Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospective cohort studyCoppo A, Bellani G, Winterton D, Di Pierro M, Soria A, Faverio P, Cairo M, Mori S, Messinesi G, Contro E, Bonfanti P, Benini A, Valsecchi MG, Antolini L, Foti G.Lancet Respir Med. 2020 Aug;8(8):765-774.Doi:10.1016/S2213-2600(20)30268-X.BackgroundThe COVID-19 pandemic is challenging advanced health systems, which are dealing with an overwhelming number of patients in need of intensive care for respiratory failure, often requiring intubation. Prone positioning in intubated patients is known to reduce mortality in moderate-to-severe acute respiratory distress syndrome. We aimed to investigate feasibility and effect on gas exchange of prone positioning in awake, non-intubated patients with COVID-19-related pneumonia.背景COVID-19大流行正在挑战先进的卫生系统，这些系统正在处理大量因呼吸衰竭而需要重症监护的患者，这些患者往往需要插管。插管病人俯卧位可降低中重度急性呼吸窘迫综合征的死亡率。我们的目的是研究俯卧位在清醒、未插管的COVID-19相关肺炎患者中的可行性和对气体交换的影响。MethodsIn this prospective, feasibility, cohort study, patients aged 18–75 years with a confirmed diagnosis of COVID-19-related pneumonia receiving supplemental oxygen or non-invasive continuous positive airway pressure were recruited from San Gerardo Hospital, Monza, Italy. We collected baseline data on demographics, anthropometrics, arterial blood gas, and ventilation parameters. After baseline data collection, patients were helped into the prone position, which was maintained for a minimum duration of 3 h. Clinical data were re-collected 10 min after prone positioning and 1 h after returning to the supine position. The main study outcome was the variation in oxygenation (partial pressure of oxygen [PaO2]/fractional concentration of oxygen in inspired air [FiO2]) between baseline and resupination, as an index of pulmonary recruitment. This study is registered on ClinicalTrials.gov, NCT04365959, and is now complete.方法在这项前瞻性、可行性、队列研究中，来自意大利蒙扎圣杰拉尔多医院的18-75岁确诊为COVID-19相关肺炎的患者接受补充氧气或无创持续气道正压治疗。我们收集了人口统计学、人体测量学、动脉血气和通气参数的基线数据。收集基线数据后，帮助患者进入俯卧位，并保持至少3小时。在俯卧位10分钟后和回到仰卧位1小时后重新收集临床数据。主要研究结果是作为肺复张指数的氧合（氧分压[PaO2]/吸入空气中氧分浓度[FiO2]）的变化。本研究已注册临床实验.gov，NCT04365959，现在已完成。FindingsBetween March 20 and April 9, 2020, we enrolled 56 patients, of whom 44 (79%) were male; the mean age was 57.4 years (SD 7.4) and the mean BMI was 27·5 kg/m2 (3.7). Prone positioning was feasible (ie, maintained for atleast 3 h) in 47 patients (83.9% [95% CI 71.7 to 92·4]). Oxygenation substantially improved from supine to prone positioning (PaO2/FiO2 ratio 180.5 mm Hg [SD 76.6] in supine position vs 285.5 mm Hg [112.9] in prone position; p<0.0001). After resupination, improved oxygenation was maintained in 23 patients (50.0% [95% CI 34.9–65.1]; ie, responders); however, this improvement was on average not significant compared with before prone positioning (PaO2/FiO2 ratio 192.9 mm Hg [100.9] 1 h after resupination;p=0.29). Patients who maintained increased oxygenation had increased levels of inflammatory markers (C-reactive protein: 12.7 mg/L [SD 6.9] in responders vs 8.4 mg/L [6.2] in non-responders; and platelets: 241·1 × 103/μL [101.9] vs 319.8 × 103/μL [120.6]) and shorter time between admission to hospital and prone positioning (2.7 days [SD 2.1] in responders vs 4.6 days [3.7] in non-responders) than did those for whom improved oxygenation was not maintained. 