Pediatr Cardiol DOI 10.1007/s00246-014-0891-9
ORIGINAL ARTICLE
Necrotizing Enterocolitis in Infants With Congenital Heart Disease: The Role of Red Blood Cell Transfusions Anand C. Baxi • Cassandra D. Josephson Glen J. Iannucci • William T. Mahle
•
Received: 14 November 2013 / Accepted: 26 February 2014 Springer Science+Business Media New York 2014
Abstract Necrotizing enterocolitis (NEC) is a rare but catastrophic complication that may occur in newborns with congenital heart disease (CHD). In the preterm population, transfusion of red blood cells (RBCs) and use of RBCs with longer storage time have been independently associated with the development of NEC. To date, it is not known whether similar associations exist for the term newborn with CHD. This retrospective study identified the incidence of NEC among 1,551 newborns admitted to the authors’ cardiac intensive care unit between 7 January 2002 and 7 January 2010. The study was limited to term newborns ([36 weeks gestation). To understand the impact of RBC transfusions on the development of NEC, a nested 2:1 matched case–control analysis was undertaken to compare RBC transfusion patterns between an age-matched group and a cardiac lesion-matched control group. In the study population, NEC developed in 45 term infants during the postoperative period. Of these 45 infants, 30 (66.7 %) had single-ventricle heart defects, whereas 22 (48.8 %) required surgery for aortic arch obstruction. The median patient age at NEC diagnosis was 21 days. The RBC transfusion rate was higher among the patients who
A. C. Baxi G. J. Iannucci W. T. Mahle (&) Division of Pediatric Cardiology, Sibley Heart Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, 1405 Clifton Road, NE, Atlanta, GA 30322-1062, USA e-mail: [email protected] A. C. Baxi e-mail: [email protected] C. D. Josephson Pathology, and Pediatrics, Children’s Healthcare of Atlanta, Blood and Tissue Services, Emory University School of Medicine, Atlanta, GA 30322, USA
experienced NEC (0.21/day) than among the control subjects (0.10/day) (p = 0.048). A multivariate analysis indicated that onset of NEC was associated with a greater number of RBC transfusions (odds ratio [OR] 1.83; 95 % confidence interval [CI] 1.07–7.47; p = 0.045). The duration of RBC storage was not significantly longer in the NEC group (9 days) than in the control cohort (7 days) (p = 0.16). Increased exposure to RBC transfusions is associated with the development of NEC in term infants with CHD. Longer storage of RBCs does not appear to increase this risk. Although causality cannot be confirmed, these data prompt a careful review of RBC transfusion practices with this population. Keywords Congenital heart disease Necrotizing enterocolitis Blood transfusion
Introduction Necrotizing enterocolitis (NEC) is a rare but often catastrophic complication experienced by young infants. As a result, it is among the leading causes of gastrointestinal morbidity and mortality in neonatal intensive care units (ICUs) [5]. Although it is seen most frequently in verylow-birth-weight infants, NEC is not unique to this population. Reports show that NEC occurs 10–100 times more frequently in the congenital heart disease (CHD) population than in term infants without CHD [16]. Depending on the severity of the lesion, the incidence of NEC may approach that seen among very-low-birth-weight infants [12, 13, 17]. In the case of hypoplastic left heart syndrome, the incidence often is significantly higher [3, 7]. A number of recent studies have demonstrated an independent association between red blood cell (RBC)
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transfusions and the development of NEC in premature infants [2, 18]. The mechanism of this association in not fully understood but may relate to acute inflammatory or immunomodulatory effects of RBC transfusion [4]. In addition, some investigations have suggested that the duration of RBC storage may increase the risk of NEC [9, 14]. These relationships have not been evaluated in term infants with CHD. Transfusion of RBCs is common after neonatal heart surgery to maintain adequate systemic oxygen delivery, especially in those with cyanotic heart lesions [10, 11, 25]. For our study, we hypothesized that postsurgical RBC transfusions contribute to the development of NEC in term infants with CHD.
