ASSESSING THE IMPACT OF HOLDING FEEDINGS DURING PRBC TRANSFUSION ON THE INCIDENCE OF TRAGI Justin Ayala Delaine Winn Rachana Singh, MD, MS Robert Rothstein, MD

OVERVIEW  NEC Background  Previous / Future Studies  Our historical prospective chart review

NECROTIZING ENTEROCOLITIS (NEC)  Acute necrosis of the intestinal mucosa leading to bacterial translocation and infection of gut  Results in death of bowel tissue  Affects 7-13% of all very low birth weight (VLBW) infants 1  Incidence in US = / 1000 births 1  Mortality rate = 10-44% 1  Treated medically (antibiotics) or surgically X-ray of an infant with NEC showing pneumatosis intestinalis

PREVENTING AND CARING FOR NEC  Incidence of NEC inversely proportional to gestational age (GA)  Etiology unknown – thought to be multifactorial  Known risk factors include:  Prematurity  Anemia of Prematurity (AOP)  Early and rapid advancement enteral feeds  Use of post-natal steroids  PDA and indomethacin treatment  Breast milk vs. formula feedings  Presence of umbilical catheters

 No preventative measures known  Efforts include: - Slow feeding advancements - Promote breast milk feedings - Limit antibiotic use  Adverse long-term outcomes 5  Failure to thrive  Short Gut Syndrome (SGS)  Neurodevelopmental Disability  Intestinal stricture  Malabsorption Intestinal autopsy showing NEC and pneumatosis intestinalis (image via CDC) PREVENTING AND CARING FOR NEC

PREVIOUS STUDIES  Transfusion Associated Necrotizing Enterocolitis (TANEC)  2006: First study linking PRBC transfusions to NEC 2  Subsequent studies confirm relationship  NEC onset has temporal relationship with Tx  <48 hrs post Tx Of all NEC cases, 20-35% are transfusion associated 3,4

TRANSFUSION RELATED NEC (TANEC/TRAGI)  “TANEC/TRAGI” now an established Dx  = A sub- class of NEC seen in healthy growing preterm infants  Link between AOP and NEC also established 1  AOP = low hct = higher risk of NEC PROBLEM:  Anemia = NEC risk  Tx = NEC risk  Tx = Intervention for anemia

RESEARCH GAPS  How can the risk of TANEC be minimized?  Feedings may play role  Transfusion may start a cascade of inflammation by unknown mechanisms  Enteral Feedings during transfusion may cause additional stress QUESTION: Do feedings affect incidence of TANEC?

RESEARCH GAPS  Recent studies show incidence of NEC increases when patient is fed before, during, and after transfusions 6  Randomized control trials = ideal  Ongoing study 6 : Withhold feeds peri-transfusion: ≤2 before, 2 after, 1 during  Most NICUs lack special feeding protocol for time surrounding Tx  Difficult to analyze relationship

OUR STUDY  Intervention :  2011 Protocol change – withhold feeds during and 24 hrs after a PRBC transfusion  Outcomes :  Compare incidence of TRAGI before and after the intervention  Hypothesis : “PRBC transfusions may increase the occurrence of TRAGI and withholding feeds during transfusions will result in lower incidence of TRAGI”

OUR STUDY What’s different about our study?  Cohort size: Largest cohort (appx pts) of any study looking at association of TANEC and withholding feeds  Time of feeds held: Longest length of time (24 hrs) holding feeds at tx initiation

METHODS / DATA DESCRIPTION  Cohort inclusion: All neonates admitted to NICU ( ) ≤34 weeks GA = ~1600 subjects  Exclusion: Known congenital heart disease / chromosomal anomalies  Comparison groups:  Infants receiving PRBC transfusions in the pre and post intervention

DATA COLLECTION  Demographics: GA, BW, Gender  Clinical Data:  Mat. History  APGARs/MOD/Resuscitation  Mechanical ventilation  Feeds started/discharge (BM, Formula), TPN  Central line placement  Use of Antacid  Other risk factors: Hypotension, SGS, DIC, ROP, IVH, CLD, PDA, Cholestasis, Positive blood culture, SIP Note all transfusions (excluding transfusions ≤7 days after NEC diagnosis)

STATISTICAL ANALYSIS  Frequency distributions for categorical variables  Means and standard deviations for continuous data  Medians and ranges for count/ordinal data  Logistic regression to compare odds of TRAGI in both time periods