13 (28%) of 46 patients were eventually intubated, seven (30%) of 23 responders and six (26%) of 23 non-responders (p=0.74). Five patients died during follow-up due to underlying disease, unrelated to study procedure.结果从2020年3月20日至4月9日，共纳入56例患者，其中男性44例（79%），平均年龄57.4岁（标准差7.4），平均体重指数27.5kg/m2（3.7）。47例（83.9%[95%ci71.7～92.4]）中俯卧位是可行的（即至少维持3h）。从仰卧位到俯卧位氧合量明显改善（仰卧位PaO2/FiO2比值为180.5 mm Hg[SD 76.6]，俯卧位为285.5 mmHg[112.9]；p<0.0001）。复吸后，23例患者的氧合状态得到改善（50.0%[95%CI34.9-65.1]；即有反应者）；但与俯卧位前相比，平均无明显改善（复吸后1小时PaO2/FiO2比值192.9mmHg[100.9]p=0.29）。维持氧合增加的患者炎症标志物（C反应蛋白：有反应者为12.7 mg/L[SD 6.9]，无反应者为8.4 mg/L[6.2]；血小板：241.1×103/μL[101.9]vs319.8×103/μL[120.6]），入院至俯卧位之间的时间（有反应者2.7天[SD 2.1]，无反应者4.6天[3.7]）。46例患者中13例（28%）最终插管，23例有反应者中7例（30%）和23例无反应者中6例（26%）最终插管（p=0.74）。5名患者在随访期间死于潜在疾病，与研究程序无关。
DiscussionIn this observational prospective study, we investigated the feasibility and effect of prone positioning in spontaneously breathing,non-intubated patients with COVID-19-related pneumonia. We found that prone positioning was safe and feasible in most patients, and that it substantially improved physiological measures of oxygenation, although this effect was lost after reverting to the supine position. We found that earlier prone positioning and a more activated inflammatory response were associated with maintenance of improvement in oxygenation after resupination. Finally, we showed that patients who responded to prone positioning had no significant difference in the rate of intubation compared with non-responders.Use of prone positioning in awake, spontaneously breathing patients has been reported before. In 2003, Valter and colleagues reported on four patients in whom awake prone positioning rapidly increased oxygenation and allowed the avoidance of intubation. Feltracco and colleagues reported on five recipients of lung transplants who successfully underwent awake prone positioning with non-invasive ventilation, with the resolution of refractory hypoxaemia. However, because these studies were case series, little evidence can be extrapolated.Scaravilli and colleagues did a retrospective study in 2015 on 15 non-intubated patients who overall underwent 43 prone positioning procedures. They found the procedure to be feasible in 95% of all procedures, and reported a significant increase in PaO2 from before prone positioning to after supine repositioning, with PaO2 returning to baseline levels 6 h after repositioning. However, the study by Scaravilli and colleagues is limited by its retrospective nature, the variation of ventilatory interface and settings between procedures, and the small number of patients contributing to a relatively large number of prone positioning procedures. By contrast, our study features a prospective design, in which prone positioning, ventilation interface and parameters, and data collection were standardised. Our study supports the feasibility of prone positioning in spontaneously breathing awake patients. Our results also show the absence of a long-lasting improvement in oxygenation, which is confirmed even when restricting the analysis to patients with a baseline PaO2/FiO2 ratio of less than 300 mm Hg. This finding can be explained by the fact that prone positioning might not determine stable recruitment of the dorsal lung regions, as previously described. Further supporting good tolerance among patients who are compliant, prone positioning