A new multicenter RCT in preterm infants has just been published. The ARIPI trial which was led by Dean Fergusson from Ottawa and included our NICU as one of the sites (Christian Lachance was our local lead investigator and is a co-author). ARIPI stands for Age of Red cells In Preterm Infants. The study was a response to many observational publications in older children and adults, that showed worse outcomes in intensive care patients when they receive older red blood cell transfusions (we rarely give actual blood any more, blood cells are divided up before we transfuse, so what you might call a blood transfusion is a suspension of red cells in a mix of plasma and some special solution to preserve the red cell function and stop the blood from clotting) compared to if they receive freshly donated red cells.

The trial compared what has become the norm in NICU; which is to give the first transfusion that a baby needs from a relatively freshly donated unit of red cells, then to give subsequent transfusions from the same unit until it is very old (often as much as 42 days); the investigators compared this to giving relatively fresh blood for every transfusion.

Very old red cells look weird under the microscope (see image below taken from an article in ‘Transfusion’ in 2006) and also don’t work very well as oxygen transporters. So the idea in older patients has been that these weird looking red cells actually induce inflammation without having a real benefit, But all of the adult and older child data is observational stuff, not a single prospective RCT. The idea was that giving fresh blood each time might improve all of those diseases that are related to inflammation and reactive oxygen species, but would have the downside of increasing donor exposure. I don’t know if anyone non-medical will have read this far 😉 but each new donor increases the risk of a viral infection such as hepatitis or HIV. But, and it is a big but, blood transfusions, or should I say red cell transfusions, are now incredibly safe. The risk of HIV is less than 1 in 1,000,000 transfusions. Blood transfusions are one of the safest things that we do in medicine, (despite the hysteria generated by politicians that means we now, in Canada, have to get individual signed informed parental consent on government approved forms prior to giving any kind of blood product) much safer than other routine therapy such as giving antibiotics, or intubating patients….

Anyway, to return to the new study, the idea was that the fresh blood arm might well have fewer complications than the ‘old’ blood arm of the study, and that this might overcome the very tiny extra risks of being exposed to more donors. The study was powered to show a 15% difference in a combined outcome of bad stuff death or one of 4 major morbidities : bronchopulmonary dysplasia, retinopathy of prematurity stage 3 or more, necrotizing enterocolitis stage 2 or more, and intraventricular hemorrhage grade 3 or 4.

What they found was…. (drum roll)…. nothing. That is right not any whisper of a difference in outcomes between the groups. The primary outcome was found in 52.9% versus 52.7%, BPD was as you would expect the commonest of the components of the primary outcome, 33% vs 32%, IVH was slightly higher, and retinopathy slightly lower with fresh red cells, neither remotely significant. Now you could argue that the study was underpowered. That a sample size of 377 infants doesn’t give you enough power to say with confidence that there is no effect. That is true, but we can say with confidence that there is no very large difference in outcomes, and that there is no difference in outcomes anywhere near as large as the observational studies suggested. You could also criticize the composite primary outcome variable, as lumping together a number of things with different pathophysiology that could go wrong with a preterm baby. But the fact remains that this was a very difficult study to get organized (but once the blood banks were interested, the logistics were easier than I thought they were going to be), and a difficult study to design and get approved and get funded.

So congratulations to the investigators. Now we know that our standard practice is not substantially worse than giving fresh red blood cells; even though we still don’t really know when to give transfusions! The study does show, yet again, that observational data are of very limited value, they can give you a pointer as to what we should study, but then the studies that we need to direct therapy, are large RCTs. Preferably really large. simple, multinational, RCTs.