PEDIATRICS Vol. 118 No. 5 November 2006, pp. 1999-2003 (doi:10.1542/10.1542/peds.2006-0272)
ARTICLE |
Doppler Flow Velocimetry in the Superior Mesenteric Artery on the First Day of Life in Preterm Infants and the Risk of Neonatal Necrotizing Enterocolitis
a Neonatal Intensive Care Unit, Addenbrooke's Hospital, Cambridge, United Kingdom
b Neonatal Intensive Care Unit, Royal London Hospital, Whitechapel, London, United Kingdom
c Department of Obstetrics and Gynaecology, Cambridge University, Cambridge, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. The purpose of this work was to relate Doppler indices of splanchnic perfusion and vascular resistance to the risk of developing necrotizing enterocolitis.
METHODS. We conducted a prospective cohort study with analysis of Doppler flow velocity waveforms of splanchnic vessels on the first day of life. Clinical management and diagnosis of necrotizing enterocolitis were performed blind to the Doppler results in a tertiary NICU on 64 eligible preterm neonates admitted for intensive care. We measured necrotizing enterocolitis using an objective diagnostic classification.
RESULTS. When adjusted for gestational age at birth, the following indices of the Doppler flow velocity wave form in the superior mesenteric artery were significantly predictive of the risk of necrotizing enterocolitis: end-diastolic velocity, mean velocity, and pulsatility index. The association between necrotizing enterocolitis and Doppler velocimetry indicative of high vascular resistance was independent of a range of other factors and comorbidities (race, mode of delivery, umbilical arterial catheter, growth restriction, patent ductus arteriosus, jaundice, respiratory distress syndrome, mechanical ventilation, and hypotension).
CONCLUSIONS. We concluded that neonates with high resistance patterns of blood flow velocity in the superior mesenteric artery on the first day of life are at increased risk of developing necrotizing enterocolitis.
Key Words: necrotizing enterocolitis • Doppler ultrasonography • splanchnic circulation • superior mesenteric artery • premature infant
Abbreviations: NEC—necrotizing enterocolitis • SMA—superior mesenteric artery • CA—celiac axis • EDV—end-diastolic velocity • PI—pulsatility index
Impaired intestinal function is a major source of morbidity and mortality in neonatal intensive care. Intestinal dysfunction is manifested by feeding intolerance, poor growth, malabsorption, and, in the severest cases, necrotizing enterocolitis (NEC). The incidence of NEC is estimated at 1 to 3 per 1000 live births, and it is associated with a mortality of 20% to 40%,1 as well as long-term morbidity, such as short gut syndrome. The risk of NEC is increased among infants who are growth restricted and, in particular, those with abnormal antenatal uteroplacental Doppler.2,3 The latter association is thought to be because of impaired perfusion of the intestinal circulation.
Previous studies have shown that high resistance patterns of mesenteric arterial Doppler flow velocimetry are associated with a significantly reduced tolerance to enteral feeding.4 Moreover, groups of infants deemed to be at increased risk of NEC tended to have high resistance patterns of flow in the superior mesenteric artery (SMA).5 However, there is no direct evidence, to our knowledge, that high-resistance flow patterns in the splanchnic vessels are associated with a subsequent increased risk of NEC in individual infants. The aim of the present study was to determine whether Doppler flow velocimetry of SMA and celiac axis (CA) was predictive of NEC in a high-risk population.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Design
We conducted a prospective cohort study of preterm infants admitted to the NICU of our hospital over a 5-year period. The inclusion criteria were that the parents consented to participation in the study and that the Doppler measurements could be made within the first 24 hours of life. Recruitment to the study depended on the allocated time of the researcher. Exclusion criteria were the presence of congenital anomalies or proven sepsis. The study received ethical permission from the institutional ethics committee.