sessions were repeated in the days after the initial session (outside of the study protocol), possibly indicating the presence of clinical or subjective benefit.A large study on this topic was a 2020 trial by Ding and colleagues, in which the authors assessed the effect of adding prone positioning to use of high-flow nasal cannulae and non-invasive ventilation in 20 patients with moderate-to-severe ARDS. They found that the addition of prone positioning might have contributed to avoidance of intubation in 11 of 20 patients, and that the PaO2/FiO2 ratio was significantly higher in patients who avoided intubation. However, interpretation of these results is limited by the small sample size and the fact that not all patients were managed with only some of the four management strategies. Our results are also in line with those published on patients with COVID-19, which became available after our original submission of this report. For example, Caputo and colleagues applied prone positioning to patients with COVID-19 in the emergency department, showing a significant improvement in peripheral oxygen saturation. Sartini and colleagues applied CPAP on medical wards and also found a significant increasein oxygenation. By contrast with these reports, Elharrar and colleagues found that oxygenation improved during prone positioning in only six (25%) of 24 participants. The proportion of patients in whom the oxygenation improvement was maintained upon supine repositioning in all these studies varied substantially.The description of our cohort provides further evidence that prone positioning in awake and spontaneously breathing patients is feasible outside of the ICU environment. Our data suggest that patients are more likely to respond to prone positioning if this procedure is done early after admission to hospital and in patients with increased inflammatory markers (eg, increased lactate dehydrogenase and C-reactive protein concentrations, and decreased platelet counts).One of the possible explanations for this finding is the typically higher proportion of potentially recruitable lung in early phases of ARDS compared with later phases. Another explanation is persistence of perfusion redistribution, with improved ventilation–perfusion matching. Awake prone positioning did not seem to substantially improve long-term oxygenation in patients with COVID-19; however, it might decrease patients' oxygen requirements and allow the delay or avoidance of tracheal intubation, which might prove particularly valuable in scenarios where ICU bed capacity is reduced. An additional benefit of the reduction in FiO2, allowed by the improved oxygenation, is the decrease in the risk of reabsorption atelectasis. Moreover, even if the study was underpowered to assess the effect of clinical outcomes of prone positioning, we observed a non-significant decrease in dyspnoea, which is consistent with the hypothesis of a reduction in self-induced lung injury allowed by prone positioning and could be investigated as an outcome in larger studies. Finally, prone positioning could be used as an additional non-invasive tool in patients with a do-not-intubate order. Our data, without a control group, do not allow us to investigate the effect of prone positioning on the risk of intubation and, given the great variability in intubation