Centralization of pediatric surgical care in the Netherlands:Lessons learned

Centralization of care is a difficult process, as there are several stakeholders that are involved and should be heard. What can be the best option for a small group of patients may be detrimental to a larger group of patients that cannot be adequately treated close to home. The weighing of these factors is different in every environment. One universal rule however is: if you don't do it yourselves, others will do it for you. In the Netherlands, pediatric oncology, including surgery, is centralized in one center (Utrecht) with the help of several shared care centers scattered throughout the country for things that can be managed close to home. (c) 2021 Elsevier Inc. All rights reserved

Current Concepts of Biliary Atresia and Matrix Metalloproteinase-7:A Review of Literature

Biliary atresia (BA) is a rare cholangiopathy of infancy in which the bile ducts obliterate, leading to profound cholestasis and liver fibrosis. BA is hypothesized to be caused by a viral insult that leads to over-activation of the immune system. Patients with BA are surgically treated with a Kasai portoenterostomy (KPE), which aims to restore bile flow from the liver to the intestines. After KPE, progressive liver fibrosis is often observed in BA patients, even despite surgical success and clearance of their jaundice. The innate immune response is involved during the initial damage to the cholangiocytes and further differentiation of the adaptive immune response into a T-helper 1 cell (Th1) response. Multiple studies have shown that there is continuing elevation of involved cytokines that can lead to the progressive liver fibrosis. However, the mechanism by which the progressive injury occurs is not fully elucidated. Recently, matrix metalloproteinase-7 (MMP-7) has been investigated to be used as a biomarker to diagnose BA. MMPs are involved in extracellular matrix (ECM) turnover, but also have non-ECM related functions. The role of MMP-7 and other MMPs in liver fibrosis is just starting to be elucidated. Multiple studies have shown that serum MMP-7 measurements are able to accurately diagnose BA in a cohort of cholestatic patients while hepatic MMP-7 expression correlated with BA-related liver fibrosis. While the mechanism by which MMP-7 can be involved in the pathophysiology of BA is unclear, MMP-7 has been investigated in other fibrotic pathologies such as renal and idiopathic pulmonary fibrosis. MMP-7 is involved in Wnt/beta-catenin signaling, reducing cell-to-cell contact by shedding of E-cadherin, amplifying inflammation and fibrosis via osteopontin (OPN) and TNF-alpha while it also appears to play a role in induction of angiogenesis This review aims to describe the current understandings of the pathophysiology of BA. Subsequently, we describe how MMP-7 is involved in other pathologies, such as renal and pulmonary fibrosis. Then, we propose how MMP-7 can potentially be involved in BA. By doing this, we aim to describe the putative role of MMP-7 as a prognostic biomarker in BA and to provide possible new therapeutic and research targets that can be investigated in the future

Near-infrared spectroscopy as a diagnostic tool for necrotizing enterocolitis in preterm infants

BACKGROUND: We aimed to investigate whether splanchnic tissue oxygen saturation (rsSO2) measured by near-infrared spectroscopy (NIRS) could contribute to the early diagnosis of necrotizing enterocolitis (NEC). METHODS: We retrospectively included infants with suspected NEC, gestational age <32 weeks and/or birth weight <1200 g in the first 3 weeks after birth. We calculated mean rsSO2, cerebral tissue oxygen saturation (rcSO2), variability of rsSO2 (coefficients of variation [rsCoVAR] = SD/mean), and splanchnic-cerebral oxygenation ratio ([SCOR] = rsSO2/rcSO2) in the period around the abdominal radiograph to confirm or reject NEC. RESULTS: Of the 75 infants, 21 (28%) had NEC (Bell's stage ≥2). Characteristics of infants with and without NEC differed only on mechanical ventilation and nil-per-os status. RsSO2 tended to be higher and rcSO2 lower in infants with NEC. RsCoVAR (median [range]) was lower (0.11 [0.03-0.34]) vs. 0.20 [0.01-0.52], P = 0.002) and SCOR higher (0.64 [0.37-1.36]) vs. 0.47 [0.16-1.09], P = 0.004) in NEC infants. Adjusted for postnatal age, mechanical ventilation, and nil-per-os status, a 0.1 higher rsCoVAR decreased the likelihood of NEC diagnosis with likelihood ratio (LR) 0.38 (95% CI 0.18-0.78) and a 0.1 higher SCOR increased it with LR 1.28 (1.02-1.61). CONCLUSIONS: Using NIRS, high SCOR may confirm NEC and high variability of rsSO2 may rule out NEC, when suspicion arises. IMPACT: Near-infrared spectroscopy may contribute to the diagnosis of necrotizing enterocolitis.When clinical signs are present a high splanchnic-cerebral oxygenation may indicate necrotizing enterocolitis.A low splanchnic-cerebral oxygenation ratio and high variability of splanchnic tissue oxygen saturation may rule out necrotizing enterocolitis.Whether a bedside real-time availability of the splanchnic-cerebral oxygenation ratio and variability of splanchnic tissue oxygen saturation improves NEC diagnosis needs to be further investigated