Splanchnic Arterial Doppler Flow Velocimetry
Doppler ultrasound measurements of blood flow velocity in the SMA and CA were taken on the first day of life during a period of cardiorespiratory stability (defined as mean arterial blood pressure 
30 mmHg, continuous oxygen saturation monitoring at 88%–95%, and/or most recent blood gas showing pH >7.25, PaCO2 at 4.6–7 kPa, and PaO2 at 7–10 kPa). Measurements were made using a Sonos 100 ultrasound unit (Hewlett Packard, Palo Alto, CA) with a 7.5-MHz imaging and 5-MHz Doppler transducer. A clear image in real-time ultrasound of the artery was obtained and correction made for the angle of insonation. Doppler sample volume was placed in the proximal portion of the artery near its origin from the aorta and pulsed wave Doppler traces recorded to videotape. From the recorded Doppler tracings, peak systolic velocity, end-diastolic velocity (EDV), and time-averaged mean velocity were obtained from the peak velocity envelope of 5 consecutive cardiac cycles. From this information, the pulsatility index (PI) was calculated as PI = (peak systolic velocity – EDV)/time-averaged mean velocity. At each time point, 3 sets of measurements were recorded from each artery, and the final measurements were the mean of these 3 readings. The interobserver variability of these measurements has been reported previously.6 The ultrasonic view where measurements are made is illustrated (Fig 1).
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Clinical Management of Cases
The result of splanchnic vessel Doppler flow velocimetry was not revealed to the attending clinicians, so that the clinical management of cases, including the timing and volumes of feed and the diagnosis of NEC and comorbidities, were performed blind to the Doppler results. NEC was classified according to the British Association of Perinatal Medicine classification.7 Briefly, grade 1 was defined as any 2 of the following clinical features: abdominal distension; blood in feces; hypotonia, lethargy, or apnea; and meconium plug. Grade 2 was defined as grade 1 with any additional features of abdominal tenderness or rigidity, tissue in feces, radiologic features of hepatoportal venous gas, or free gas. A confirmed diagnosis was defined as a case where radiologic investigations demonstrated hepatoportal venous gas or intestinal intramural gas or where the diagnosis was confirmed at the time of laparotomy.
The feeding protocol of the unit was to commence enteral feeding once all of the umbilical catheters were removed and sustained cardiorespiratory stability was achieved. Enteral feeding was delayed by 5 to 7 days in preterm infants who had had absent or reversed end-diastolic flow on antenatal Doppler studies. Hypotension was defined as a mean arterial pressure of <30 mmHg and was treated initially with fluid volume and subsequently with inotropes if required. Patent ductus arteriosus was defined as cases where a nonsteroidal anti-inflammatory drug was administered to close the vessel.
Statistics
Univariate comparison of continuous variables was performed using the Mann-Whitney U test and categorical data using Fisher's exact test. Statistical significance was assumed at 2-sided values of P < .05. Multivariate analysis was performed using logistic regression.8 Because of the large number of potential confounders and the relatively small number of cases, selection of covariates in multivariate models was performed using backward stepwise regression. All of the statistical analyses were performed using the Stata 8.2 software package (Stata Corp, College Station, TX).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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There were 64 infants recruited to the study. The demographics, comorbidities, and outcome are detailed (Table 1). In univariate analysis, infants who developed NEC were less likely to be male, had lower birth weight, and were more likely to have abnormal antenatal umbilical artery Doppler. They took longer to establish 60% feeds and full feeds, but there were no significant differences in other comorbidities. Of the 10 infants who developed NEC, 6 had radiologic or surgical confirmation of the diagnosis, 8 were grade 1, and 2 were grade 2.
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There was no statistically significant correlation between gestational age and SMA peak systolic flow (r2 = 0.03; P = .16) or SMA mean velocity (r2 = 0.03; P = .19). However, in the same vessel, there were statistically significant associations between the other indices and week of gestation at birth: a negative correlation with EDV and a positive correlation with pulsatility index (Fig 2).
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, noncases; •, cases of NEC.In univariate analysis, the risk of NEC significantly decreased with increasing end-diastolic flow velocity (Table 2). After adjustment for gestational age, there was a significant positive association between the risk of NEC and SMA PI and negative associations with EDV and mean velocity. After adjustment for other characteristics, there remained a significant negative association with EDV and a significant positive association with PI. There was no significant association between any index of resistance in the CA and the risk of NEC.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The key finding of the present study was that infants who developed NEC had a high-resistance pattern of flow in the SMA, but not the celiac artery, on the first day of life. The association persisted after adjustment for gestational age. It could not be explained by bias in the diagnosis of NEC, because the diagnosis of NEC was made blind to the Doppler result. These data suggest that either abnormalities of the development of the splanchnic circulation in fetal life or vasoconstriction of the circulation in neonatal life has a role in the etiology of NEC. This is consistent with current hypotheses of the pathophysiology of NEC, which suggest that mucosal ischemia is a key initiating event. Previous studies have shown that high resistance to flow in the SMA is associated with a delay in establishing feeding4 and that infants with risk factors for NEC tend to have higher resistance patterns of flow.5 However, this study is the first, to our knowledge, to demonstrate a direct association between SMA Doppler flow velocimetry and the risk of NEC.
