PEDIATRICS Vol. 119 No. 2 February 2007, pp. 330-335 (doi:10.1542/peds.2006-2640)
ARTICLE |
Persistent Diastolic Flow Reversal in Abdominal Aortic Doppler-Flow Profiles Is Associated With an Increased Risk of Necrotizing Enterocolitis in Term Infants With Congenital Heart Disease
Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Diastolic runoff in the abdominal aorta, with subsequent circulatory mesenteric insufficiency, has been postulated as a cause of necrotizing enterocolitis in term infants with congenital heart disease. With this study we sought to determine whether Doppler-flow characteristics in the abdominal aorta can predict which infants are at specific risk, independent of gestational age and type of congenital heart disease.
PATIENTS AND METHODS. We conducted a case-control study of term infants with congenital heart disease and proven necrotizing enterocolitis (n = 18) compared with gestational age–matched and diagnosis-matched control subjects (n = 20). Abdominal aortic Doppler velocities, time intervals, and reversals were analyzed. Groups were compared, and independent risk factors for necrotizing enterocolitis were determined.
RESULTS. The groups were similar with regard to weight, pulse pressure, use of prostaglandins or inotropes, presence of a patent ductus arteriosus, and systolic function. However, 47% of the case subjects with necrotizing enterocolitis had persistent retrograde diastolic flow in the abdominal aorta compared with 15% of the control subjects. When adjusting for multiple risk factors, persistent diastolic flow reversal remained the only factor significantly associated with necrotizing enterocolitis.
CONCLUSION. Persistent diastolic flow reversal in the abdominal aortic Doppler profile is associated with an increased risk of necrotizing enterocolitis in term infants with congenital heart disease irrespective of gestational age or anatomic type of congenital heart disease.
Key Words: echocardiography • necrotizing enterocolitis • congenital heart disease
Abbreviations: CHD—congenital heart disease • NEC—necrotizing enterocolitis • PDA—patent ductus arteriosus • DFR—Doppler-flow reversal
Newborn term infants with congenital heart disease (CHD) have an increased incidence of necrotizing enterocolitis (NEC) (3%–7%) when compared with other term infants in whom NEC is rare.1–3 CHD may underlie approximately one quarter to one third of all NEC in this patient population.2,4,5
Poor systemic circulation, either long standing or episodic, is one mechanism that has been shown to contribute to the development of NEC in infants with CHD.1,2,6 Interestingly, McElhinney et al,1 in their large retrospective analysis of NEC in neonates with CHD, found that infants with hypoplastic left heart syndrome, truncus arteriosus, and aortopulmonary window had increased risk of NEC. These are anatomic heart lesions that typically result in prominent reversal of forward flow in the abdominal aorta during diastole and a resultant low-diastolic pressure. They postulated that retrograde diastolic flow in these lesions may have resulted in mesenteric circulatory insufficiency because of a diastolic "steal" phenomenon.
Doppler assessment of abdominal aortic flow is one method to evaluate this steal phenomenon. Previous investigators have noted diminished or reversed diastolic flow in the descending aorta and other abdominal arteries in premature infants with symptomatic patent ductus arteriosus (PDA).7 However, a systematic assessment of abdominal aorta Doppler characteristics in term infants with CHD has not been done.
We hypothesized that abdominal aorta Doppler characteristics may predict a subset of term infants with CHD who are at particular risk for NEC, irrespective of their type of heart lesion. Thus, we conducted a gestational age–matched and diagnosis-matched case-control study to investigate determinants of NEC risk in term infants with CHD, incorporating abdominal Doppler-flow characteristics.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Institutional review board approval was obtained for reviewing existing data, imaging, and medical charts in accordance with Health Insurance Portability and Accountability Act regulations. Eighteen patients with CHD and NEC, confirmed radiographically or at surgery, were identified as case subjects by searching the hospital medical charts database at Cincinnati Children's Hospital Medical Center between 1999 and July 2005. All of the relevant clinical and demographic data were extracted from the medical chart. The modified Bell staging criteria were used for staging the severity of the confirmed NEC (stages 2a, 2b, 3a, and 3b; Table 1). 8
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Control subjects were selected from the same time period. They were initially identified by diagnosis using the echocardiography database, then matched to case subjects by gestational age, and finally included if they had appropriate echocardiographic images done at a similar postnatal age as the case subjects. This resulted in 20 patients being included in the control group. The echocardiogram immediately before the development of NEC was selected for evaluation. In the control group, echocardiograms were selected to approximate the day of life of their NEC counterparts. Long-axis views of the abdominal aorta with subsequent pulsed wave Doppler were selected for analysis. Doppler signals after October 2003 were obtained digitally on a Vivid 7 (General Electric Corp, Stamford, CT) and analyzed with a Camtronics cardiac analysis system (Hartland, WI). Doppler signals before this time were recorded on videotape on a Sonos 5500 (Agilent, Andover, MA) and then analyzed with an offline Digisonics cardiac analysis system (Houston, TX).
