Transfusion Related Necrotizing Enterocolitis

 

Preterm infants are at risk for necrotizing enterocolitis (NEC).  Preterm infants often receive transfusions during their NICU stay.  In both cases, the lower the gestational age, the higher the risk – of either NEC or receiving more than one transfusion.  The relationship between the two has been a hot topic over the past few years.

The underlying contributors to NEC are undoubtedly multifactorial and quite a bit of speculation and research regarding NEC causative factors, prediction etc has been published.  The latest is the relationship between packed red blood cell transfusions and NEC.  The first study hinting at this association was published in 1987.1  Since 2010, several papers have been published demonstrating some association.  However, there are many questions remaining.  First, it is important to note that there have not been any randomized controlled trials to answer this question.  Instead, reviews have largely been retrospective comparisons of NEC cases in infants who were transfused within 48 hours of NEC diagnosis and those who were not.  This phenomenon is now referred to as Transfusion Associated Gut Injury or TRAGI.

First, though, what is the pathophysiology that might lead to this?  In adults, transfusion-related acute lung injury is the leading cause of transfusion-related mortality.  This occurs in approximately 1000 of 5 million recipients of blood transfusions.2  This is thought to be the end result of a process where some other insult occurs, referred to as the “first hit” followed by the transfusion (the “second hit”).  This is more often seen in patients who receive cardiac surgery and are on a bypass pump primed with blood more than 4 days old, in some cases, but certainly blood more than 2 weeks old.  Large quantities of “old” blood appears to have some causation.  Outcomes are also impacted in patients with coronary artery syndrome followed by a transfusion.2 Following this knowledge, some believe that this same phenomenon is occurring in infants, perhaps made worse by the fact that infants are transfused with adult blood when the premature infant (or even term) have primarily fetal hemoglobin.  Another theory is that there is a perfusion alteration during the transfusion although Marin concluded that gut oxygenation did not change related to feeding during a transfusion based on a study of 8 infants using NIRS (oral presentation).    In some reviews, there was a high association with a patent ductus arteriosus (PDA) that had been treated within 2 weeks of the transfusion.3

LaGamma & Blau list four common features of infants who show gut injury within 48 hours of a transfusion.2 They are that the infants have varied postnatal age as compared to typical NEC cases that have been found to cluster around 31 weeks gestation, regardless of infants gestational age at birth.  These infants who have TRAGI are more commonly of lower birth weight and gestational age and have fewer major risk factors usually associated with risk of NEC (e.g. hypotension, hypoxia, presence of umbilical catheter), and finally, the retrospective comparisons have shown that these infants have a more significant anemia that is unrelated to the timing of transfusions.  Some reviews show TRAGI occurs with later transfusions rather than earlier in life.4

There are many issues in generalizing results of the papers that have been published to date.  Many do not report specifics about the feedings that were given, not all report number of transfusions, age of blood and other specifics about the transfusion, including when to transfuse.  Even in units with transfusion guidelines, Baer, Henry, Lambert et al found 30% of the transfusions were given outside those guidelines.5  Many units don’t have guidelines or they are very general resulting in great variability in decisions around transfusions.  Additionally, while more units are holding feedings during the transfusion, that is not standard practice across the country.  Even when feedings are withheld, there is not standardization in how long this should be done.  Some believe that feeding breast milk or small feeds during and after the transfusion is safe.  While several papers have found an association between feeding and TRAGI, there are two that did not show this effect.  Blau, Calo, Dozor et al found 83% of the neonates who had TRAGI were NPO and Singh et al also found no association.3, 6  It seems insufficient, if the feeding is indeed the culprit to put the infant NPO only during the feeding and immediately after.  As LaGamma & Blau point out, the feeding fluids and nutrient contents remain in the gut once feeds have been initiated and contribute to colonization, and a specific array of protein antigen exposure.2 This alone is unlikely to be the sole culprit in the occurrence of TRAGI.  Very much like NEC in general, this relationship is an association and unlikely to be causative, in itself.

So, where does that leave us in setting clinical practice?  As so well described in an editorial by Christensen, it is important to remember that not all transfusions result in NEC nor are all cases of NEC preceded by a transfusion.4  As more and more publications have become available, more practitioners feel safer by stopping feeds during the transfusion and up to 4 hours after the transfusion.  One might ask, is there any harm in holding the feed during and after the transfusion until more definitive evidence is available?  If providing the feed increases blood flow to the gut, and this has been shown to occur at least in infants greater than 1250 gms, this additional blood flow may provide additional oxygen to the gut and be protective.7  At the very least, and for reasons other than TRAGI, human milk feeds are preferred and may be protective in several ways.  Additionally, exposure to fewer donors when transfusing and using fresher blood whenever possible may offer some protection.  There is at least one randomized clinical trial underway that may offer more guidance for practice.  In addition, there is a registry at www.tragiregistry.com where practitioners can enter cases with specific information in order to follow trends with greater numbers.  As with so many neonatal practices, the more we find out, the less we really know!

References:

1. McGrady GA, Rettig PJ, Istre GR, Jason JM, Holman RC, Evatt BL.  An outbreak of necrotizing enterocolitis.  Association with transfusion of packed red blood cells.  Am J Epidemiol.  1987;126(6):1165-1172.

2. LaGamma EF, Blau J.  Transfusion-related acute gut injury: Feeding, flora, flow and barrier defense.  Seminars in Perinatology.  2012; 36:294-305.

3. Blau J, Calo JM, Dozor D, et al.  Transfusion-related acute gut injury: Necrotizing enterocolitis in very low birth weight neonates after packed red blood cell transfusion.  Transfusion.  2011;158(3):403-409.

4. Christensen RD.  Association between red blood cell transfusions and necrotizing enterocolitis.  J Pediatr.  2011;158(3):349-350.

5. Baer VL, Henry E, Lambert DK, et al.  Impelmenting a program to improve compliance with neonatal intensive care unit transfusion guidelines was accompanied by a reduction in transfusion rate: a pre-post analysis within a multihospital health care system.  Transfusion.  2011;51(2):264-269.

6. Singh R, Visintainer PF, Frantz ID et al.  Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions in preterm infants.  J Perinatol.  2011;31:176-182.

7. Krimmel GA, Baker R, Yanowitz TD.  Blood transfusion alters the superior mesenteric artery blood flow velocity response to feeding in premature infants.  Am J Perinatology.  2009;26(2):99-105.

 

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