Comment & Response
March 6, 2018
Lung Recruitment and Positive End-Expiratory Pressure Titration in Patients With Acute Respiratory Distress Syndrome
Andrew C. McKown, Matthew W. Semler, Todd W. Rice
JAMA. 2018;319(9):932-933. doi:10.1001/jama.2017.21856
To the Editor The trial by the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators1 compared a low positive end-expiratory pressure (PEEP) strategy2 with one combining a recruitment maneuver and PEEP titration personalized to respiratory system compliance among adults with moderate to severe acute respiratory distress syndrome (ARDS). The recruitment maneuver and personalized PEEP approach lowered driving pressure but increased mortality. Although one potential explanation for increased mortality is the negative effects of the recruitment maneuver, another is ventilator-induced lung injury from overdistension of alveoli at end-inspiration (tidal hyperinflation) resulting from the method of personalizing PEEP.
致编辑：ART研究比较了低PEEP策略与联合肺复张及根据呼吸系统顺应性个体化设置PEEP策略对中重度成年ARDS患者的疗效。肺复张及个体化PEEP设置虽然降低了驱动压，但增加病死率。尽管病死率增加的可能原因之一是肺复张的副作用，但另一种可能是个体化设置PEEP的方法导致吸气末肺泡过度膨胀。
The ART intervention protocol used a tidal volume of 5 mL/kg predicted body weight to determine the PEEP of maximal compliance. If multiple PEEP levels had similar compliance (within 1 mL/cm H2O), PEEP was set at 2 cm above the highest of these levels. This approach inherently leads to ventilation near the upper inflection point of the pressure-volume curve at a tidal volume of 5 mL/kg predicted body weight. The mean tidal volume on day 1 in the intervention group was 5.6 mL/kg predicted body weight, suggesting that many patients were ventilated at tidal volumes above those used to identify maximal compliance in the decremental PEEP trial.
ART研究方案采用潮气量5 ml/kg理想体重，在此条件下根据最大顺应性确定PEEP。如果多个PEEP水平下的顺应性相似（在1 mL/cm H2O内），则将PEEP设置为上述最大值以上2 cm。这种方法可能导致在潮气量5 ml/kg理想体重的情况下，通气接近PV曲线的高位转折点。治疗组第一天平均潮气量为5.6 mL/kg理想体重，提示很多患者接受的潮气量超过了PEEP递减法中确定最大顺应性使用的潮气量。
Much has been made of personalizing therapy in critical illness. Is it possible that the personalization of PEEP in the intervention group of the ART trial inadvertently introduced injurious tidal hyperinflation, which was avoided in the control group by applying a simple one-size-fits-all approach to lower PEEP?
危重病时我们作出很多努力实施个体化治疗。是否有可能ART研究的治疗组个体化设置PEEP无意中造成了吸气末过度膨胀，而在对照组采用统一方法设置较低PEEP避免了这种危害？
Comment & Response
March 6, 2018
Lung Recruitment and Positive End-Expiratory Pressure Titration in Patients With Acute Respiratory Distress Syndrome
Carmen Silvia Valente Barbas, Sérgio Nogueira Nemer
JAMA. 2018;319(9):933. doi:10.1001/jama.2017.21840
To the Editor In a systematic review and meta-analysis of 2299 patients with moderate or severe ARDS, lower mortality was found in the high-PEEP group compared with the low-PEEP group (34.1% vs 39.1%, respectively; P = .049).1 In a second systematic review and meta-analysis of 1594 patients with ARDS, alveolar recruitment maneuvers were associated with reduced in-hospital mortality without increasing the risk of adverse events.2 In addition, a multicenter, randomized clinical trial of 200 patients with moderate to severe ARDS showed that an open-lung approach improved oxygenation and driving pressure, without detrimental effects on mortality, ventilator-free days, or barotrauma.3
致编辑：在一项纳入2299名中重度ARDS患者的系统回顾及meta分析中，与低PEEP相比，高PEEP组病死率降低（分别为34.1% vs 39.1%；P = .049）。在另一项1594名ARDS患者的系统回顾与meta分析中，肺复张伴随住院病死率降低，且不增加不良事件风险。另外，一项200名中重度ARDS患者的随机临床试验显示，肺开放策略改善氧合及驱动压，对病死率、无机械通气时间或气压伤没有不良影响。
In contrast, the ART investigators reported the results of a multicenter, randomized clinical trial of 1010 patients who either received an alveolar recruitment maneuver followed by best-compliance PEEP titration or a low-PEEP strategy.4 The study found high 6-month mortality in both groups, which was higher in the intervention group (65.3% vs 59.9%, respectively; P = .04). How can these unexpected results be explained?
与此相反，ART研究者报告了一项1010名患者的多中心随机临床试验结果，研究中患者接受肺复张后根据最佳顺应性设置PEEP，或接受低PEEP。研究发现，两组患者6个月病死率均很高，且试验组更高（分别为65.3% vs 59.9%；P = .04）。发生这种情况的原因如何解释？
First, the recruitment maneuver was abrupt and short and not monitored with lung imaging. Second, no check for the efficiency of the recruitment maneuver was conducted, and, because the study was multicenter, trained but inexperienced physicians might not have noticed and fixed the possible but reversible complications that could occur during the maneuver.