Neonatal anemia relates to intestinal injury in preterm infants

BACKGROUND: Anemia is associated with decreased tissue oxygenation in preterm infants and may contribute to developing necrotizing enterocolitis (NEC). We aimed to investigate whether hemoglobin level is associated with intestinal injury, by comparing anemic infants 10 days prior to red blood cell (RBC) transfusion with non-anemic controls. METHODS: A nested case-control study in which we matched anemic preterms (gestational age (GA) < 32 weeks) with non-anemic controls (1:1), based on GA, birth weight (BW), and postnatal age. We measured urinary intestinal fatty acid-binding protein, I-FABP, marker for intestinal injury, twice weekly. Simultaneously, we assessed splanchnic oxygen saturation (rsSO2) and rsSO2 variability. RESULTS: Thirty-six cases and 36 controls were included (median GA 27.6 weeks, BW 1020 grams). Median I-FABP level was higher in cases from 6 days to 24-h before transfusion (median ranging: 4749-8064 pg/ml versus 2194-3751 pg/ml). RsSO2 and rsSO2 variability were lower in cases than controls shortly before transfusion. Hemoglobin levels correlated negatively with rsSO2 and rsSO2 variability in cases, and negatively with I-FABP in cases and controls together. CONCLUSIONS: Urinary I-FABP levels were higher in anemic infants before RBC transfusion than in non-anemic matched controls, suggesting intestinal injury associated with anemia. This may predispose to NEC in some anemic preterm infants. IMPACT: Anemia is a common comorbidity in preterm infants and may lead to impaired splanchnic oxygen saturation and intestinal tissue hypoxia, a proposed mechanism for NEC. Lower hemoglobin level is associated with higher urinary I-FABP levels, a marker for intestinal injury, both in anemic preterm infants and in cases and controls together. Lower splanchnic oxygen saturation and reduction of its variability are associated with higher urinary I-FABP levels in anemic preterm infants before their first RBC transfusion. These results support the hypothesis that anemia in very preterm infants results in intestinal cell injury, which may precede NEC development in some

Predicting intestinal recovery after necrotizing enterocolitis in preterm infants

Background: Intestinal recovery after NEC is difficult to predict in individuals. We evaluated whether several biomarkers predict intestinal recovery after NEC in preterm infants. Methods: We measured intestinal tissue oxygen saturation (rintSO2) and collected urinary intestinal-fatty acid binding protein (I-FABPu) levels 0–24 h and 24–48 h after NEC onset, and before and after the first re-feed. We assessed intestinal recovery in two ways: time to full enteral feeding (FEFt; below or equal/above group’s median) and development of post-NEC complications (recurrent NEC/post-NEC stricture). We determined whether the rintSO2, its range, and I-FABPu differed between groups. Results: We included 27 preterm infants who survived NEC (Bell’s stage ≥ 2). Median FEFt was 14 [IQR: 12–23] days. Biomarkers only predicted intestinal recovery after the first re-feed. Mean rintSO2 ≥ 53% combined with mean rintSO2range ≥ 50% predicted FEFt < 14 days with OR 16.7 (CI: 2.3–122.2). The rintSO2range was smaller (33% vs. 51%, p < 0.01) and I-FABPu was higher (92.4 vs. 25.5 ng/mL, p = 0.03) in case of post-NEC stricture, but not different in case of recurrent NEC, compared with infants without complications. Conclusion: The rintSO2, its range, and I-FABPu after the first re-feed after NEC predicted intestinal recovery. These biomarkers have potential value in individualizing feeding regimens after NEC