RESULTS - DEMOGRAPHICS VariablePrePostTotalp-value Gestational age(weeks) 31.26(3.00)31.47(3.02)31.36(3.01) Gender (%) Males Females Birth weight (Grams, mean & SD) (576.82) (572.70) (574.63) Mode of delivery (%) C-section Vaginal Apgar score at 1min (median, mean, SD) 8, 6.70 (2.3) 8, 6.68 (2.35) 8, 6.69, Apgar score at 5 mins (median, mean, SD) 9, 7.92 (1.69) 9, 8.0 (1.54) 9, 7.95 (1.62) Maternal history: PIH PPROM Chorioamnionitis Prenatal steroids 16.29% % %

RESULTS - DEMOGRAPHICS  Demographics & Maternal History data equivalent between pre/post groups  No Selection bias  Chorioamnionitis = only statistically significant difference  Higher incidence in pre- intervention group

RESULTS – OUTCOME VARIABLES VariablePrePostTotalp-value Diagnosis of NEC (%) NEC stage (n) 1, Suspicious 2, Medical NEC 3, Surgical NEC Dx of NEC (n) Transfusion 48 hrs prior to Dx of NEC (n) % TANEC12.5%0%6.1 % % TANEC cases feeding at time of Tx 100 % (n=2)N/A (n=0) Surgery for NEC (n) 134

RESULTS – OUTCOME VARIABLES  Overall incidence of NEC = similar (16 pre vs. 17 post)  Incidence of TANEC pre = 12.5% of all NEC cases  100% (2/2) TANEC patients also feeding at time of Tx  Incidence of TANEC post = 0% of all NEC cases  Statistically significant difference

RESULTS – SECONDARY OUTCOMES VariablePrePostTotalp-value SGS (n, %)3 (0.36)1 (0.13)4 (0.25) Discharge Status (%) Alive Dead Mean age at discharge (days) (26.69)28.10 (26.34)29.96 (26.58) Age at death (med, mean, SD) in days 7, (19.48)4, (37.15)7, (28.73) Mechanical Ventilation (Yes, %) <0.001 Diagnosis of CLD (%) <0.001 Steroid use for CLD(%) DX of PDA (%) Dx of DIC (%) Dx of IVH (%) <0.001 Dx of ROP (%) Dx of Cholestasis (%)

RESULTS – SECONDARY OUTCOMES  Between post and pre groups:  Statistically significant decrease in incidence of CLD, PDA, IVH  Statistically significant decrease in mean discharge age and mean length of use of mechanical ventilation

CONCLUSIONS  No patient admitted to NICU developed TANEC from  12.5% (2 of 16) of NEC patients ( ) were actually of the subset TANEC  Both patients were feeding at time of tx (feeds were not held)  0% (0 of 17) of NEC patients ( ) belonged to this subset This preliminary analysis suggests likely association between withholding feeds during/after tx and low incidence of TANEC

LIMITATIONS  Preliminary data

APPRECIATIONS  Summer Student Scholars Program  Rachana Singh, MD, MS  Robert Rothstein, MD  Krishna Vemuri, MD  Paul Visintainer, Ph.D.  Alexander Knee, MS  NICU staff

REFERENCES  1 Singh R, Visintainer PF, Frantz III ID, Shah BL, Meyer KM, Favila SA, et al. Association of necrotizing enterocolitis with anemia and packed red blood cell transfusions inpreterm infants. J Perinatol 2011;31:176–82.  2 Mally P, Golombek SG, Mishra R, La Gamma EF, Nigam S, Mohandas K et al. “Association of necrotizing enterocolitis with elective packed red blood cell transfusions in premature neonates. Am J Perinatol 2006; 23(8): 451–458.”  3 Christensen RD, Wiedmeier SE, Baer VL, Henry E, Gerday E, Lambert DK et al. Antecedents of bell stage III necrotizing enterocolitis. J Perinatol 2010; 30: 54– 57.  4 Christensen RD, Wiedmeier SE, Baer VL, Henry E, Gerday E, Lambert DK et al. Antecedents of bell stage III necrotizing enterocolitis. J Perinatol 2010; 30: 54– 57.  5  5 Springer, Shelley C. "Necrotizing Enterocolitis." Necrotizing Enterocolitis. N.p., 23 Apr Web. 09 July  6  6 "Withholding Feeds During Red Blood Cell Transfusion and TRAGI (Tx-TRAGI)." Withholding Feeds During Red Blood Cell Transfusion and TRAGI. Zekai Tahir Burak Maternity and Teaching Hospital, 17 Apr Web. 09 July