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A debate broke out recently at one of our rounds when someone asked whether a recent case of NEC was possibly related to a transfusion that a baby received. Much has been written about Transfusion Associated Necrotizing Enterocolitis (TANEC) with the pendulum swinging back and forth between it existing as a real entity or simply being an association that is not causative in the least. Using one of my favourite sources, a retrospective analysis of the Canadian Neonatal Network database found no difference in mortality or morbidities for those who had a transfusion and NEC vs those without. Despite this we continue to see those who “hold feeds” for a few hours prior to transfusion and then resume them a few hours later. Why does this happen? Risk vs Benefit Those who hold feeds argue that in Neonatology we hold feeds for far less. Furthermore, what is the harm? If a baby develops NEC within 24 hours of a transfusion and we held the feeds we feel we have done all we could. If a baby is fed and develops NEC we are left asking “what if?”. The purists out there would argue the contrary though, that the evidence is not strong enough to support the practice and may require the insertion of an IV which is a painful procedure and places the infant at risk of infection from one or more skin breaks. Additionally, does the interruption of feeds potentially alter the microbiome of the patient and with it risk potential downstream consequences. In case you are wondering, I have tended to sit on the side of holding a feed although more often when I am asked about it than ordering it upfront. The fact is I just don’t know. The evidence has never been solid in this regard but it is hard to ignore the possibility when you have been bitten once or twice before (whether it was causative or not!). I doubt it really exists but then again what if there is something there? It May Not Be The Transfusion But Anemia Itself A recent paper Association of Red Blood Cell Transfusion, Anemia, and Necrotizing Enterocolitis in Very Low-Birth-Weight Infants may have found a possible explanation to the ongoing debate. Research papers associating transfusions with NEC may all have one thing in common in that they have not been able to prove causation. When you have many papers finding the same thing it leads medical teams to begin to believe there is causation. Something else may be at play at this paper suggests another association which again may not be causative but at least in my mind is perhaps biologically plausible. It may be that those patients who are transfused when their hemoglobin is below a threshold of 80 g/L are at increased risk of developing NEC rather than all patients transfused. This study was a secondary analysis of a prospective study on transfusion transmission of cytomegalovirus in preterm infants < 1500g. The authors chose 80 g/L as a cutoff based on previous studies suggesting this threshold as an important one for transfusion practices. Forty eight out of 60 eligible infants developed NEC and it is from this 48 that multivariable analysis sought to identify factors predisposing to the outcome in question of NEC. The factor with the greatest hazard risk for NEC was severe anemia in a given week with an approximate 6 fold risk (range 2 – 18) while receiving an RBC transfusion in a given week of life did not meet statistical significance. What does this mean? Before embracing the result and concluding we have the answer we have to acknowledge the authors have gone on a fishing expedition of sorts. Any secondary analysis of a study that is done carries with it some words of warning. There may be variables that were not controlled for that are affecting the results. As well when looking at many many variables it could be by chance that something or several things come up by chance. Lastly it may be that again there is nothing more than an association here at play. Having said that, there is some biologic plausibility at least here. Delivery of oxygen to the tissues is dependent on HgB level. The oxygen content of blood is described by: O2 content = (gm Hbg)(1.34 ml O2/gm Hbg)(% sat) + 0.003(pO2) = ml O2/dL. Oxygen delivery = cardiac output X O2 concentration (or content) Could RBCs become less deformable and increase viscosity in low O2 environments? This could be the case when the HgB declines below 80 g/L. Such changes to deformability have been demonstrated at mild levels of hypoxia as might exist in low pO2 conditions at the tissue level with anemia. So imagine we have fewer RBCs carrying as much oxygen as they can but eventually you cross a threshold where there is not enough O2 being delivered at the tissue level and the RBCs become lodged or perhaps sluggish as they move through capillaries of the intestines. Add to this that NEC occurs in watershed areas most commonly and you have the potential setup for NEC. Can we use the results of this study? I suppose statistical purists out there will argue that it is merely an association. The fact remains that there are many people who are holding feeds for varying amounts of time despite the lack of conclusive evidence that TANEC exists. I wonder if a middle ground might be to be more cautious and restrict such practice to those with low HgB values below 80 g/L as the authors here have found. To me at least there is biologic plausibility as outlined above. It would seem to me that to hold feeds for all babies is excessive and likely without evidence but could the threshold actually matter which it comes to oxygen content. Given that NEC is a condition related to ischemia, the authors here have provided another association that makes me at the very least scratch my head.