Blood group AB is associated with poor outcomes in infants with necrotizing enterocolitis

BACKGROUND: Necrotizing enterocolitis (NEC) is a neonatal disease associated with necrosis and perforation of the bowel. We investigated the association between blood group and NEC outcomes and the potential contribution of fetal-maternal blood group incompatibility. METHODS: Retrospective study including all preterm-born infants with NEC (≥ Bell's stage IIa) admitted to our NICU between January 2008 and October 2019. We analyzed the association between infants' blood groups and fetal-maternal blood group incompatibility with Bell stage severity, need for surgery, and mortality due to NEC. RESULTS: We included 237 NEC patients. In univariable analyses both AB blood group and fetal-maternal blood group incompatibility increased infants' risk of severe outcomes, with odds ratios (OR) ranging from 6.57 to 12.06 and 1.97 to 2.38, respectively. When adjusted for gestational age only AB blood group remained significant with OR 7.47 (95% confidence interval, 1.95-28.53, P = 0.003), 12.37 (2.63-58.20, P = 0.001), and 8.16 (2.28-29.14, P = 0.001) for NEC Bell's stage III, need for surgery, and NEC related mortality, respectively. Blood group incompatibility adjusted for gestational age was not related to worse outcomes with OR 1.84 (0.87-3.89, P = 0.11, 2.08 (0.98-4.41, P = 0.06) 1.52 (0.68-3.42, P = 0.31), for NEC Bell's stage III, need for surgery, and NEC related mortality, respectively. CONCLUSION: Our data confirm an association between blood group AB and worse outcomes in NEC infants, but this is not based on fetal-maternal blood group incompatibility

Maturation of Intestinal Oxygenation:A Review of Mechanisms and Clinical Implications for Preterm Neonates

Nutrient requirements of preterm neonates may be substantial, to support growth and maturation processes in the presence of challenging post-natal circumstances. This may be accompanied by substantial intestinal oxygen requirements. Preterm neonates may not be able to meet these oxygen requirements, due to a developmental delay in intestinal oxygenation regulation mechanisms. This review summarizes the available literature on post-natal maturation of intestinal oxygenation mechanisms and translates these changes into clinical observations and potential implications for preterm neonates. The different mechanisms that may be involved in regulation of intestinal oxygenation, regardless of post-natal age, are first discussed. The contribution of these mechanisms to intestinal oxygenation regulation is then evaluated in newborn and mature intestine. Finally, the course of clinical observations is used to translate these findings to potential implications for preterm neonates

Controversies in Choledochal Malformation in Children:An International Survey among Pediatric Hepatobiliary Surgeons and Gastroenterologists

Background: While congenital choledochal malformation (CCM) is relatively well known within the pediatric surgical and pediatric gastroenterological communities, many controversies and questions remain. Methods: In this paper, we will discuss the results of an international Delphi survey among members of the European Reference Network RARE-LIVER and of the faculty of the Biliary Atresia and Related Diseases (BARD) network to identify the most common practices as well as controversies regarding diagnosis, treatment and follow-up of this still enigmatic disease. Results: Twenty-two individual respondents completed the survey. While there seems to be agreement on the definitions of CCM, preoperative workup, surgical approach and follow-up still vary considerably. The mainstay of treatment remains the removal of the entire extrahepatic biliary tract, clearance of debris both proximally and distally, followed by reconstruction with (according to 86% of respondents) a Roux-en-Y hepaticojejunostomy. Nonetheless, both laparoscopic and robotic-assisted resections are gaining ground with the suggestion that this might be facilitated by concentration of care and resources in specialized centers. However, long-term outcomes are still lacking. Conclusions: As even post-surgical CCM has to be considered as having premalignant potential, follow-up should be well-organized and continued into adulthood. This seems to be lacking in many centers. International cooperation for both benchmarking and research is paramount to improving care for this rare disease

