But in the case of the current prone positioning study, we may be smitten by the very small P-value, which means literally that "if the null hypothesis is true and there is in reality no mortality difference between prone and supine, the probability of finding a difference as large or larger than the result the authors found is less than 0.1%" - a very small probability indeed. So the difference is not only large, but statistically robust. Have we seen this before?
- The 2001 Gattinoni study of proning in ALI/ARDS showed a mortality difference at 10 days of 3.9% in favor of proning, but with a P-value of 0.41 (my calculation). Among the many critiques of the study were that the patients were not sick enough and were not proned for enough hours each day and for enough days.
- Guerin et al followed with a study published in JAMA in 2004 enrolling the broader and less restrictive group of patients with hypoxemic acute respiratory failure (of which ALI/ARDS is a subset). The mortality was 31.5% in the supine and 32.4% in the prone groups with a P-value of 0.77. Fail.
- If being less selective in your enrollment criteria doesn't work, you can always try to be more selective. In answer to the critiques of the Gattinoni study, namely that the patients weren't sick enough or proned for long enough, Mancebo et al reportedin 2006 a study of prolonged proning in severe ARDS. Intensive care unit mortality (the primary endpoint) was 43% in the prone group and 58% in the supine group. (I just realized that I cannot reproduce these numbers with the data reported. I get mortality to be 41.6% and 56.6% with a P-value of 0.08. There must be some adjustment somewhere that was not transparently reported in the Methods or the Results.) I remember being impressed by this study when it came out. There is a large and almost statistically significant benefit of proning in this study.
- In yet another response to the critiques and limitations of prior trials, Taccone et al (JAMA, 2009) reported the results of the Prone-Supine II (PSII) trial. In the overall cohort, mortality was 31% for prone and 32.8% for supine, P-value 0.72. Is anyone else seeing a pattern here? That's a rhetorical question, and the answer depends on who's answering it. The true-believers see the subset of patients with severe hypoxemia in Table 2 of the article where the mortality difference is in favor of prone by about 8% with a P-value of 0.31. The disinterested among us see the overall negative results in trial after trial after trial.
[Addendum 6/2/2013: Several trusted colleagues have commented that my supposition that sedation will be higher is unfounded. I agree. I wanted the post to focus on the evidence, but end with my summary position, namely that I will not immediately adopt this practice for routine care, and I used the sedation example as one reason why. The other major reasons are:
- There is no on-site intensivist during the full 24 hours in the ICUs in which I work. Proning and supining cannot therefore be intensivist supervised routinely, and ETT malposition incidents will be more disruptive. The ED physician will have to be called emergently to respond to any tube reposition needs.
- Our ICUs sometimes have a very low census (the reason for that would be a good post for the status iatrogenicus blog). Some nights there are only two nurses in the ICU. With those low staffing levels, it is simply not feasible to prone and supine a patient for nursing care and repositioning.
- Note the restrictive inclusion criteria in the current study: ARDS for less than 36 hours, PF ratio less than 150 on at least FiO2 0.6 and PEEP greater than or equal to 5, and these criteria had to be reconfirmed (that is met again) after 12-24 hours in the ICU. These patients are a mionority subset of the total ALI/ARDS cohort. In my practice, we will have perhaps a dozen patients per year that meet inclusion criteria.
- The exclusion criteria are available here for subscribers. Note that MAP less than 65, non-invasive ventilation for 24 hours prior to inclusion, chronic oxygen use, and various other criteria led to exclusion from enrollment. I mention this not only in relation to the bullet point above, but also because, if you believe the historical legacy of trials of prone positioning, and you believe that investigators have refined their inclusion and exclusion criteria to "hone in" on exactly which patients benefit and thusly finally got a positive result, then strict attention to inclusion/exclusion criteria is warranted, even more than in the usual case.
[Addendum 6/7/2013: In this week's JAMA, Murad and Montori discuss the imperative to consider not just single studies in isolation, but the totality of the evidence, as I attempted to do above.]