To continue with my diatribe about the OHRP decision concerning the SUPPORT trial:
At one point in the document sent to the University of Alabama, the OHRP quote an editorial by Jay Greenspan:
‘…Although maintaining ranges of hemoglobin oxygen saturation in the vulnerable preterm population in the proximity of 85% to 90% is gaining increasing acceptance, marked variability in opinion exists.” In short, the research and data analyses that had occurred prior to the SUPPORT study demonstrated that the use of higher versus lower levels of oxygen could significantly affect the likelihood of a premature infant developing ROP and other aspects of morbidity and mortality.’
Although they quote the editorial they clearly show by this statement that they have not understood it. All of the research and the analyses prior to support demonstrated that it was completely uncertain whether the use of higher versus lower levels of oxygen could significantly affect the likelihood of a premature infant developing ROP and other aspects of morbidity and mortality. They also refer to the Cochrane review of oxygen therapy in the preterm infant. Again they have not understood this sentence, the final one of the abstract
‘The results of this systematic review confirm that (the now historical) policy of unrestricted, unmonitored oxygen therapy has potential harms without clear benefits. However, the question of what is the optimal target range for maintaining blood oxygen levels in preterm/LBW infants was not answered by the data available for inclusion in this review.’
As I noted in the previous post, the prior studies were completely uninformative for modern neonatology.
Further on in this letter the OHRP notes that the study
‘specifically enrolled very premature infants and randomized them to one of two levels of oxygen. For many of those infants, the level of oxygen they received was different from what they would have received had they not participated in the study’
This seems to be the crux of the OHRP argument, because we had no idea if either of these ranges were preferable, and therefore some babies were haphazardly being exposed to higher or lower oxygen targets in their NICUs, it was somehow problematic to systematically randomize them. That is, doing this ethically, and collecting the data was somehow worse than allowing the on-going uncertainty. Because some babies who would have had high sat ranges with an increased risk of RoP, would instead have received less oxygen to achieve low saturations with an increased chance of dying. And vice versa.
The OHRP notes that the consent form includes the following: “It is possible that using lower pulse oximeter ranges will result in fewer babies with severe Retinopathy of Prematurity (ROP).” But then they castigate the investigators for not saying ‘that being in the upper range group may result in the greater risk of developing ROP.’ Now I don’t know about you, but if being in the lower range may decrease the risk, then it seems self-evident that the contrary is true!
I know that the early history of clinical research was sullied by several examples of unethical research practice, and that we need to protect human subjects. I know that introducing new medications and innovative practices do need to be carefully regulated to avoid the patients and parents that voluntarily participate in our trials being harmed. But the standards for consent to participate in research comparing 2 differing standard approaches, either of which is within the limits of usual clinical practice, and which are in current use in NICUs with high quality care, have to be different.
If not how will we determine whether volume ventilation is really better, in terms of important clinical outcomes, than pressure ventilation; or whether permissive hypotension is better than treating everyone with a low blood pressure with dopamine? Sure it may turn out that pressure ventilation is associated with higher mortality, or with lower mortality. We don’t have any reason to believe that right now, but the only way to be sure is to do good research like SUPPORT.