For each patient, 
3 Doppler waveforms were measured and averaged for time-velocity integrals, peak velocities, and time for both antegrade and retrograde flows in the abdominal and/or descending thoracic aorta. Doppler-flow reversal (DFR) ratio was calculated by dividing the time-velocity integral of the retrograde flow by the time-velocity integral of the antegrade flow, as developed by Rychik et al.9 Retrograde/antegrade time ratios were calculated by dividing the time spent in retrograde flow by the time spent in antegrade flow. The presence or absence of persistent Doppler diastolic flow reversal was noted (Fig 1). All of the measurements were done by a single researcher (Dr Carlo), who was blinded to the status (case versus control) of the subject.
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Statistical analysis was performed using Intercooled Stata 8.2 (Stata Corp, College Station, TX). Normally distributed continuous data were compared between groups using independent t tests, and the Wilcoxon rank-sum test was used for skewed data. Categorical variables were compared with
2 analysis. Independent predictors for NEC were initially identified using univariate regression analysis. These independent variables were then entered into a multiple stepwise forward logistic regression model, with the development of NEC as the dependent variable. |
RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Eighteen patients with NEC and 20 control patients were identified. The cardiac diagnoses of the patients with NEC are listed in Table 2. Seventeen of the 18 patients with NEC were proven to have NEC according to modified Bell staging criteria (stage 2a in 10 patients, stage 2b in 2, and stage 3b in 5). One patient who was classified according to the modified Bell staging criteria as stage 1b was included in the analysis for the confirmed NEC group because he had surgically confirmed NEC noted on exploratory surgery done for abdominal distention and strictures 3 weeks later, although the analyzed echocardiogram was coincident with the clinical diagnosis of stage 1b NEC. In addition, 2 of the stage 2a patients and all of the stage 3b patients had surgically confirmed NEC. Two of the stage 3b patients died from NEC.
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These 18 infants had confirmed NEC at a median age of 5 days of life (range: 1–24 days). There were no differences between the NEC and control infants in terms of birth weight, estimated gestational age, Apgar scores, presence of umbilical arterial catheter or umbilical venous catheter, use of prostaglandins or inotropes at any time before development of NEC, pulse pressure, presence of a PDA, systolic function, and types of cardiac lesions (Table 3). Patients with NEC were fed significantly earlier than control subjects. Five of the patients with NEC had undergone cardiac catheterization before developing NEC, and 4 had undergone cardiac surgery. The median age at which the analyzed echocardiograms were completed was 2 days of life (range: 0–21 days) for the patients with NEC and 1 day of life (range: 0–15 days) for the control patients (P = .61). There was an average of 3 days between the echocardiogram and the diagnosis of NEC in the NEC infants.
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Doppler measurements of peak velocities, time intervals, and DFR ratios were not significantly different between the groups (Table 4) However, 47% of the case subjects with NEC had persistent retrograde diastolic flow in the abdominal aorta compared with 15% of the control subjects (P = .04). Furthermore, all but 1 of the patients (86%) with either stage 2b or 3b NEC had persistent retrograde diastolic flow.
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The results from univariate analysis of independent variables predicting NEC are presented in Table 5. The presence of persistent retrograde flow in the abdominal aorta was the only variable that achieved statistical significance (P = .04). There is a trend toward increased incidence of NEC in patients who were fed early or who were fed formula, although the association was not statistically significant. The presence of umbilical artery or venous catheters and the use of prostaglandins were not associated with the probability of developing NEC.
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When adjusting for infant weight, the presence of an umbilical artery catheter, pulse pressure, age at first feeding, and type of feeding in a stepwise forward multivariate model, persistent retrograde diastolic flow was the only significant independent predictor of NEC that remained in the model (odds ratio: 11.2; 95% confidence interval: 1.6–78.5).