rates reported for patients with COVID-19, making a direct comparison is difficult. At the same time, the intubation rate in our study (28%) does not seem worryingly high for a cohort of patients with an average baseline PaO2/FiO2 ratio of 180.5 mm Hg (SD 76.6).To our knowledge, this study is the largest prospective trial to analyse prone positioning in awake patients, and particularly in those with COVID-19-related pneumonia. This procedure in awake patients with COVID-19 has been unofficially reported in several personal communications among clinicians and on social networks. Hence, we believe that a formal assessment of prone positioning effects in this setting was required. The study protocol was clear, simple, and well defined, and we collected high quality, complete data. The external validity of our study is strengthened by the fact that patients were enrolled in various clinical settings within the study centre, each with differently experienced staff and resource availability.Our study has several limitations. As stated, the lack of a control group (and randomisation) does not allow inference on patient-centred outcomes, such as mortality or need for tracheal intubation and ICU stay. Furthermore, enrolment of non-consecutive patients on the basis of recommendations made by the medical emergency team might have led to selection bias; however, the enrolled cohort seemed to be representative of the whole population of patients admitted to hospital with COVID-19 during the study period, at least for two crucial parameters, PaO2/FiO2 and C-reactive protein. Also, we did not collect data on lung morphology and effects of subsequent cycles of prone positioning that patients might have undergone. We did not prespecify in our protocol the collection of data on specific adverse events because we reasoned that the most likely complications due to prone positioning (eg, vomiting, nausea, device displacement) would have been clinically evident. However, none of these adverse events occurred. Clearly some complications would have required specific monitoring—eg, a doppler scan for venous thromboembolism—and as such might have been missed in our data collection. Additionally, a limitation of our study is that it is a single-centre study, and so might not be generalisable. Most patients were receiving CPAP, which is a standard of care in our institution, while high-flow oxygen is not available and non-invasive ventilation is limited to a few high-dependency units. Finally, the inclusion of patients both on CPAP and on conventional oxygen therapy might have diluted the effects of prone positioning on patients' oxygenation because those on CPAP might have more severe illness, while CPAP might also correct hypoxaemia more than standard oxygen delivery. Further studies exploring the effect of prone positioning on the delay and avoidance of intubation, need for ICU, duration of weaning from oxygen support, duration of hospital stay, and respiratory-related mortality are urgently warranted.In summary, we found that prone positioning in awake, spontaneously breathing patients is feasible outside of the critical care environment in most patients. We observed improvement in oxygenation during prone positioning, which was maintained upon resupination by half of the patients for at least 1h, and non-significant decrease in dyspnoea. With minimal patient discomfort, prone positioning was found to be a useful and patient-engaging technique to ameliorate blood gas parameters in the short term in patients with COVID-19-related pneumonia.