The TOP trial has just been published in the FPNEJM (Kirpalani H, et al. Higher or Lower Hemoglobin Transfusion Thresholds for Preterm Infants. N Engl J Med. 2020;383(27):2639-51). It was a multicenter, non-masked RCT among 1800 babies of less than 1 kg birthweight, between 22 weeks and <29 weeks and <48 hours of age. They had not had a previous red cell transfusion unless they had needed an emergency transfusion before 6 hours of age (which happened in about 5%). The infants were randomized to a higher or lower transfusion threshold, and the primary outcome was survival without Neurological impairment or developmental delay at about 2 years corrected age.

The study was therefore almost twice as large as the ETTNO trial that I posted about earlier this year, with similar entry criteria, except that in ETTNO babies could be enrolled up to 72 hours of age, and 25% of them had already had at least one transfusion. The average difference in haematocrit between the 2 groups in ETTNO was about 3% from week 3 to week 10, equivalent to about a haemoglobin difference of 1.1 g/100mL. This was a smaller haemoglobin separation between groups than TOP (average 1.9 g/100mL)

The primary outcome of TOP was not different between higher and lower transfusion threshold groups, and no part of the primary was different. Important, pre-specified secondary outcomes were also all just about identical between the 2 groups. This included brain injury as diagnosed on ultrasound, bronchopulmonary dysplasia (very slightly more frequent in the group transfused at a higher threshold, 59% vs 56%) and necrotising enterocolitis, 10% in each group.

The other trials with similar treatment comparisons are the aforementioned ETTNO, and PINT, as well as the Iowa transfusion trial. The Iowa trial was a little different in that it included babies up to 1300 gr (just up to 1 kg in the other trials) and had the same transfusion thresholds throughout the study, depending only on respiratory status and not changing with postnatal age. Here are the thresholds for the 4 trials, converted where necessary into Haemoglobins (g/100mL) and rounded to the nearest 0.5:

Or presented as Haematocrit, rounded to the nearest 1%.

The definition of “Sick” and “Not Sick” are somewhat different between the studies. For TOP it was entirely respiratory they used “a higher threshold when respiratory support was warranted. Respiratory support was defined as mechanical ventilation, continuous positive airway pressure, a fraction of inspired oxygen (Fio2) greater than 0.35, or delivery of oxygen or room air by nasal cannula at a flow of 1 liter per minute or more).”

In EttNO being sick meant “having at least 1 of the following criteria: invasive mechanical ventilation, continuous positive airway pressure with fraction of inspired oxygen >0.25 for >12 hours per 24 hours, treatment for patent ductus arteriosus, acute sepsis or necrotizing enterocolitis with circulatory failure requiring inotropic/vasopressor support, >6 nurse-documented apneas requiring intervention per 24 hours, or >4 intermittent hypoxemic episodes with pulse oximetry oxygen saturation <60%”

In PINT it was just respiratory support “assisted ventilation, continuous positive airway pressure, or supplemental oxygen” without further specification.

As I have ranted on about before, this makes no sense. Why do we think that a preterm infant with a saturation of 92% in 30% oxygen needs to have a higher haemoglobin than a baby with this saturation in 21% oxygen? Or if they are intubated? Maybe if they are intubated on high-frequency ventilation with a very high mean airway pressure there might be enough impact on their cardiac function to limit tissue oxygen delivery, but in the majority of patients, moderate respiratory disease or respiratory support should have no impact on tissue oxygenation or transfusion needs.

Infants with a limited cardiac output might need to have a higher haemoglobin to maintain oxygen delivery to the tissues, but I actually think that is unlikely to be a common problem; perhaps in septic shock, or with a cardiomyopathy, but most babies can probably increase their cardiac output to respond down to quite low haemoglobin concentrations. The ETTNO trial inclusion of needing cardiovascular support makes much more sense than the other criteria for demanding a higher threshold.

As you may know, the PINT outcome study showed no major difference in long term development between the high and low threshold groups, but, there were some minor differences in Bayley Scores, which appeared to favour the high threshold group, the proportion of survivors with a Bayley II MDI less than 70 was 18% in the high group vs 24% in the low group, so being extra careful they also analysed the proportion of survivors who had an MDI <85, which looked different between groups, 34% high threshold vs 45% low threshold. As a result, there remained a concern that perhaps a higher threshold would be preferable, these 2 new studies demonstrate that is not the case. Transfusion thresholds in the low columns above are consistent with good practice, and will lead to fewer babies being transfused without measurable adverse effects.

One other thing that I noticed is that the Iowa trial showed some differences in apneas between the groups, with the babies who received fewer transfusions having more apneas, and more severe apneas.

In both TOP and ETTNO, with the difficulty in clinical research of accurately quantifying apnea, the only data point they give that is relevant is when the caffeine was finally stopped (with nearly 100% of these babies having received caffeine) in the 2 trials caffeine was stopped at about the same time in the groups, suggesting that persistent apnea is not more common if you let the haemoglobin fall to these levels.

In these 2 linked blog posts I have tried to answer the question of when to transfuse, and have avoided the question of “why?”

The “why” should surely be to prevent complications or improve outcomes. The “why” on a physiologic basis is to improve oxygen-carrying capacity, when that oxygen-carrying capacity is too low to allow adequate oxygen delivery and when this leads to tissue hypoxia. There is no sign from these new data, when analyzed together with the older information, that transfusing above the Low Transfusion Thresholds is of any benefit, and I think we are way above the threshold where tissue hypoxia becomes an issue, further data of clinical situations where a transfusion is necessary would be really helpful (Do babies in shock benefit from a transfusion?). There is also, of course, no clear evidence of any harm from an approach to transfusion which follows either the high or low thresholds, or something in between!

With delayed cord clamping, initial blood work done on whatever blood is left in the placenta when possible, and restricted blood sampling throughout hospitalisation, we should be able to dramatically reduce transfusion requirements. Then we should ask the parents of infants at-risk of needing a transfusion whether they would prefer that their infant receives erythropoietin (or darbepoetin) in order to reduce the probability even further. We can ask them that while still reassuring them that blood transfusion is extremely safe.