Maarten Schurink

Intestinal Fatty Acid-Binding Protein as a Diagnostic Marker for Complicated and Uncomplicated Necrotizing Enterocolitis: A Prospective Cohort Study

Background Early NEC symptoms are non-specific and diagnostic tests lack discriminative power. Intestinal fatty acid-binding protein (I-FABP), mainly located in small bowel enterocytes, is released into the blood following NEC-associated enterocyte disruption. Aim of this prospective cohort trial was to determine the diagnostic value of I-FABP measured in plasma (I-FABPp) and urine (I-FABPu) for the presence of NEC, to evaluate I-FABP levels during NEC development, and to assess its prognostic value for the progression from suspected to complicated disease. Methods Between 2010 and 2012 we prospectively enrolled neonates with suspected NEC. We measured I-FABP levels eight-hourly from onset of suspected NEC for at least 48 hours, or until surgery. NEC diagnosis was confirmed radiologically or during operation. We defined NEC as complicated if it resulted in surgery and/or death. We determined disease course and diagnostic I-FABP cut-off points. Results The study comprised 37 neonates (24M, 13F), gestational age 28 (24–36) weeks, birth weight 1190 (570–2,400) grams. We found significantly higher I-FABPp and I-FABPu levels in NEC patients (n = 22) than in patients with other diagnoses (n = 15). Cut-off values for diagnosing NEC were 9 ng/mL I-FABPp and 218 ng/mL I-FABPu, with corresponding likelihood ratios (LRs) of 5.6 (95% CI 0.89–35) and 5.1 (95% CI 0.73–36), respectively. I-FABP levels were highest in the first eight hours after symptom onset and gradually decreased over time. Cut-off values for complicated disease were 19 ng/mL I-FABPp and 232 ng/mL I-FABPu, with LRs of 10 (95% CI 1.6–70) and 11 (95% CI 1.6–81), respectively. Conclusions Both plasma and urinary I-FABP levels specifically identify NEC in preterm infants prior to appearance of diagnostic radiological signs suggestive for NEC. Moreover, serial I-FABP measurements accurately predict development of complicated disease.

Intestinal fatty acid-binding protein in neonates with imminent necrotizing enterocolitis.

Background: Intestinal fatty acid-binding protein (I-FABP) is a promising marker for necrotizing enterocolitis (NEC). It can be measured in plasma (I-FABPp) and urine (I-FABPu). Data on the best way to measure I-FABP (in plasma or urine) and the necessity of simultaneous measurement of the urinary creatinine concentration to correct for physiological variations in urine concentration are not available. This holds also true for the reciprocal relation between I-FABPp, I-FABPu and other more conventional laboratory parameters. Objectives: To evaluate the above-mentioned correlations of I-FABP measurements in neonates with suspected NEC. Methods: All neonates with suspected NEC were prospectively included. I-FABPp and I-FABPu were analyzed at regular intervals during the first 24 h after onset of symptoms. Correlation and agreement were assessed between these and other parameters (i.e. IL-6, WBC, platelet count, CRP, pH and lactate). Results: Included were 24 boys, 13 girls [median (range) GA 28 weeks (24-36), median birth weight 1,190 g (570-2,400)]. I-FABPu correlated strongly with I-FABPp (r 0.80, p < 0.001) with an adequate agreement. A very strong correlation between I-FABPu and I-FABPu/urine creatinine ratio (r 0.98, p < 0.001) existed. Correlations between I-FABPp/u and conventional parameters were moderate to strong until 8 h after onset of symptoms. Conclusion: In neonates with suspected NEC, I-FABPu correlates strongly with I-FABPp, offering an opportunity to choose the most appropriate way of measuring I-FABP. Calculating urinary IFABP/creatinine ratio seems redundant. Moderately strong correlations between I-FABPu and IL-6, WBC and lactate were found.

Ostomy creation in neonates with acute abdominal disease: friend or foe?