A 28 week preterm infant now two weeks of age develops bilious emesis and abdominal distension. An x-ray reveals an intestinal perforation and surgery is consulted. Arrangements are made to go to the operating room for a laparotomy and due to apnea and hypotension the baby is both intubated and placed on dopamine. The resident on service ensures that blood is available in the operating room and an hour after presentation the baby is found to have a HgB of 102 g/L with a HcT of 35%. I don’t know about you but if I am then asked whether we should give blood now or in the OR I might say at that level with the degree of illness to give blood or I might say wait till the baby gets to the OR if perhaps they were fairly stable on the support. You the reader might be more convinced of your actions but if I manipulate the numbers a little bit to say 105 g/l and HcT of 37% might you feel different? What about 110 g/L and 39%? You get the picture. Where is that magic cutoff where we say prior to an OR that a baby needs blood or can wait? In our heads of course we conjure up the equation for delivery of O2 to tissues Cardiac output X (1.39 X HgB X Sat +0.003*pO2) and realize that the delivery of oxygen is critically dependent on HgB level but how much is enough? The truth is I don’t think we really know but we do a good job of coming up with some markers such as lactate or more recently near infrared spectroscopy to give us an idea of how much O2 the tissues are seeing. How much HgB does a baby need before surgery? Although this may seem like something that is well known, the truth is we don’t really know. We may have an inkling though based on a recent paper entitled Association of Preoperative Anemia With Postoperative Mortality in Neonates by S. Goobie et al. They performed a retrospective review of a US surgical quality database to examine mortality after operations and identified 2764 neonates out of 114395 children who underwent surgery. Similar to previous studies the neonatal postoperative mortality rate was higher at 3.4% than the rest of childhood at 0.6%. When examining the effect of low hematocrit prior to surgery they further identified a cutoff of 40% below which the risk of mortality increased. Of the neonatal group that survived 31% had a preop hematocrit of 40% or more while of those who died 72% had a hematocrit < 40%. Hematocrit was not the only factor predicting mortality though as ASA class 3 – 5 (an anesthesiology risk score where these scores indicate severe systemic disease or emergencies), weight < 2 kg, preoperative ventilation and inotropic support. Put simply, sicker small patients have worse outcomes which I suppose should not surprise anyone. So how do we interpret this data? One important point that this article does not control for is the specific type of condition that the patient had. Clearly all conditions of the newborn are not the same as for example an umbilical flap closure of gastroschisis compared to fulminant necrotizing enterocolitis. The authors do try and control somewhat for this by demonstrating that the ASA categories demonstrate if you have severe systemic disease you are worse off but where does this leave the hematocrit? The other possible explanation is that the anemia is simply a reflection of the critical nature of the patient. Sicker patients are more likely to be anemic and also patients who present later are as well. A baby needing a colostomy for a bowel obstruction diagnosed after birth is likely to have low risk of mortality and also have a normal HgB. Contrast this with the baby who develops NEC at 3 weeks of age who is likely anemic or close to being so when they present and in the presence of shock and DIC becomes even more so. Is the low HcT just a proxy for severity of disease? I suspect for the otherwise well infant who is electively intubated for surgery, having a hematocrit alone below 40% is not dangerous. What do we do though with the baby who is on inotropes for example. To truly answer this question we need a randomized controlled trial comparing transfusing patients with a hematocrit below 40% vs choosing a higher threshold of say 50% to say whether it makes a difference. That doesn’t help us though in the here and now. This gold standard for studies won’t tell me what to do for a few years but right now I have to decide what to do for a patient in front of me. Not everyone may agree with me on this but I think in such circumstances I would transfuse based on this publications results. To the naysayers out there I would suggest that whether I choose to give the blood or not before the operation, they will be getting it after they enter the OR. Why not give them a boost before they undergo the knife? It is not a question of whether they will be transfused or not it is a difference in time. If I have the chance I will “top them up” but what will you do?

My first post in your forum. Congratulations and keep up the good work. I would like to know your clinical prctice regarding diagnosis and management of NAIT. 1. Which combination of clinical symptoms and lab results are suggesting NAIT, taking into consideration that current anti platelet Ab detection has a high rate of false negatives? 2. What kind of trnsfusion product do you use. Random donor platelets, do you have typed platelets, do you perform mother platelet apheresis? 3. Have you come across any non-responders? 4. What about genetic councelling to parents of NAIT neonates? Dimtris Anastasiou Neonatology Resident Athens, Greece