One of the strengths of the present study is that it was a prospective study, and we were able to assess Doppler indices before the onset of NEC. Previous studies, which have assessed resistance indices in the SMA among infants with NEC, have shown decreased resistance to flow in association with development of the condition.9 This may reflect an infective and inflammatory component in active NEC, because infants with perinatal sepsis also develop splanchnic hyperemia.10 This suggests that the pattern of splanchnic resistance among infants who develop NEC may be biphasic with an initial high resistance, which precedes the development of the condition. This may be followed by low resistance because of the effects of inflammation and sepsis as the condition becomes manifested. This underlines the importance of a prospective study design and of a standardized early point in neonatal life where measurements are made.
The major weakness of the present study is its relatively small size. However, the population studied was high risk, as evidenced by the relatively high incidence of NEC (16%). We included cases of both suspected and radiologically/histologically confirmed NEC. The absence of a confirmed diagnosis in all of the cases is a relative weakness of the present study, but the diagnosis was made independently of the Doppler results, precluding the possibility of bias.
This study indicates that SMA Doppler flow velocimetry may be clinically useful to identify infants at increased risk of NEC. However, additional studies including greater numbers of infants will be required to confirm the present findings before this can be incorporated into risk assessment. These studies could also further address whether the SMA Doppler flow velocimetry provides information that is independent of the results of antenatal umbilical artery Doppler. Although antenatal Doppler data are potentially useful in postnatal risk assessment,2 these data will only be available on a minority of infants. In our study, only one third of infants had antenatal Doppler data available. One of the advantages of assessing SMA Doppler flow velocimetry is that it should be possible to obtain this measurement in all infants admitted for neonatal intensive care. Reductions in fetal aortic blood flow occur in the growth-restricted fetus in response to uteroplacental insufficiency, producing fetal hypoxia and redistribution of blood flow toward the brain.11 The changes seen on the first day of life most likely represent a persistence of these fetal redistribution patterns into postnatal life. However, the observation that the risk of NEC was not associated with the resistance in the celiac artery suggests a specific association with the SMA. Thus, it is likely that SMA Doppler flow velocimetry may be more informative than the less specific measures of arterial redistribution, which are performed prenatally.
In the present study, we also assessed the relationship between gestational age at birth and resistance indices in the SMA on the first day of life. We found a positive correlation between gestational age and SMA PI and a negative correlation between gestational age and end-diastolic flow (Fig 2). Therefore, preterm infants tended to have Doppler flow indices that indicate lower resistance. The basis for this will require further study. It is possible that these Doppler indices vary with gestational age because of the influence of other factors, such as blood volume or blood pressure. This observation underlined that it was crucially important to adjust the association between NEC and Doppler flow measurements for the effect of gestation, because it may be negatively confounded, that is, a given increase in resistance indices in a preterm infant is of greater significance than the same measure in a more mature infant, because it represents a greater deviation from the reference range.
Clinically, a method for predicting infants at risk of NEC might be used to inform clinical management, in particular, of feeding. In animal models, local oxygen delivery can be maintained with ischemia in neonates who are fasted. However, feeding of these animals leads to impaired oxygen delivery,12 which is thought to be a key precipitating factor in the pathophysiology of NEC.13 It is possible that Doppler interrogation of the SMA in early neonatal life may identify infants who are liable to develop intestinal hypoxia when fed enterally.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We show in a prospective cohort study of high-risk infants that patterns of Doppler flow velocimetry indicating increased resistance in the SMA are associated with an increased risk of NEC. This finding suggests that splanchnic flow is compromised immediately after birth among many infants who go on to develop NEC. This association could form the basis of biophysical risk scoring for NEC among extreme preterm neonates, which could, in turn, help in making informed clinical management decisions, such as feeding regimens, in these infants.
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FOOTNOTES |
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Accepted Jun 7, 2006.
Address correspondence to Edile Murdoch, BM, MRCP, Department of Neonatology, Box 226, Rosie Hospital, Hills Rd, Cambridge CB2 2SW, United Kingdom. E-mail: edile.murdoch{at}addenbrookes.nhs.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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