BACKGROUND An ostomy seems a safe alternative in neonates with an acute abdomen when immediate restoration of bowel continuity is deemed undesirable. Faced with several complications in our center, and the feeling we are not the only center with these complications, we decided to assess the rate and type of complications after both ostomy creation and closure. METHODS All data regarding neonates (<30 days of age) who underwent a laparotomy for a suspected abdominal emergency in the period 2000 to 2010 were retrospectively analyzed. These data included demographics such as gender, gestational age, and birth weight. Disease etiology was defined and various features of the enterostomy were analyzed. These features included type, location, time to ostomy take down, and complications and mortality directly related to both creation and closure of the ostomy. RESULTS A total of 155 patients who underwent a laparotomy for suspect acute abdomen were identified. Median gestational age was 33 weeks (range 25 to 40) and median birth weight was 1926 g (range 560 to 4380). Median age at laparotomy was 8 days (range 0 to 30). Indications for surgery were necrotizing enterocolitis (n = 38), spontaneous intestinal perforation (n = 11), intestinal atresia (n = 9) or obstruction (n = 5), and volvulus (n = 4). An ostomy was created in 67 patients (67/155: 43%): 38 boys and 29 girls. There were 8 jejuno-, 49 ileo-, and 10 colostomies created. In almost all cases (94%), a mucous fistula was also constructed.In 23 patients (23/67: 34%) ostomy-related complications occurred. Most frequent were high output ostomy (n = 10) and necrosis of the enterostomy (n = 7). Due to either one of the complications, nine patients (9/67: 13%) needed a reoperation.In this study, 11 patients died before ostomy closure could occur. In 53 patients, the ostomy was closed after a median of 107 days (range 4 to 299).After ostomy closure, complications occurred in 13 cases (13/53: 25%). Seven patients (7/53: 13%) needed another reoperation because of anastomotic leakage (n = 4), adhesions (n = 2), or incisional hernia (n = 1). There was no closure-related mortality. CONCLUSION Although creating a temporary ostomy in newborns is preferable in certain situations, there is a considerable occurrence of complications and reoperations.

Assessing cerebrovascular autoregulation in infants with necrotizing enterocolitis using near-infrared spectroscopy

Background:We assessed cerebrovascular autoregulation (CAR) in preterm infants with definite necrotizing enterocolitis (NEC), Bell’s stage 2 or 3, and infants without NEC, using near-infrared spectroscopy. We hypothesized that CAR would be more often impaired in infants with NEC compared with infants without NEC.Methods:We measured cerebral regional tissue oxygen saturation, arterial oxygen saturation, and mean arterial blood pressure (MABP) during 48 h. We calculated the correlation between cerebral fractional tissue oxygen extraction and MABP for each patient. A statistically significant negative correlation reflected impaired CAR.Results:We included 15 infants with definite NEC (median (range) gestational age 27.4 (25.6–34.7) wk; birth weight 1,070 (670–2,400) g) and 13 infants without NEC (gestational age 27.9 (26.3–34.7) wk; birth weight 980 (640–2,640) g). Fourteen infants had a statistically significant negative correlation (ρ −0.468 to−0.104), of whom five were infants without NEC (5/13; 38%) and nine with definite NEC (9/15; 60%). The difference in prevalence of impaired CAR was not statistically significant.Conclusion:Impaired CAR is present in a substantial proportion of infants with definite NEC, which may predispose them to NEC-associated neurological damage.

Near-Infrared Spectroscopy to Predict the Course of Necrotizing Enterocolitis

Objectives To investigate whether cerebral, liver, and infraumbilical regional tissue oxygen saturation (rSO2) and fractional tissue oxygen extraction (FTOE) could be used to diagnose necrotizing enterocolitis (NEC) and complicated NEC (Bell’s stage 3B or death) during its early stages. Methods A prospective observational cohort study of preterm infants with suspected or diagnosed NEC. We compared the mean eight-hour cerebral, liver, and infraumbilical rSO2 and FTOE values of infants with no NEC and definite NEC and of infants with uncomplicated and complicated NEC in the first forty-eight hours after onset of symptoms, suspicious for NEC. Furthermore, we determined cut-off values by generating receiver operating characteristics curves in case of significant differences in the first eight-hour mean values of rSO2 between infants with no NEC and definite NEC and between infants with uncomplicated and complicated NEC. Results We included 33 patients: 13 no NEC, 10 with uncomplicated NEC, and 10 with complicated NEC. We found no significant differences in the first twenty-four hours after onset of symptoms in rSO2 and FTOE between infants with no NEC and definite NEC. In preterm infants with complicated NEC, we observed significantly lower cerebral, liver, and infraumbilical rSO2 and higher FTOE within twenty-four hours after onset of symptoms compared with infants with uncomplicated NEC. A continuous cerebral rSO2 ≤ 71% and liver rSO2 ≤ 59% in the first eight hours after onset of symptoms predicted the onset of complicated NEC with a sensitivity of 1.0 and specificity of 0.8, and a sensitivity of 1.0 and specificity of 1.0, respectively. Conclusions By measuring the cerebral and splanchnic oxygenation it is possible to differentiate complicated NEC from uncomplicated NEC. In our sample, NIRS monitoring did not proof useful for distinguishing between definite NEC and no NEC in preterm infants with clinical signs suspicious of NEC.