Table 1 Institutional red blood cell (RBC) transfusion guidelines for neonates 1. Transfuse for Hct B 20–22 % in otherwise well infant. No signs of anemia required 2. Transfuse for Hct B 28 % if: • Receiving mechanical ventilation ? FiO2 B 0.4 and MAP B 9 cm H2O • Receiving CPAP or Oxyhood ? FiO2 [ 0.4 • For nasal cannula, refer to chart and transfuse based on delivered FiO2 • ELBW infants on low vent settings but experiencing unexplained swings in SpO2 some \75 % transiently • Unexplained tachycardia (HR C 170) or tachypnea (RR C 80) lasting [24–48 h • Unexplained apnea: [10 spells/day or 2 spells/day requiring bag-mask resuscitation
Methods
• Unexplained lethargy • Weight gain \10 g/day during 1 week despite adequate calories
We previously conducted a nested 2:1 matched case–control study to assess the impact that mode of feeding has on the risk of NEC development in infants either before or after cardiac surgery [6]. Because new data are emerging regarding the potential role of RBC transfusion in the development of NEC, we undertook the current analysis using a subset of this previously described cohort to analyze the role of our postoperative RBC transfusion strategy in the development of NEC. After obtaining approval from our institution’s institutional review board, we reviewed the records of patients admitted to either cardiology or cardiothoracic surgery service at Children’s Healthcare of Atlanta from 7 January 2002 through 7 January 2010. Patients were identified through review of an institutional database of complications and an independent International Classification of Diseases (ICD)-9 query of hospital records. At our institution, findings consistent with NEC include abdominal distension with hematochezia, elevated lactic acid, thrombocytopenia, or radiographic changes. Patients with these findings are evaluated by a pediatric surgery consultant, who confirms the diagnosis of NEC and assists with subsequent management. We chose to focus on infants with an estimated gestational age greater than 36 weeks to evaluate risk factors independent of prematurity. In addition, to isolate specific risk factors for NEC further, we excluded from the study population infants with gastrointestinal malformations (e.g., gastroschisis or duodenal atresia), isolated postoperative pneumoperitoneum, NEC that occurred beyond the first 90 days of life, and isolated transitional lesions (e.g., patent ductus arteriosus, atrial septal defect). During the study period, the approach to feeding remained relatively constant. We used 20-calorie formula or breast milk until full volume was achieved and then advanced the calories. The majority of high-risk infants
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3. Transfuse for Hct \35 % if: • Receiving mechanical ventilation ? FiO2 [ 0.4 and MAP [ 9 cm H2O • Hypotension 4. Transfuse for Hct B 45 % if: • Congenital cyanotic heart disease • Significant L/R shunt (e.g., PDA, VSD) • Pre and postoperative open heart surgery 5. Acute blood loss [10 % blood volume or [10 mL/kg 6. ECMO and pre-ECMO/‘‘critical’’ infants • Target Hct 35–40 unless baseline SpO2 \ 90 % 7. Surgical cases (preoperative and immediate postoperative) • May transfuse for Hct B 30 based on underlying disease state Hct hematocrit, FiO2 fraction of inspired oxygen, CPAP continuous positive airway pressure, ELBW extremely low birth weight, SpO2 oxygen saturation, HR heart rate, MAP mean arterial pressure, L left, R right, PDA patent ductus arteriosis, VSD ventricular septal defect, pRBC packed red blood cells, ECMO extracorporeal membrane oxygenation
received at least some of their feeds via nasogastric tube. We did not routinely place a gastric tube for high-risk neonates or infants. For each study patient, the medical record was reviewed, and information regarding the infants’ presentation at time of NEC diagnosis was collected. Each subject then was retrospectively staged according to the modified Bell criteria for NEC [22]. Furthermore, patients with suspected NEC according to the Bell criteria also were included in the study because this diagnosis is clinically significant and often requires multiple days of intravenous nutrition, bowel rest, and parenteral antibiotics [16, 19]. The RBC transfusion protocol at the institution called for the administration of 15 mL/kg leukoreduced, irradiated, CPDA-1-preserved
Pediatr Cardiol
RBCs, similar to the recommendations of the American Association of Blood Banks (Table 1) [8]. In this retrospective study, a transfusion event was qualified as an order, and the completion time for the transfusion was recorded on the chart. Surgeons and intensivists generally target hematocrit levels of 40 % and higher in infants with cyanotic lesions and 35 % and higher in those with noncyanotic lesions. The rationale for maintaining an elevated serum hematocrit level in the postoperative period relates to the contribution of hemoglobin to the oxygen-carrying capacity of RBCs. Increasing the oxygen-carrying capacity is the strategy used to improve oxygen delivery, especially in infants experiencing low cardiac output syndrome after cardiopulmonary bypass. To evaluate the role that different RBC transfusion strategies may have played in the development of NEC, a nested 2:1 matched case–control study was designed. Each NEC case was matched with two control subjects based on type of congenital heart defect and surgical procedure. Risk adjustment for congenital heart surgery criteria was used to select control subjects with similar heart disease severity/ risk profiles when exact matches could not be obtained [24]. Our primary risk factor of interest was the RBC transfusion rate. For the control cohort, this was defined as the number of RBC transfusions per ICU day, excluding those on the day of surgery. For the NEC cohort, this was defined as number of RBC transfusions per hospital day, excluding those on the day of surgery, before diagnosis of NEC. In addition we examined the cumulative number of RBC transfusions and the age of RBCs at the time of transfusion. Our secondary risk factors of interest were gender, prenatal diagnosis, chromosomal anomaly, heterotaxy syndrome, single-ventricle physiology, and presence of aortic arch obstruction. To account for the matching, we first performed conditional univariate logistic regression for each risk factor stratified by the matching. To estimate odds ratios (ORs), we performed conditional multivariate logistic regression for those factors with an initial p value lower than 0.10 using backward elimination to determine the final significant risk factors. All statistics were computed using SAS version 9.2 (SAS, Cary, NC, USA). An alpha of 0.05 was used to determine statistical significance in the multivariate models.
Results During the 8-year study period, NEC developed in 45 term or near-term infants with CHD. The majority of the infants in whom NEC developed (66.7 %) had a single-ventricle
Table 2 Demographics and congenital heart disease (CHD) lesions for children with necrotizing enterocolitis (NEC) Characteristic
No. of infants (%)
Total no.
