About a year ago, I commented on an article that suggested that a partial pressure of oxygen (PaO2) between 95 and 110 mm Hg was optimal for patients with acute respiratory distress syndrome (ARDS).[1,2] The argument was that driving up the PaO2 would optimize neurocognitive recovery, a laudable goal. I was skeptical, as were two reviews I cited as part of my discussion.[3] I concluded by stating that I'd need to see a randomized controlled trial (RCT) demonstrating that a higher PaO2 is beneficial. Well, an RCT evaluating oxygen targets in the intensive care unit (ICU) was recently published.
1年前，一篇文章推荐对于ARDS患者而言，PaO2在95-110mmHg可能比较理想，理由是提高PaO2将优化神经认知功能恢复，当时这一结论在讨论中引用了2个综述。我表示质疑，现在，一个以氧供为评估指标的RCT试验发表了。
Panwar and colleagues[4] enrolled 103 patients who were on mechanical ventilation (MV) for less than 24 hours and randomly assigned them to different oxygen saturation (SpO2), not PaO2, targets. Using a fraction of inspired oxygen (FiO2) between 0.21 and 0.80, the bedside clinicians targeted an SpO2 of 88%-92% in the conservative group and greater than 96% in the liberal group. The primary outcomes were all related to oxygen variables and not clinical endpoints. Secondary outcomes were clinical and included change in sequential organ function assessment (SOFA) score, new-onset ARDS, change in creatinine, incidence of hemodynamic instability, vasopressor-free days (to day 28), arrhythmia-free days (to day 28), ICU mortality, and 90-day mortality. Less than 30% of patients in the study had ARDS, and the reasons for ICU admission were otherwise heterogeneous and included medical (majority), surgical, and trauma patients.[5]
Panwar和他的同事研究了103例机械通气时间少于24小时的患者，并随机给予不同的SpO2，FiO2 调至0.21-0.80，负责医生将常规组的SpO2调至88%-92%，自由组SpO2调至大于96%，首要终点指标是氧相关变量，次要终点指标是SOFA（sequential organ function assessment）评分，新出现的ARDS、Cr变化、不稳定的血流动力学事件发生率、不使用血管加压药的时间（天）、无心律不齐的时间（天）、ICU期间死亡率、90天死亡率。这个研究中有不到30%的患者出现ARDS，患者入住ICU的原因包括内科（大多数）、外科手术和创伤。
The authors found that a "permissive hypoxemia" approach is "feasible," but no secondary outcomes reached statistical significance. In fairness, the study wasn't powered to detect clinically significant differences. There were a few semi-interesting findings: (1) Patients in the liberal group spent more time on mandatory modes of MV; (2) 22% of the SpO2 readings in the liberal group were >96% (hyperoxia); (3) in a prespecified subgroup analysis (PaO2/FiO2 <300), the adjusted hazard ratio for mortality at day 90 in the conservative arm was 0.49 (95% confidence interval, 0.20-1.17; P=.10); and (4) vasopressor dosing was lower in the liberal arm. The authors speculated that clinicians felt that patients in the conservative group were eligible for weaning earlier, and this drove the decrease in use of mandatory modes of MV. This is difficult to prove, and because there was no difference in MV-free days between groups, it's of little consequence even if it's true.
作者发现，“自由氧供”的方向是可行的，但次要终点没有达到统计学意义，公平地说，这项研究的目的不是检测临床显著性差异，研究发现了下面几个有趣的现象：
1.自由组的患者花费更多的时间在强制性机械通气模式；
2.自由组22%的患者SpO2 读数>96%（氧过量）；
3.预先设定的亚组分析（PaO2/FiO2 <300）显示，调整后的风险率（90天死亡率）在常规组为0.49（95%可信区间为0.20-1.17，P =0.10）；
4.自由组的血管加压药剂量降低，作者推断临床医生认为常规组的患者适合早期脱机，使得这一人群减少了强制性机械通气模式的使用，这一点很难去证明，因为两组之间的自由通气天数没有差异，即使这个结果是真的，对最终结果的影响也很小。
Unfortunately, this wasn't the RCT I was looking for when I concluded my earlier post. It's a great start, though, and the authors should be commended for completing a multisite RCT in which oxygen levels were successfully manipulated in a critically ill population. The authors of the RCT noted that there are two additional multicenter RCTs targeting oxygen levels in the ICU (NCT01319643 [OXYGEN-ICU] and NCT01722422 [HYPER-2S]) that were recently completed. According to ClinicalTrials.gov, OXYGEN-ICU is designed to enroll 660 patients with 30-day mortality as the primary outcome. They're comparing normoxia (94%-98%) vs hyperoxia (>97%). HYPER-2S will be complete after enrollment of 441 patients. The trial design is more complicated than OXYGEN-ICU or the recently published Panwar paper. In addition to looking at oxygen levels, they're also assessing the effects of hypertonic saline. Again, the primary outcome is 30-day mortality.
In any case, it looks as if we'll be getting more information soon. The jury's still out on the appropriate oxygen target. As more randomized data are published, we'll start to obtain clarity. Until then, physiology would dictate that we continue to avoid hyperoxia, maintain permissive hypoxia when appropriate for patients with chronic obstructive pulmonary disease, and otherwise keep SpO2 above 90%.
不幸的是，这不是我之前寻找的那个RCT研究。但这是一个很好的开始，应该表扬那些在危重症患者人群中成功操纵氧供的RCT研究。根据ClinicalTrials官网的消息，有2个最近完成的多中心RCT研究将ICU的氧供水平作为终点指标（NCT01319643 [OXYGEN-ICU] 和NCT01722422 [HYPER-2S]），OXYGEN-ICU设计入组660例患者，首要终点指标是30天死亡率，比较普通氧供（94%-98%）和高氧供（>97%）的区别。HYPER-2S 计划入组441例患者，研究设计比OXYGEN-ICU更加复杂，增加了对氧供水平的观察，同时也评价生理盐水的影响，首要终点指标也是30天死亡率。
更多的研究结果即将发表，我们会越来越清楚，到那时，患者生理机能将会提示我们要继续避免高氧供，对慢性阻塞性肺疾病的患者维持相对自由的氧供可能更恰当，否则保持SpO2 90%以上。
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