Abdominal near-infrared spectroscopy in preterm infants: A comparison of splanchnic oxygen saturation measurements at two abdominal locations

BACKGROUND Splanchnic tissue oxygenation monitoring has been performed at both the liver and the infra-umbilical regions. It is unknown whether these measurements could be substituted one for the other when interpreting splanchnic oxygenation since they have not been measured simultaneously before. AIMS To evaluate the feasibility and safety of liver and infra-umbilical near-infrared spectroscopy (NIRS) monitoring in preterm infants with suspected necrotizing enterocolitis (NEC) and to assess the correlation and agreement between NIRS measurements performed simultaneously at the two abdominal locations. STUDY DESIGN AND SUBJECTS This study was part of a prospective observational cohort study. Preterm infants who were suspected of NEC or who had been diagnosed with NEC were included. OUTCOME MEASURES Liver oxygen saturation and infra-umbilical oxygen saturation were monitored simultaneously and continuously for 48h by NIRS. RESULTS NIRS monitoring was performed in 20 out of 24 infants for the entire 48-hour study period. No adverse effects were observed. Values of liver and infra-umbilical oxygen saturation correlated weakly (Spearmans rho=0.244, P<.001). On the Bland-Altman plot liver oxygen saturation was higher than infra-umbilical oxygen saturation (mean difference 6.6%, SD 22.5%). CONCLUSIONS Using NIRS as method for monitoring oxygen saturation simultaneously in both the liver and infra-umbilical regions is safe and feasible. Additionally, we demonstrated that values of liver and infra-umbilical oxygen saturation cannot be randomly substituted one for the other for the purpose of assessing splanchnic oxygenation.

The relation between splanchnic ischaemia and intestinal damage in necrotising enterocolitis

Objectives The underlying pathophysiology of necrotising enterocolitis (NEC) remains incompletely understood, particularly the role of intestinal perfusion. We aimed to determine the relation between cerebral and splanchnic fractional tissue oxygen extraction (FTOE), a marker for tissue underperfusion, with intestinal fatty acid-binding protein in plasma (I-FABPp), a marker for intestinal damage, in infants with NEC. Furthermore, we investigated the combined courses of cerebral and splanchnic FTOE values and I-FABPp levels in uncomplicated (conservative treatment) and complicated NEC (surgery or death). Design This study was part of a prospective observational cohort study. Patients We included 19 preterm infants with NEC (9 uncomplicated, 10 complicated). Interventions Using near-infrared spectroscopy, we measured regional cerebral and splanchnic tissue oxygen saturations continuously for 48 h after NEC onset. We measured I-FABPp levels simultaneously. Main outcome measures We used Spearman correlation tests to calculate correlation coefficients between FTOE values and I-FABPp levels in uncomplicated and complicated NEC. Results Median (range) gestational age was 28 (25–36) weeks and median (range) birth weight was 1290 (740–2400) g. Cerebral and splanchnic FTOE values correlated strongly with I-FABPp levels (rho between .745 and 0.900; p<0.001–0.037) during the first 16 h after NEC onset. Thereafter, in uncomplicated NEC, splanchnic FTOE values increased while I-FABPp levels decreased concomitantly. In complicated NEC both splanchnic FTOE values and I-FABPp levels decreased. Conclusions Combining cerebral and splanchnic FTOE values with I-FABPp levels, gives insight in the pathological chain of events resulting in progression or recovery of intestinal ischaemia in NEC. Trial registration number NTR3239.

Bloodstream infections during the onset of necrotizing enterocolitis and their relation with the pro-inflammatory response, gut wall integrity and severity of disease in NEC.