45
Males
28 (62)
Single-ventricle physiology Aortic arch obstruction
30 (67) 22 (49)
Unobstructed aortic arch
8 (18)
Heterotaxy
6 (13)
Chromosomal abnormality
11 (24)
Stage 1 palliation
16 (36)
Norwood/Sano
12 (27)
Norwood/modified Blalock–Taussig shunt
4 (9)
Modified Blalock–Taussig shunt without aortic arch surgery
14 (31)
Cardiac surgery before NEC diagnosis
37 (82)
Table 3 Characteristics of children with necrotizing enterocolitis (NEC) compared with matched control subjects Characteristic
NEC cohort (n = 45) n (%)
Match controls (n = 90) n (%)
p value
Male gender Prenatal diagnosis
28 (62) 28 (62)
54 (60) 53 (59)
0.81 0.71
Mean birth weight
3.00
3.11
0.29
IUGR
7 (16)
20 (22)
0.36
Exposure to breast milk
15 (33)
36 (40)
0.45
Single ventricle
30 (67)
53 (59)
0.38
Arch obstruction
22 (49)
39 (43)
0.54
Heterotaxy
6 (13)
8 (9)
0.57
Death
14 (31)
14 (16)
0.04
IUGR intrauterine growth restriction
physiology. Aortic arch obstruction was found in 22 patients (48.8 %), whereas 6 patients (13.3 %) had heterotaxy. In all, 11 patients (24.4 %) had a chromosomal anomaly. The median patient age at NEC diagnosis was 21 days. In the NEC cohort, 16 (35.6 %) of 45 patients had undergone stage 1 Norwood palliation. Of these patients, 12 (26.6 %) had received a Norwood/Sano, whereas the remaining 4 (8.9 %) had received a Norwood/modified Blalock–Taussig shunt. In addition, 14 patients (31.1 %) underwent modified Blalock–Taussig shunt placement without aortic arch surgery. Two patients (4.4 %) in the NEC cohort had not undergone cardiac surgery. The remaining 43 cases of NEC (82.2 %) occurred in the postoperative period, primarily within the first 3 weeks after surgery (Table 2). In the comparisons of birth weight, intrauterine growth rate (IUGR), exposure to breast milk, age at the time of
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Pediatr Cardiol Table 4 Comparison of red blood cell (RBC) transfusions between children with congenital heart disease (CHD) who experienced necrotizing enterocolitis (NEC) and matched control subjects
Median transfusions per patient
Fig. 1 Red blood cell (RBC) transfusion rate of children in whom necrotizing enterocolitis (NEC) developed versus matched control subjects
surgery, duration of the cardiopulmonary bypass, and length of aortic cross-clamp time, no significant differences between the NEC cohort and the matched control subjects were found. The median ICU stay for the NEC cohort was 17.5 days compared 8 days with for the control population (p \ 0.001). The median hospital stay for the NEC cohort was 39.5 days, whereas that for the control cohort was 19 days (p \ 0.001). Of the patients who experienced NEC, 14 (31.1 %) died, whereas 14 patients (15.6 %) in the control group died (Table 3). Of the patients who experienced NEC, 38 (84.4 %) had received transfusions on a day other than their surgery day before the onset of NEC. Of these 38 patients, 21 (55.2 %) received transfusions within 48 h after the diagnosis. The absolute number of transfusions given to NEC patients did not differ significantly from the number given to the control patients (2.0 vs 1.0; p = 0.082). However, the RBC transfusion rate was higher in the NEC patients (0.21/day) than in the control patients (0.10/day) (p = 0.048) (Fig. 1). Based on the protocol for transfusing 15 mL/kg of leukoreduced, irradiated packed RBCs for an anemic patient, the median RBC transfusion volume for the NEC patients before the NEC diagnosis did not differ significantly from that for the control patients during their ICU stay (99.00 vs 57.91 mL; p = 0.46). A multivariate analysis was conducted and indicated that onset of NEC was associated with a greater RBC transfusion rate (OR 1.83; 95 % confidence interval [CI] 1.07–7.47; p = 0.045). The median age of RBCs transfused in the NEC population was 9 days, whereas that in the control population was 7 days (p = 0.16) (Table 4). A multivariate analysis was conducted and indicated that age of RBCs transfused was not associated with the incidence of NEC.
