2O。已有证据显示，肺复张多发生在持续充气10秒内，在此之后，低血压的风险就会增加，因此，我们的肺复张操作时间很短（1分钟）。其次，Barbas及其同事认为，ICU医生对肺复张操作缺乏经验，有时可能未能注意到可逆性的并发症。ART试验中，我们采取了多种措施保证试验方案的实施。我们对所有中心进行实地访查和培训（除一个中心接受网上培训外），采用床旁说明书指导具体操作步骤，并在每名患者入选后立即联系参研中心，以保证研究方案的依从性。我们还举办定期电话会议，发放每月进度通讯。有关缺乏经验可能解释研究结果的假设并没有数据支持：没有证据表明不同中心病死率存在异质性，包括那些经验丰富研究者所在的中心。第三，Barbas及其同事表示，约22%的患者在PEEP滴定后未接受第二次肺复张。事实上，根据试验方案要求，第一次肺复张过程中一旦发生并发症，就不应进行第二次肺复张。第四，Barbas等人认为，试验组多数患者在第1-7天未接受肺复张，而对照组部分患者则接受了肺复张。与既往研究相似，在第一天后，仅当氧合恶化或呼吸机管路脱开时才进行肺复张。多数患者氧合持续改善，因此不应重复肺复张。对照组的治疗遵循ARDS网络方案，该方案对于顽固性低氧血症患者允许进行肺复张。第五，在PROSEVA试验证实俯卧位的疗效后，引入俯卧位通气符合伦理学研究，而且不应作为混杂因素，因为两组患者接受俯卧位通气的比例相似。
All patients were submitted to Fio2 of 100% for 30 minutes before defining eligibility with the aim of enrolling those with a higher amount of lung collapse.5 Dr Morris and colleagues suggest that the association of hyperoxia after Fio2 of 100% and alveolar stretch in the intervention group might help explain the results. Although interaction between hyperoxia and alveolar stretch has been suggested in physiological studies,6 its clinical significance is unknown. Nevertheless, we agree this association might have had a detrimental role.
所有患者均接受FiO2 100%持续30分钟，旨在入选那些肺塌陷程度更为严重的患者。Morris医生及其同事认为，治疗组患者FiO2 100%后的高氧及肺泡牵张可能解释研究结果。尽管生理研究提示高氧与肺泡牵张之间存在相互作用，但临床意义尚不明确。然而，我们同意其观点，即上述相互影响可能造成不良后果。