讨论在这项前瞻性观察性研究中，我们研究了俯卧位在自主呼吸、未插管的COVID-19相关肺炎患者中的可行性和效果。我们发现俯卧位在大多数患者中是安全可行的，并且它大大改善了氧合的生理指标，尽管这种效果在恢复到仰卧位后就消失了。我们发现早期俯卧位和更活跃的炎症反应与复苏后维持氧合改善有关。最后，我们发现对俯卧位有反应的患者与无反应者相比，插管率没有显著差异。在清醒的，自发呼吸的病人中使用俯卧位以前就有报道。2003年，Valter和colleagues报道了四名患者，他们醒着俯卧位可以迅速增加氧合，避免插管。Feltracco和colleagues报道了5例肺移植受者，他们成功地接受了无创通气的清醒俯卧位，并解决了顽固性低氧血症。然而，由于这些研究都是病例系列，因此很少有证据可以推断。斯卡拉维利和同事于2015年对15名未插管患者进行了回顾性研究，这些患者接受了43个俯卧定位手术。他们发现，在所有手术中95%的程序是可行的，报告PaO2从俯卧位前到仰卧复位后显著增加，PaO2在复位后6h恢复到基线水平。然而，斯卡拉维利和同事的研究由于其回顾性、通气界面的变化和手术间设置的变化以及导致相对较多俯卧定位程序的患者数量较少而受到限制。相比之下，我们的研究具有前瞻性设计，其中俯卧位、通风接口和参数以及数据采集标准化。本研究支持了自主呼吸清醒患者俯卧位的可行性。我们的结果还显示，氧合没有长期改善，即使将分析限制在基线PaO2/FiO2比值小于300 mm Hg的患者身上，也得到证实。这一发现可以解释为俯卧位可能无法确定像以前那样稳定的肺背区的招募描述。进一步支持符合要求的患者的良好耐受性，在初始疗程后的几天（研究方案之外）重复进行俯卧定位试验，可能表明存在临床或主观利益。关于这一主题的一项大型研究是由丁和他的同事在2020年进行的一项试验，在该试验中，作者评估了使用高流量鼻插管和无创通气增加俯卧位对20例中重度ARDS患者的效果。他们发现，在20名患者中，增加俯卧位可能有助于避免插管，而避免插管的患者的PaO2/FiO2比值明显更高。然而，这些结果的解释受到小样本量和事实的限制，即并非所有患者都只采用四种管理策略中的一种。我们的结果也与发表在COVID-19患者身上的结果一致，这是在我们最初提交这篇文章之后才获得的报告。为例如，Caputo和他的同事在急诊科对COVID-19患者应用俯卧位，显示外周氧有显著改善饱和。萨蒂尼和同事们在内科病房应用CPAP，也发现氧合显著增加。与这些报告相比，埃尔哈拉尔和他的同事发现，24名参与者中只有6人（25%）在俯卧位时氧合得到改善。在所有这些研究中，仰卧位后维持氧合改善的患者比例有很大差异。我们队列的描述提供了进一步的证据，在ICU环境之外，清醒和自主呼吸的病人俯卧姿势是可行的。我们的数据表明，如果在入院后早期进行俯卧位手术，并且患者的炎症标志物增加（例如乳酸脱氢酶和C反应蛋白浓度增加，这一发现的一个可能的解释是急性呼吸窘迫综合征早期与晚期相比，潜在可招募肺的比例通常更高阶段。另一个解释是持续的灌注再分配，改善了通气-灌注匹配。清醒俯卧位似乎不能显著改善COVID-19患者的长期氧合；然而，它可能降低患者的需氧量，并允许延迟或避免气管插管，这在ICU床位容量减少的情况下尤其有价值。通过改善氧合，减少血氧饱和度的另一个好处是减少再吸收性肺不张的风险。此外，即使研究动力不足，无法评估俯卧位对临床结果的影响，我们观察到呼吸困难的减少并不显著，这与俯卧位允许的自感肺损伤减少的假设相一致，可以作为更大研究的结果进行调查。最后，俯卧位可以作为一个额外的非侵入性工具，病人不能插管。在没有对照组的情况下，我们的数据不允许我们研究俯卧位对插管风险的影响，而且，鉴于COVID-19患者插管率的巨大差异性，很难进行直接比较。同时，对于平均基线PaO2/FiO2比值为180.5 mm Hg（SD 76.6）的患者，我们研究中的插管率（28%）似乎并不高得令人担忧。据我们所知，这项研究是分析清醒患者俯卧姿势的最大前瞻性试验，尤其是那些与COVID-19相关的肺炎患者。在醒着的COVID-19患者中，这一过程已经在一些临床医生的个人交流和社会交往中被非正式地报道过网络。因此，我们认为，在这种情况下，需要对俯卧位的影响进行正式评估。研究方案清晰、简单、明确，我们收集了高质量、完整的数据。我们研究的外部有效性通过以下事实得到了加强：患者在研究中心的不同临床环境中登记，每一个都有不同经验的工作人员和资源可用性。我们的研究有几个局限性。如前所述，缺乏对照组（和随机分组）不允许推断以病人为中心的结果，如死亡率或需要气管插管和ICU住院。此外，根据医疗急救小组的建议，非连续性患者的登记可能会导致选择偏差；然而，登记的队列似乎代表了研究期间住院的COVID-19患者的全部人群，至少在两个关键参数方面，PaO2/FiO2与C反应蛋白。同时，我们也没有收集病人可能经历过的肺部形态和随后俯卧位周期的影响的数据。我们没有在我们的研究方案中预先规定特定不良事件的数据收集，因为我们推断，由于俯卧姿势（如呕吐、恶心、设备移位）引起的最可能的并发症在临床上是明显的。然而，这些不良事件均未发生。显然，有些并发症需要特殊的监测，例如，静脉血栓栓塞的多普勒扫描，因此在我们的数据收集中可能遗漏了。此外，我们研究的一个局限性是它是一个单中心研究，因此可能不具有普遍性。大多数患者接受的是CPAP，这是我们机构的标准护理，而高流量氧气不可用，无创通气仅限于少数高度依赖的单位。最后，CPAP和常规氧疗的患者都被纳入可能会稀释俯卧位对患者氧合的影响，因为CPAP患者可能会有更严重的疾病，而CPAP也可能比标准氧气输送更能纠正低氧血症。进一步研究俯卧位对气管插管延迟和避免的影响，对ICU的需要，停止氧气支持的时间，住院时间和呼吸相关死亡率的影响是迫切需要的。综上所述，我们发现，在大多数患者的重症监护环境之外，清醒、自主呼吸患者的俯卧姿势是可行的。我们观察到俯卧位时氧合的改善，其中一半的病人在复吸至少1小时后，呼吸困难无明显改善。在患者不适感最小的情况下，俯卧位被发现是一种有用且能吸引患者的技术，可以在短期内改善COVID-19相关肺炎患者的血气参数。InterpretationProne positioning was feasible and effective in rapidly ameliorating blood oxygenation in awake patients with COVID-19-related pneumonia requiring oxygen supplementation. The effect was maintained after resupination in half of the patients. Further studies are warranted to ascertain the potential benefit of this technique in improving final respiratory and global outcomes.结论俯卧位对需要补充氧气的COVID-19相关肺炎清醒患者的血氧饱和度快速改善是可行和有效的。一半的病人在复吸后仍能保持这种效果。有必要进一步研究，以确定这种技术在改善最终呼吸和整体预后方面的潜在益处。首都医科大学附属北京友谊医院平谷区医院 李振良 译