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NEC patients
Control subjects
2.0
1.0
p value 0.082
RBC transfusion rate per day
0.21
0.10
0.048
Median age (in days) of RBCs transfused
9.0
7.0
0.16
Median volume of RBCs transfused (mL)
99.0
57.1
0.46
Median ICU stay (days)
17.5
8.0
\0.001
Median stay (days)
39.5
19.0
\0.001
ICU intensive care unit
Discussion In this study, a relationship between the rate of RBC transfusions per day and the subsequent development of NEC was found. A number of studies have investigated the role of RBC transfusion practices in NEC in the premature infant population. Premature infants are among the most often transfused populations, with more than half of verylow-birth-weight infants receiving at least one RBC transfusion during their hospital stay [1]. The largest studies completed to date indicate that among all cases of NEC, approximately 25–40 % received a RBC transfusion in the preceding 24–48 h, and neonates in whom transfusion-associated NEC develops are typically born at a younger gestational age than those who experience NEC unrelated to RBC transfusion [21]. However, all these studies have been case–control studies. To prove a correlation, a randomized control trial is needed. In addition, RBC transfusion practices vary widely between and within institutions, which further calls for a randomized controlled trial to establish a correlation between RBC transfusion and NEC [23]. Because a large number of infants with CHD require cardiopulmonary bypass surgery, RBC transfusions continue to be integral to the care of these patients because they have been shown to increase oxygen delivery. Although available data regarding negative outcomes of transfusion practices in this population are limited, findings have shown that RBC transfusion is associated with pediatric cardiac surgery patients and increased length of stay due to higher risks of infection, acute kidney injury, and long duration of mechanical ventilation [20]. In this study, we identified an association between RBC transfusions and the development of NEC in term infants with CHD. To our knowledge this relationship has not been explored previously in those with CHD. Although the patients in the NEC cohort received more transfusions per
Pediatr Cardiol
day than those in the control group, the median number of transfusions and the median transfusion volume over the duration of the hospital stay did not differ significantly between the two groups. This likely is the result of the significantly higher death rate in the NEC group. Admittedly, many factors likely prompt a clinician to consider RBC transfusion including hemodynamic instability, laboratory studies such as lactic acidosis, and severity of underlying heart disease. We attempted to adjust for some of these variables in a multivariate model. However, other clinical findings likely exist that are not easy to define in a retrospective analysis. Whether RBC transfusion predisposes to NEC through immunomodulation or whether RBC transfusion is simply a marker of a higher-risk CHD patients cannot be determined from this analysis. For the preterm population, considerable interest is focused on the duration of RBC storage before transfusion and the timing of RBC transfusion before NEC onset. Findings show that RBCs with longer storage times are associated with increased adhesions and aggregation as well as loss of nitric oxide [17]. As a result, these transfusions can cause a reduction in oxygen delivery, subsequent vasoconstriction, and ischemic injury to the intestine [15]. Thus, we also investigated the potential role that RBC age may play in the development of NEC in term infants with CHD. However, in this study the children who experienced NEC were not more likely to have been transfused with older RBCs. It should be recognized, however, that our institutional policy is to administer only RBCs stored for less than 14 days to those patients undergoing congenital heart surgery. As such, the narrow range of RBC storage times may have limited this analysis. Moreover, we cannot comment about the potential benefits or risks of fresh whole blood, which is used routinely in some pediatric congenital heart programs, vis-a`-vis the development of NEC. Because this study was a retrospective, case–control investigation, a cautious evaluation of the data is necessary. Potential sources of confounding are difficult to account for including the fact that critically ill patients are more likely to be transfused and that these same patients may be more likely to experience NEC. Also, there is some reason to believe that other blood products such as platelets and cryoprecipitate also may modulate the immune system. We chose not to focus on these products because they are nearly always administered within a few hours after surgery, and it would be challenging to disentangle the direct impact of these products on NEC development from the complexity of the immediate postoperative course. Among term newborns with CHD, NEC is relatively uncommon but may be catastrophic. Our study shows that an increased number of transfusions per day is associated
with a greater incidence of NEC. However, no significant link exists between the age of RBCs and the development of NEC. These findings warrant a thorough review of transfusion practices for newborns in an effort to decrease the development of NEC in this vulnerable population. Conflict of interest There are no relevant financial disclosures or conflicts of interest for any of the above authors.
References 1. Amin SC, Remon JI, Subbarao GC, Maheshwari A (2012) Association between red cell transfusions and necrotizing enterocolitis. J Matern Fetal Neonatal Med 25:85–89 2. Christensen RD (2011) Association between red blood cell transfusions and necrotizing enterocolitis. J Pediatr 158:349–350 3. del Castillo SL, McCulley ME, Khemani RG, Jeffries HE, Thomas DW, Peregrine J et al (2010) Reducing the incidence of necrotizing enterocolitis in neonates with hypoplastic left heart syndrome with the introduction of an enteral feed protocol. Pediatr Crit Care Med 11:373–377 4. El-Dib M, Narang S, Lee E, Massaro AN, Aly H (2011) Red blood cell transfusion, feeding and necrotizing enterocolitis in preterm infants. J Perinatol 31:183–187 5. Hsueh W, Caplan MS, Qu XW, Tan XD, De Plaen IG, GonzalezCrussi F (2003) Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Develop Pathol 6:6–23 6. Iannucci GJ, Oster ME, Mahle WT (2013) Necrotising enterocolitis in infants with congenital heart disease: the role of enteral feeds. Cardiol Young 23(4):553–559 7. Jeffries HE, Wells WJ, Starnes VA, Wetzel RC, Moromisato DY (2006) Gastrointestinal morbidity after Norwood palliation for hypoplastic left heart syndrome. Ann Thorac Surg 81:982–987 8. Jenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI (2002) Consensus-based method for risk adjustment for surgery for congenital heart disease. J Thorac Cardiovasc Surg 123:110–118 9. Josephson CD, Wesolowski A, Bao G, Sola-Visner MC, Dudell G, Castillejo MI et al (2010) Do red cell transfusions increase the risk of necrotizing