The effect of enteral bolus feeding on regional intestinal oxygen saturation in preterm infants is age-dependent:a longitudinal observational study

Background The factors that determine the effect of enteral feeding on intestinal perfusion after preterm birth remain largely unknown. We aimed to determine the effect of enteral feeding on intestinal oxygen saturation (r(int)SO(2)) in preterm infants and evaluated whether this effect depended on postnatal age (PNA), postmenstrual age (PMA), and/or feeding volumes. We also evaluated whether changes in postprandial r(int)SO(2) affected cerebral oxygen saturation (r(c)SO(2)). Methods In a longitudinal observational pilot study using near-infrared spectroscopy we measured r(int)SO(2) and r(c)SO(2) continuously for two hours on postnatal Days 2 to 5, 8, 15, 22, 29, and 36. We compared preprandial with postprandial values over time using multi-level analyses. To assess the effect of PNA, PMA, and feeding volumes, we performed Wilcoxon signed-rank tests or logistic regression analyses. To evaluate the effect on r(c)SO(2), we also used logistic regression analyses. Results We included 29 infants: median (range) gestational age 28.1 weeks (25.1-30.7) and birth weight 1025 g (580-1495). On Day 5, r(int)SO(2) values decreased postprandially: mean (SE) 44% (10) versus 35% (7), P = .01. On Day 29, r(int)SO(2) values increased: 44% (11) versus 54% (7), P = .01. Infants with a PMA >= 32 weeks showed a r(int)SO(2) increase after feeding (37% versus 51%, P = .04) whereas infants with a PMA = 32 weeks when greater volumes of enteral feeding are tolerated. We speculate that at young gestational and postmenstrual ages preterm infants are still unable to increase intestinal oxygen saturation after feeding, which might be essential to meet metabolic demands. Trial registration: For this prospective longitudinal pilot study we derived patients from a larger observational cohort study: CALIFORNIA-Trial, Dutch Trial Registry NTR4153

Hypoxic/ischemic hits predispose to necrotizing enterocolitis in (near) term infants with congenital heart disease:a case control study

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating disease that is relatively frequently diagnosed in term infants with congenital heart disease (CHD), compared with term infants without CHD, in whom NEC is rare. The exact pathogenesis of NEC in term infants with CHD is unknown, but it is hypothesized that ischemia of the intestines plays a pivotal role. We aimed to explore whether (near) term CHD infants, who develop NEC, exhibit more clinical signs of hypoxia/ischemia and low body perfusion directly after birth and during the first 48 hours after admission to the neonatal intensive care unit, when compared with (near) term CHD infants who did not develop NEC. METHODS: 956 infants with CHD born after ≥ 35 weeks of gestational age were retrospectively reviewed for this case-control study between January 1999 and February 2020. We included infants with radiographically confirmed pneumatosis intestinalis and controls matched by type of CHD. Seven infants were diagnosed with transposition of the great arteries, six with left and four with right ventricular outflow tract obstruction. Several parameters suggestive of (relative) hypoxia/ischemia were used for analyses. RESULTS: We included sixteen CHD infants with NEC and selected sixteen controls. There were no significant demographic differences between both groups. Apgar score at one and five minutes (median [IQR]) were lower in infants who developed NEC compared with control infants (8 [7-8]) vs. (9 [8-9], P = .011) and (8 [8-9]) vs. (9 [9-10], P = .009). A higher proportion of infants with NEC required respiratory support in the delivery room (11(69) vs. 2(13), P = .001). The (median [IQR]) diastolic blood pressure on the second day after admission (39 mmHg [34-42], vs. 43 mmHg [37-51], P = .112) and lowest (median [IQR]) pH in the 48 hours after admission (7.24 [7.17-7.35] vs. 7.38 ([7.27-7.43], P = .157) were not significantly lower in NEC infants but both demonstrated a similar direction towards (relative) hypoxia/ischemia in NEC infants. CONCLUSIONS: Our clinical results support a hypoxic/ischemic pathophysiology of NEC in (near) term CHD infants, with lower Apgar scores, more respiratory support in the delivery room and a tendency towards a lower diastolic blood pressure and pH in CHD infants who develop NEC