首先，肺复张时间很短，且没有通过肺影像学检查进行监测。其次，研究未对肺复张的效果进行检查。由于此研究为多中心研究，经过培训但缺乏经验的临床医生可能未能发现并及时处理肺复张过程中可能出现的可逆性并发症。
Third, 21.6% of the ARDS patients did not perform the second alveolar recruitment maneuver after PEEP titration as established by protocol, compromising the efficacy of the recruitment and PEEP titration strategy. Fourth, recruitment was not repeated from day 1 to day 7 in 62.7% of patients in the intervention group, whereas 28 patients in the control group received recruitment maneuvers. Fifth, the authors introduced the use of the prone position prior to the recruitment maneuver after publication of the Proning Severe ARDS Patients (PROSEVA) study in 2013, possibly introducing a new confounder to the study results.5
第三，21.6%的ARDS患者未能根据治疗方案的要求，在设置PEEP后进行第二次肺复张，这可能影响了肺复张及PEEP策略的疗效。第四，第1-7天内治疗组62.7%的患者未能重复肺复张，而对照组中28名患者却接受了肺复张。第五，在2013年PROSEVA研究发表后，作者开始在肺复张前使用俯卧位，这可能对研究结果造成新的影响。
Comment & Response
March 6, 2018
Lung Recruitment and Positive End-Expiratory Pressure Titration in Patients With Acute Respiratory Distress Syndrome
Idunn S. Morris, Andrew S. Lane, Ian Seppelt
JAMA. 2018;319(9):933-934. doi:10.1001/jama.2017.21844
To the Editor The ART investigators performed a multicenter randomized clinical trial comparing a high-PEEP strategy using lung recruitment with titrated PEEP vs a low-PEEP strategy in patients with ARDS.1The trial, however, still leaves unanswered questions.
致编辑：ART研究者进行了一项多中心随机临床试验，比较了ARDS患者使用高PEEP（肺复张及PEEP滴定）与低PEEP的疗效。然而，这项研究仍然遗留了一些未能回答的问题。
Hyperoxia-induced lung injury causes an ARDS-type picture with edema, fibrosis, and vascular remodeling,2 although the mechanisms by which reactive oxygen species promote cellular apoptosis and necrosis are not yet fully understood. All patients with ARDS are exposed to prolonged high fractional inspired concentrations of oxygen (Fio2) to manage hypoxemia. In the ART trial, participants were subjected to an additional Fio2 of 1.0 for 30 minutes prior to alveolar stretch, the necessity of which is unclear, because this is neither a required step for establishing the presence of ARDS nor grading its severity.3
高氧造成的肺损伤能够引起水肿、纤维化及血管重构等类似ARDS的改变，尽管活性氧促进细胞凋亡和坏死的确切机制尚未完全阐明。所有ARDS患者均接受了高FiO2以纠正低氧血症。在ART试验中，患者在肺复张前还使用FiO2 30分钟，这一举措的必要性并不明确，因为这并非是诊断ARDS或确定其严重程度的必要步骤。
Hyperoxia when combined with alveolar stretch may cause more harm to alveolar epithelial cells than either of these processes in isolation.2,4,5 The combination of population selection and these events as part of the trial protocol may have led to the poorer outcomes demonstrated in the high-PEEP strategy group.
高氧联合肺泡牵张可能对肺泡上皮细胞造成更多危害。试验方案中对患者的选择，以及上述行为可能造成高PEEP组的不良预后。
Therefore, this study may not mean the end of the open-lung principle but may highlight the need for a more proactive approach to ARDS management by performing recruitment maneuvers and targeted PEEP strategies earlier as part of ARDS prevention rather than treatment. Rationally, the timing for this would be a clinical compromise between ensuring optimal fluid resuscitation and cardiac stability vs avoidance of prolonged exposure to a high Fio2 prior to a recruitment maneuver. From a practical perspective, this could be achieved as soon as optimal fluid responsiveness is reached after intubation. This approach is similar to the use of greater fluid resuscitation in the first 6 to 12 hours followed by a more conservative approach.
因此，这项研究可能并不表明肺开放策略的终结，反而提示需要采取更积极的措施治疗ARDS，更早进行肺复张及PEEP目标管理，作为预防ARDS而非治疗ARDS的措施。当然，采取上述措施的时机应当兼顾适当的液体复苏及循环稳定，同时避免在肺复张前长时间使用较高的FiO2。从实用角度出发，可能在插管后确定适当的液体反应性后即应进行上述操作。这种方法类似于在最初6-12小时进行积极的液体复苏，然后采取比较保守的策略。
The deleterious synergistic effects of hyperoxia and volutrauma should be considered in the context of this trial, and further studies are required before the era of open-lung ventilation is truly considered to be over.
在这项试验中，应当考虑高氧和容积伤的不良协同效应，在宣称肺开放通气策略时代终结之前，还需要进行进一步的研究。