enterocolitis in premature infants? J Pediatr 157(972–978):e1–e3 10. Kliegman RM, Walsh MC (1987) Neonatal necrotizing enterocolitis: pathogenesis, classification, and spectrum of illness. Curr Probl Pediatr 17:213–288 11. Krimmel GA, Baker R, Yanowitz TD (2009) Blood transfusion alters the superior mesenteric artery blood flow velocity response to feeding in premature infants. Am J Perinatol 26:99–105 12. Leung MP, Chau KT, Hui PW, Tam AY, Chan FL, Lai CL et al (1988) Necrotizing enterocolitis in neonates with symptomatic congenital heart disease. J Pediatr 113:1044–1046 13. Lin PW, Stoll BJ (2006) Necrotising enterocolitis. Lancet 368:1271–1283 14. Mally P, Golombek SG, Mishra R, Nigam S, Mohandas K, Depalhma H et al (2006) Association of necrotizing enterocolitis with elective packed red blood cell transfusions in stable, growing, premature neonates. Am J Perinatol 23:451–458 15. Marin T, Strickland OL (2013) Transfusion-related necrotizing enterocolitis: a conceptual framework. Adv Neonatal Care 13:166–174 16. McElhinney DB, Hedrick HL, Bush DM, Pereira GR, Stafford PW, Gaynor JW et al (2000) Necrotizing enterocolitis in neonates
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with congenital heart disease: risk factors and outcomes. Pediatrics 106:1080–1087 Mukherjee D, Zhang Y, Chang DC, Vricella LA, Brenner JI, Abdullah F (2010) Outcomes analysis of necrotizing enterocolitis within 11,958 neonates undergoing cardiac surgical procedures. Arch Surg 145:389–392 Paul DA, Mackley A, Novitsky A, Zhao Y, Brooks A, Locke RG (2011) Increased odds of necrotizing enterocolitis after transfusion of red blood cells in premature infants. Pediatrics 127:635–641 Pickard SS, Feinstein JA, Popat RA, Huang L, Dutta S (2009) Short- and long-term outcomes of necrotizing enterocolitis in infants with congenital heart disease. Pediatrics 123:e901–e906 Reber KM, Nankervis CA, Nowicki PT (2002) Newborn intestinal circulation: physiology and pathophysiology. Clin Perinatol 29:23–39
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21. Ringer SA, Richardson DK, Sacher RA, Keszler M, Churchill WH (1998) Variations in transfusion practice in neonatal intensive care. Pediatrics 101:194–200 22. Roseff SD, Luban NL, Manno CS (2002) Guidelines for assessing appropriateness of pediatric transfusion. Transfusion 42:1398–1413 23. Salvin JW, Scheurer MA, Laussen PC, Wypij D, Polito A, Bacha EA et al (2011) Blood transfusion after pediatric cardiac surgery is associated with prolonged hospital stay. Ann Thorac Surg 91:204–210 24. Strauss RG (1997) Practical issues in neonatal transfusion practice. Am J Clin Pathol 107:S57–S63 25. Szabo JS, Mayfield SR, Oh W, Stonestreet BS (1987) Postprandial gastrointestinal blood flow and oxygen consumption: effects of hypoxemia in neonatal piglets. Pediatr Res 21:93–98
ORIGINAL ARTICLE
Necrotizing Enterocolitis in Infants With Congenital Heart Disease: The Role of Red Blood Cell Transfusions Anand C. Baxi • Cassandra D. Josephson Glen J. Iannucci • William T. Mahle
•
Received: 14 November 2013 / Accepted: 26 February 2014 Springer Science+Business Media New York 2014
Abstract Necrotizing enterocolitis (NEC) is a rare but catastrophic complication that may occur in newborns with congenital heart disease (CHD). In the preterm population, transfusion of red blood cells (RBCs) and use of RBCs with longer storage time have been independently associated with the development of NEC. To date, it is not known whether similar associations exist for the term newborn with CHD. This retrospective study identified the incidence of NEC among 1,551 newborns admitted to the authors’ cardiac intensive care unit between 7 January 2002 and 7 January 2010. The study was limited to term newborns ([36 weeks gestation). To understand the impact of RBC transfusions on the development of NEC, a nested 2:1 matched case–control analysis was undertaken to compare RBC transfusion patterns between an age-matched group and a cardiac lesion-matched control group. In the study population, NEC developed in 45 term infants during the postoperative period. Of these 45 infants, 30 (66.7 %) had single-ventricle heart defects, whereas 22 (48.8 %) required surgery for aortic arch obstruction. The median patient age at NEC diagnosis was 21 days. The RBC transfusion rate was higher among the patients who
A. C. Baxi G. J. Iannucci W. T. Mahle (&) Division of Pediatric Cardiology, Sibley Heart Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, 1405 Clifton Road, NE, Atlanta, GA 30322-1062, USA e-mail: [email protected] A. C. Baxi e-mail: [email protected] C. D. Josephson Pathology, and Pediatrics, Children’s Healthcare of Atlanta, Blood and Tissue Services, Emory University School of Medicine, Atlanta, GA 30322, USA
experienced NEC (0.21/day) than among the control subjects (0.10/day) (p = 0.048). A multivariate analysis indicated that onset of NEC was associated with a greater number of RBC transfusions (odds ratio [OR] 1.83; 95 % confidence interval [CI] 1.07–7.47; p = 0.045). The duration of RBC storage was not significantly longer in the NEC group (9 days) than in the control cohort (7 days) (p = 0.16). Increased exposure to RBC transfusions is associated with the development of NEC in term infants with CHD. Longer storage of RBCs does not appear to increase this risk. Although causality cannot be confirmed, these data prompt a careful review of RBC transfusion practices with this population. Keywords Congenital heart disease Necrotizing enterocolitis Blood transfusion
Introduction Necrotizing enterocolitis (NEC) is a rare but often catastrophic complication experienced by young infants. As a result, it is among the leading causes of gastrointestinal morbidity and mortality in neonatal intensive care units (ICUs) [5]. Although it is seen most frequently in verylow-birth-weight infants, NEC is not unique to this population. Reports show that NEC occurs 10–100 times more frequently in the congenital heart disease (CHD) population than in term infants without CHD [16]. Depending on the severity of the lesion, the incidence of NEC may approach that seen among very-low-birth-weight infants [12, 13, 17]. In the case of hypoplastic left heart syndrome, the incidence often is significantly higher [3, 7]. A number of recent studies have demonstrated an independent association between red blood cell (RBC)
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transfusions and the development of NEC in premature infants [2, 18]. The mechanism of this association in not fully understood but may relate to acute inflammatory or immunomodulatory effects of RBC transfusion [4]. In addition, some investigations have suggested that the duration of RBC storage may increase the risk of NEC [9, 14]. These relationships have not been evaluated in term infants with CHD. Transfusion of RBCs is common after neonatal heart surgery to maintain adequate systemic oxygen delivery, especially in those with cyanotic heart lesions [10, 11, 25]. For our study, we hypothesized that postsurgical RBC transfusions contribute to the development of NEC in term infants with CHD.