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This case-control study found that persistent diastolic flow reversal in the descending aorta was associated with an increased likelihood of NEC in term infants with CHD. This increased risk persists despite matching patients for gestational age and anatomic type of CHD.
This study associates echocardiographic markers of mesenteric insufficiency with an increased risk of NEC. Coombs et al10 noted lower blood flow velocities in the superior mesenteric arteries of premature infants who were deemed at highest risk for development of NEC, although only 11% of those patients developed NEC. Fetal echocardiographic studies have demonstrated absent or reversed end-diastolic frequencies in the umbilical arteries11 and the aorta12 of fetuses who subsequently developed NEC as premature infants. Previous studies have demonstrated increased flow velocities in abdominal arteries in infants who already had developed NEC, although these studies did not investigate any flow patterns before developing NEC.13,14
Our results support the theory that mesenteric circulatory insufficiency secondary to a diastolic steal phenomenon in patients with CHD may predispose to NEC. Persistent retrograde diastolic flow was noted in patients with NEC with a variety of CHD lesions: 2 with total anomalous pulmonary venous return; 2 with coarctation of the aorta; and 1 each with aortic stenosis, truncus arteriosus, and Ebstein's anomaly. The 3 control patients with persistent retrograde diastolic flow had coarctation of the aorta, aortic stenosis, and truncus arteriosus. All of these patients had PDAs except for the 2 with truncus arteriosus. Therefore, the potential for circulatory shunting existed in all of the patients with persistent diastolic retrograde flow. However, a majority of patients in our study without persistent diastolic retrograde flow also had PDAs. Also, there was no overall difference in PDAs between the control patients and those with NEC. Therefore, whereas circulatory shunting likely plays a role in the pathogenesis of NEC in CHD infants, this physiology is absent before some episodes of NEC. This indicates that although there may be the anatomic substrate for diastolic runoff, not all patients exhibit it, and the degree varies between similar patients. Other factors, such as pulmonary vascular resistance, may be responsible for some of this variation.
An alternative hypothesis for the pathophysiology of NEC in these patients is the presence of discrete episodes of poor systemic perfusion leading directly to mesenteric insufficiency. McElhinney et al1 found that episodes of poor systemic perfusion or shock placed infants with CHD at additional risk of NEC. Leung et al2 noted higher rates of prostaglandin-associated apnea and hypotension in infants with CHD who later developed NEC. Our study did not address this hypothesis directly. However, we did not find a significant association between development of NEC and prostaglandin usage, inotrope use, cardiac catheterization, or surgery. It is likely that infants with CHD are susceptible to either or both of these pathophysiologic mechanisms.
Our study analyzed other possible risk factors for NEC. Perhaps limited by study size, we found no significant differences between the control patients and those with NEC with regard to presence of a PDA, Apgar scores, and umbilical vessel catheterization.2–4,6 Furthermore, our study matched infants for gestational age and, therefore, was not designed to find differences in age or birth weight, both NEC risk factors in infants with CHD.1 We did find a trend toward younger age at first feeding and feeding with formula in patients that developed NEC, although the trend was not statistically significant. This conforms to previous findings,6 although the largest study on infants with CHD by McElhinney et al1 did not find any association between either breast milk or early feeding and NEC.
Limitations in this study include the variable time interval between the echocardiograms and the diagnosis of NEC. In addition, using only a single echocardiogram immediately before the detection of NEC may not be ideal, because the circulatory insult might be episodic or have occurred earlier in the postnatal period. Finally, our relatively small sample size places us at risk for a type II error, especially with regard to the evaluation of other potentially significant independent predictors of NEC.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our investigation of the descending aortic blood flow Doppler patterns measured by echocardiography reveals that persistent diastolic flow reversal is associated with an increased risk of NEC in term infants with CHD, irrespective of anatomic diagnosis and gestational age. This finding supports the hypothesis that mesenteric diastolic steal plays a role in the pathogenesis of NEC. Routine imaging of the descending abdominal aorta should be standard during any echocardiogram, such that the observation of persistent diastolic flow reversal may heighten clinical suspicion for NEC in CHD infants with compatible clinical symptoms.
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FOOTNOTES |
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Accepted Oct 12, 2006.
Address correspondence to Waldemar F. Carlo, MD, Division of Cardiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail: waldemar.carlo{at}cchmc.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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