INTRODUCTION Bacterial involvement is believed to play a pivotal role in the development and disease outcome of NEC. However, whether a bloodstream infection (BSI) predisposes to NEC (e.g. by activating the pro-inflammatory response) or result from the loss of gut wall integrity during NEC development is a longstanding question. OBJECTIVE We hypothesize that the occurrence of a BSI plays a complementary role in the pathogenesis of NEC. The first aim of the study was to correlate the occurrence of a BSI during the early phase of NEC with intestinal fatty acid-binding protein (I-FABP) levels, as a marker for loss of gut wall integrity owing to mucosal damage, and Interleukin (IL)-8 levels, as a biomarker for the pro-inflammatory cascade in NEC. The second aim of the study was to investigate the relation between the occurrence of a BSI and disease outcome. MATERIAL AND METHODS We combined data from prospective trials from two large academic pediatric surgical centers. Thirty-eight neonates with NEC, 5 neonates with bacterial sepsis, and 14 controls were included. RESULTS BSIs occurred in 10/38 (26%) neonates at NEC onset. No association between the occurrence of BSIs and I-FABP levels in plasma (cohort 1: median 11ng/mL (range 0.8-298), cohort 2: median 6.8ng/mL (range 1.3-15)) was found in NEC patients (cohort 1: p=0.41; cohort 2: p=0.90). In addition, the occurrence of BSIs did not correlate with IL-8 (median 1562pg/mL (range 150-7,500); p=0.99). While the occurrence of a BSI was not correlated with Bells stage (p=0.85), mortality was higher in patients with a BSI (p=0.005). CONCLUSION The low incidence of BSIs and the absent association of both the markers for loss of gut wall integrity and the pro-inflammatory response during the early phase of NEC, support the hypothesis that the presence of a BSI does not precede NEC.

Clinical Importance of a Fixed Bowel Loop in the Treatment of Necrotizing Enterocolitis

Background: The need for surgical treatment in neonates with necrotizing enterocolitis (NEC) is associated with high mortality. Although pneumoperitoneum and progressive disease are generally accepted indications for surgery, it is unclear whether a fixed bowel loop (FBL) should prompt surgery. Objective: To determine the relationship between an FBL, type of treatment, and death in the management of NEC. Methods: Retrospective analysis (January 2000-December 2011) of all neonates with definite NEC in a tertiary neonatal intensive care unit. FBL was defined as a persistent (i.e. >24 h) dilated intestinal segment present on serial abdominal X-rays. Results: NEC was diagnosed in 141 neonates (median gestational age 30 weeks; median birth weight 1,340 g). An FBL was reported in 38 (27%) patients, of whom 18 were treated surgically. Mortality among FBL patients was independent of the type of treatment (surgical versus conservative): 8/18 and 7/20, respectively (p = 0.55). Of the 103 patients without FBL, 37 (36%) were treated surgically, which is comparable to the FBL group. Again, mortality was not related to the type of treatment (surgical versus conservative): 5/37 and 6/66, respectively (p = 0.49). The presence of an FBL was associated with mortality: more patients with an FBL (15/38, 39%) died than without an FBL (11/103, 11%; odds ratio 5.45, 95% confidence interval 2.21-13.45; p < 0.01). Conclusions: In NEC patients, an FBL is associated with increased mortality. On its own it has moderate significance to guide treatment. Nevertheless, because it reflects disease severity, early recognition is important and prompt (surgical) treatment should be considered.

Risk factors for refractory anastomotic strictures after oesophageal atresia repair: a multicentre study

Objective To determine the incidence of refractory anastomotic strictures after oesophageal atresia (OA) repair and to identify risk factors associated with refractory strictures. Methods Retrospective national multicentre study in patients with OA born between 1999 and 2013. Exclusion criteria were isolated fistula, inability to obtain oesophageal continuity, death prior to discharge and follow-up <6 months. A refractory oesophageal stricture was defined as an anastomotic stricture requiring ≥5 dilations at maximally 4-week intervals. Risk factors for development of refractory anastomotic strictures after OA repair were identified with multivariable logistic regression analysis. Results We included 454 children (61% male, 7% isolated OA (Gross type A)). End-to-end anastomosis was performed in 436 (96%) children. Anastomotic leakage occurred in 13%. Fifty-eight per cent of children with an end-to-end anastomosis developed an anastomotic stricture, requiring a median of 3 (range 1–34) dilations. Refractory strictures were found in 32/436 (7%) children and required a median of 10 (range 5–34) dilations. Isolated OA (OR 5.7; p=0.012), anastomotic leakage (OR 5.0; p=0.001) and the need for oesophageal dilation ≤28 days after anastomosis (OR 15.9; p<0.001) were risk factors for development of a refractory stricture. Conclusions The incidence of refractory strictures of the end-to-end anastomosis in children treated for OA was 7%. Risk factors were isolated OA, anastomotic leakage and the need for oesophageal dilation less than 1 month after OA repair.