Table 1 Institutional red blood cell (RBC) transfusion guidelines for neonates 1. Transfuse for Hct B 20–22 % in otherwise well infant. No signs of anemia required 2. Transfuse for Hct B 28 % if: • Receiving mechanical ventilation ? FiO2 B 0.4 and MAP B 9 cm H2O • Receiving CPAP or Oxyhood ? FiO2 [ 0.4 • For nasal cannula, refer to chart and transfuse based on delivered FiO2 • ELBW infants on low vent settings but experiencing unexplained swings in SpO2 some \75 % transiently • Unexplained tachycardia (HR C 170) or tachypnea (RR C 80) lasting [24–48 h • Unexplained apnea: [10 spells/day or 2 spells/day requiring bag-mask resuscitation
Methods
• Unexplained lethargy • Weight gain \10 g/day during 1 week despite adequate calories
We previously conducted a nested 2:1 matched case–control study to assess the impact that mode of feeding has on the risk of NEC development in infants either before or after cardiac surgery [6]. Because new data are emerging regarding the potential role of RBC transfusion in the development of NEC, we undertook the current analysis using a subset of this previously described cohort to analyze the role of our postoperative RBC transfusion strategy in the development of NEC. After obtaining approval from our institution’s institutional review board, we reviewed the records of patients admitted to either cardiology or cardiothoracic surgery service at Children’s Healthcare of Atlanta from 7 January 2002 through 7 January 2010. Patients were identified through review of an institutional database of complications and an independent International Classification of Diseases (ICD)-9 query of hospital records. At our institution, findings consistent with NEC include abdominal distension with hematochezia, elevated lactic acid, thrombocytopenia, or radiographic changes. Patients with these findings are evaluated by a pediatric surgery consultant, who confirms the diagnosis of NEC and assists with subsequent management. We chose to focus on infants with an estimated gestational age greater than 36 weeks to evaluate risk factors independent of prematurity. In addition, to isolate specific risk factors for NEC further, we excluded from the study population infants with gastrointestinal malformations (e.g., gastroschisis or duodenal atresia), isolated postoperative pneumoperitoneum, NEC that occurred beyond the first 90 days of life, and isolated transitional lesions (e.g., patent ductus arteriosus, atrial septal defect). During the study period, the approach to feeding remained relatively constant. We used 20-calorie formula or breast milk until full volume was achieved and then advanced the calories. The majority of high-risk infants
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3. Transfuse for Hct \35 % if: • Receiving mechanical ventilation ? FiO2 [ 0.4 and MAP [ 9 cm H2O • Hypotension 4. Transfuse for Hct B 45 % if: • Congenital cyanotic heart disease • Significant L/R shunt (e.g., PDA, VSD) • Pre and postoperative open heart surgery 5. Acute blood loss [10 % blood volume or [10 mL/kg 6. ECMO and pre-ECMO/‘‘critical’’ infants • Target Hct 35–40 unless baseline SpO2 \ 90 % 7. Surgical cases (preoperative and immediate postoperative) • May transfuse for Hct B 30 based on underlying disease state Hct hematocrit, FiO2 fraction of inspired oxygen, CPAP continuous positive airway pressure, ELBW extremely low birth weight, SpO2 oxygen saturation, HR heart rate, MAP mean arterial pressure, L left, R right, PDA patent ductus arteriosis, VSD ventricular septal defect, pRBC packed red blood cells, ECMO extracorporeal membrane oxygenation
received at least some of their feeds via nasogastric tube. We did not routinely place a gastric tube for high-risk neonates or infants. For each study patient, the medical record was reviewed, and information regarding the infants’ presentation at time of NEC diagnosis was collected. Each subject then was retrospectively staged according to the modified Bell criteria for NEC [22]. Furthermore, patients with suspected NEC according to the Bell criteria also were included in the study because this diagnosis is clinically significant and often requires multiple days of intravenous nutrition, bowel rest, and parenteral antibiotics [16, 19]. The RBC transfusion protocol at the institution called for the administration of 15 mL/kg leukoreduced, irradiated, CPDA-1-preserved
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RBCs, similar to the recommendations of the American Association of Blood Banks (Table 1) [8]. In this retrospective study, a transfusion event was qualified as an order, and the completion time for the transfusion was recorded on the chart. Surgeons and intensivists generally target hematocrit levels of 40 % and higher in infants with cyanotic lesions and 35 % and higher in those with noncyanotic lesions. The rationale for maintaining an elevated serum hematocrit level in the postoperative period relates to the contribution of hemoglobin to the oxygen-carrying capacity of RBCs. Increasing the oxygen-carrying capacity is the strategy used to improve oxygen delivery, especially in infants experiencing low cardiac output syndrome after cardiopulmonary bypass. To evaluate the role that different RBC transfusion strategies may have played in the development of NEC, a nested 2:1 matched case–control study was designed. Each NEC case was matched with two control subjects based on type of congenital heart defect and surgical procedure. Risk adjustment for congenital heart surgery criteria was used to select control subjects with similar heart disease severity/ risk profiles when exact matches could not be obtained [24]. Our primary risk factor of interest was the RBC transfusion rate. For the control cohort, this was defined as the number of RBC transfusions per ICU day, excluding those on the day of surgery. For the NEC cohort, this was defined as number of RBC transfusions per hospital day, excluding those on the day of surgery, before diagnosis of NEC. In addition we examined the cumulative number of RBC transfusions and the age of RBCs at the time of transfusion. Our secondary risk factors of interest were gender, prenatal diagnosis, chromosomal anomaly, heterotaxy syndrome, single-ventricle physiology, and presence of aortic arch obstruction. To account for the matching, we first performed conditional univariate logistic regression for each risk factor stratified by the matching. To estimate odds ratios (ORs), we performed conditional multivariate logistic regression for those factors with an initial p value lower than 0.10 using backward elimination to determine the final significant risk factors. All statistics were computed using SAS version 9.2 (SAS, Cary, NC, USA). An alpha of 0.05 was used to determine statistical significance in the multivariate models.
Results During the 8-year study period, NEC developed in 45 term or near-term infants with CHD. The majority of the infants in whom NEC developed (66.7 %) had a single-ventricle
Table 2 Demographics and congenital heart disease (CHD) lesions for children with necrotizing enterocolitis (NEC) Characteristic
No. of infants (%)
Total no.
45
Males
28 (62)
Single-ventricle physiology Aortic arch obstruction
30 (67) 22 (49)
Unobstructed aortic arch
8 (18)
Heterotaxy
6 (13)
Chromosomal abnormality
11 (24)
Stage 1 palliation
16 (36)
Norwood/Sano
12 (27)
Norwood/modified Blalock–Taussig shunt
4 (9)
Modified Blalock–Taussig shunt without aortic arch surgery
14 (31)
Cardiac surgery before NEC diagnosis
37 (82)
Table 3 Characteristics of children with necrotizing enterocolitis (NEC) compared with matched control subjects Characteristic
NEC cohort (n = 45) n (%)
Match controls (n = 90) n (%)
p value
Male gender Prenatal diagnosis
28 (62) 28 (62)
54 (60) 53 (59)
0.81 0.71
Mean birth weight
3.00
3.11
0.29
IUGR
7 (16)
20 (22)
0.36
Exposure to breast milk
15 (33)
36 (40)
0.45
Single ventricle
30 (67)
53 (59)
0.38
Arch obstruction
22 (49)
39 (43)
0.54
Heterotaxy
6 (13)
8 (9)
0.57
Death
14 (31)
14 (16)
0.04
IUGR intrauterine growth restriction
physiology. Aortic arch obstruction was found in 22 patients (48.8 %), whereas 6 patients (13.3 %) had heterotaxy. In all, 11 patients (24.4 %) had a chromosomal anomaly. The median patient age at NEC diagnosis was 21 days. In the NEC cohort, 16 (35.6 %) of 45 patients had undergone stage 1 Norwood palliation. Of these patients, 12 (26.6 %) had received a Norwood/Sano, whereas the remaining 4 (8.9 %) had received a Norwood/modified Blalock–Taussig shunt. In addition, 14 patients (31.1 %) underwent modified Blalock–Taussig shunt placement without aortic arch surgery. Two patients (4.4 %) in the NEC cohort had not undergone cardiac surgery. The remaining 43 cases of NEC (82.2 %) occurred in the postoperative period, primarily within the first 3 weeks after surgery (Table 2). In the comparisons of birth weight, intrauterine growth rate (IUGR), exposure to breast milk, age at the time of
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Pediatr Cardiol Table 4 Comparison of red blood cell (RBC) transfusions between children with congenital heart disease (CHD) who experienced necrotizing enterocolitis (NEC) and matched control subjects
Median transfusions per patient
Fig. 1 Red blood cell (RBC) transfusion rate of children in whom necrotizing enterocolitis (NEC) developed versus matched control subjects
surgery, duration of the cardiopulmonary bypass, and length of aortic cross-clamp time, no significant differences between the NEC cohort and the matched control subjects were found. The median ICU stay for the NEC cohort was 17.5 days compared 8 days with for the control population (p \ 0.001). The median hospital stay for the NEC cohort was 39.5 days, whereas that for the control cohort was 19 days (p \ 0.001). Of the patients who experienced NEC, 14 (31.1 %) died, whereas 14 patients (15.6 %) in the control group died (Table 3). Of the patients who experienced NEC, 38 (84.4 %) had received transfusions on a day other than their surgery day before the onset of NEC. Of these 38 patients, 21 (55.2 %) received transfusions within 48 h after the diagnosis. The absolute number of transfusions given to NEC patients did not differ significantly from the number given to the control patients (2.0 vs 1.0; p = 0.082). However, the RBC transfusion rate was higher in the NEC patients (0.21/day) than in the control patients (0.10/day) (p = 0.048) (Fig. 1). Based on the protocol for transfusing 15 mL/kg of leukoreduced, irradiated packed RBCs for an anemic patient, the median RBC transfusion volume for the NEC patients before the NEC diagnosis did not differ significantly from that for the control patients during their ICU stay (99.00 vs 57.91 mL; p = 0.46). A multivariate analysis was conducted and indicated that onset of NEC was associated with a greater RBC transfusion rate (OR 1.83; 95 % confidence interval [CI] 1.07–7.47; p = 0.045). The median age of RBCs transfused in the NEC population was 9 days, whereas that in the control population was 7 days (p = 0.16) (Table 4). A multivariate analysis was conducted and indicated that age of RBCs transfused was not associated with the incidence of NEC.
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NEC patients
Control subjects
2.0
1.0
p value 0.082
RBC transfusion rate per day
0.21
0.10
0.048
Median age (in days) of RBCs transfused
9.0
7.0
0.16
Median volume of RBCs transfused (mL)
99.0
57.1
0.46
Median ICU stay (days)
17.5
8.0
\0.001
Median stay (days)
39.5
19.0
\0.001
ICU intensive care unit
Discussion In this study, a relationship between the rate of RBC transfusions per day and the subsequent development of NEC was found. A number of studies have investigated the role of RBC transfusion practices in NEC in the premature infant population. Premature infants are among the most often transfused populations, with more than half of verylow-birth-weight infants receiving at least one RBC transfusion during their hospital stay [1]. The largest studies completed to date indicate that among all cases of NEC, approximately 25–40 % received a RBC transfusion in the preceding 24–48 h, and neonates in whom transfusion-associated NEC develops are typically born at a younger gestational age than those who experience NEC unrelated to RBC transfusion [21]. However, all these studies have been case–control studies. To prove a correlation, a randomized control trial is needed. In addition, RBC transfusion practices vary widely between and within institutions, which further calls for a randomized controlled trial to establish a correlation between RBC transfusion and NEC [23]. Because a large number of infants with CHD require cardiopulmonary bypass surgery, RBC transfusions continue to be integral to the care of these patients because they have been shown to increase oxygen delivery. Although available data regarding negative outcomes of transfusion practices in this population are limited, findings have shown that RBC transfusion is associated with pediatric cardiac surgery patients and increased length of stay due to higher risks of infection, acute kidney injury, and long duration of mechanical ventilation [20]. In this study, we identified an association between RBC transfusions and the development of NEC in term infants with CHD. To our knowledge this relationship has not been explored previously in those with CHD. Although the patients in the NEC cohort received more transfusions per
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day than those in the control group, the median number of transfusions and the median transfusion volume over the duration of the hospital stay did not differ significantly between the two groups. This likely is the result of the significantly higher death rate in the NEC group. Admittedly, many factors likely prompt a clinician to consider RBC transfusion including hemodynamic instability, laboratory studies such as lactic acidosis, and severity of underlying heart disease. We attempted to adjust for some of these variables in a multivariate model. However, other clinical findings likely exist that are not easy to define in a retrospective analysis. Whether RBC transfusion predisposes to NEC through immunomodulation or whether RBC transfusion is simply a marker of a higher-risk CHD patients cannot be determined from this analysis. For the preterm population, considerable interest is focused on the duration of RBC storage before transfusion and the timing of RBC transfusion before NEC onset. Findings show that RBCs with longer storage times are associated with increased adhesions and aggregation as well as loss of nitric oxide [17]. As a result, these transfusions can cause a reduction in oxygen delivery, subsequent vasoconstriction, and ischemic injury to the intestine [15]. Thus, we also investigated the potential role that RBC age may play in the development of NEC in term infants with CHD. However, in this study the children who experienced NEC were not more likely to have been transfused with older RBCs. It should be recognized, however, that our institutional policy is to administer only RBCs stored for less than 14 days to those patients undergoing congenital heart surgery. As such, the narrow range of RBC storage times may have limited this analysis. Moreover, we cannot comment about the potential benefits or risks of fresh whole blood, which is used routinely in some pediatric congenital heart programs, vis-a`-vis the development of NEC. Because this study was a retrospective, case–control investigation, a cautious evaluation of the data is necessary. Potential sources of confounding are difficult to account for including the fact that critically ill patients are more likely to be transfused and that these same patients may be more likely to experience NEC. Also, there is some reason to believe that other blood products such as platelets and cryoprecipitate also may modulate the immune system. We chose not to focus on these products because they are nearly always administered within a few hours after surgery, and it would be challenging to disentangle the direct impact of these products on NEC development from the complexity of the immediate postoperative course. Among term newborns with CHD, NEC is relatively uncommon but may be catastrophic. Our study shows that an increased number of transfusions per day is associated
with a greater incidence of NEC. However, no significant link exists between the age of RBCs and the development of NEC. These findings warrant a thorough review of transfusion practices for newborns in an effort to decrease the development of NEC in this vulnerable population. Conflict of interest There are no relevant financial disclosures or conflicts of interest for any of the above authors.
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