Remote ischaemic conditioning in necrotising enterocolitis: a phase I feasibility and safety study.

OBJECTIVE: Remote ischaemic conditioning (RIC) improves the outcome of experimental necrotising enterocolitis (NEC) by preserving intestinal microcirculation. The feasibility and safety of RIC in preterm infants with NEC are unknown. The study aimed to assess the feasibility and safety of RIC in preterm infants with suspected or confirmed NEC. DESIGN: Phase I non-randomised pilot study conducted in three steps: step A to determine the safe duration of limb ischaemia (up to 4 min); step B to assess the safety of 4 repeated cycles of ischaemia-reperfusion at the maximum tolerated duration of ischaemia determined in step A; step C to assess the safety of applying 4 cycles of ischaemia-reperfusion on two consecutive days. SETTING: Level III neonatal intensive care unit, The Hospital for Sick Children (Toronto, Canada). PATIENTS: Fifteen preterm infants born between 22 and 33 weeks gestational age. INTERVENTION: Four cycles of ischaemia (varying duration) applied to the limb via a manual sphygmomanometer, followed by reperfusion (4 min) and rest (5 min), repeated on two consecutive days. OUTCOMES: The primary outcomes were (1) feasibility defined as RIC being performed as planned in the protocol, and (2) safety defined as perfusion returning to baseline within 4 min after cuff deflation. RESULTS: Four cycles/day of limb ischaemia (4 min) followed by reperfusion (4 min) and a 5 min gap, repeated on two consecutive days was feasible and safe in all neonates with suspected or confirmed NEC. CONCLUSIONS: This study is pivotal for designing a future randomised controlled trial to assess the efficacy of RIC in preterm infants with NEC. TRIAL REGISTRATION NUMBER: NCT03860701.

Surgical Management of Pediatric Inguinal Hernia: A Systematic Review and Guideline from the European Pediatric Surgeons' Association Evidence and Guideline Committee.

INTRODUCTION: Inguinal hernia repair represents the most common operation in childhood; however, consensus about the optimal management is lacking. Hence, recommendations for clinical practice are needed. This study assesses the available evidence and compiles recommendations on pediatric inguinal hernia. MATERIALS AND METHODS: The European Pediatric Surgeons' Association Evidence and Guideline Committee addressed six questions on pediatric inguinal hernia repair with the following topics: (1) open versus laparoscopic repair, (2) extraperitoneal versus transperitoneal repair, (3) contralateral exploration, (4) surgical timing, (5) anesthesia technique in preterm infants, and (6) operation urgency in girls with irreducible ovarian hernia. Systematic literature searches were performed using PubMed, MEDLINE, Embase (Ovid), and The Cochrane Library. Reviews and meta-analyses were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. RESULTS: Seventy-two out of 5,173 articles were included, 27 in the meta-analyses. Laparoscopic repair shortens bilateral operation time compared with open repair. In preterm infants, hernia repair after neonatal intensive care unit (NICU)/hospital discharge is associated with less respiratory difficulties and recurrences, regional anesthesia is associated with a decrease of postoperative apnea and pain. The review regarding operation urgency for irreducible ovarian hernia gained insufficient evidence of low quality. CONCLUSION: Laparoscopic repair may be beneficial for children with bilateral hernia and preterm infants may benefit using regional anesthesia and postponing surgery. However, no definite superiority was found and available evidence was of moderate-to-low quality. Evidence for other topics was less conclusive. For the optimal management of inguinal hernia repair, a tailored approach is recommended taking into account the local facilities, resources, and expertise of the medical team involved.

Remote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation.

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants with high mortality rate, indicating the need for precision treatment. NEC is characterized by intestinal inflammation and ischemia, as well derangements in intestinal microcirculation. Remote ischemic conditioning (RIC) has emerged as a promising tool in protecting distant organs against ischemia-induced damage. However, the effectiveness of RIC against NEC is unknown. To address this gap, we aimed to determine the efficacy and mechanism of action of RIC in experimental NEC. NEC was induced in mouse pups between postnatal day (P) 5 and 9. RIC was applied through intermittent occlusion of hind limb blood flow. RIC, when administered in the early stages of disease progression, decreases intestinal injury and prolongs survival. The mechanism of action of RIC involves increasing intestinal perfusion through vasodilation mediated by nitric oxide and hydrogen sulfide. RIC is a viable and non-invasive treatment strategy for NEC.

Mitochondrial DNA: A Biomarker of Disease Severity in Necrotizing Enterocolitis.

INTRODUCTION: There is a need to develop sensitive markers to diagnose or monitor the severity of intestinal damage in necrotizing enterocolitis (NEC). Mitochondrial deoxyribonucleic acid (mtDNA) is increased in the intestine and blood of adults in response to intestinal ischemia and can trigger secondary organ damage. We hypothesize that mtDNA is increased during experimental NEC and that mtDNA levels are correlated to the degree of intestinal injury. MATERIALS AND METHODS: NEC was induced in C57BL/6 mice (n = 18) (approval: 44032) by gavage feeding with hyperosmolar formula, hypoxia, and lipopolysaccharide administration from postnatal day (P) 5 to 9. Breastfed pups served as control (n = 15). Blood was collected by cardiac puncture and terminal ileum was harvested on P9. Reverse transcription quatitative polymerase chain reaction was used to measure mtDNA (markers COX3, CYTB, ND1) and inflammatory cytokines (interleukin 6 [IL-6] and tumor necrosis factor-α[TNF-α]) in blood and ileum. Intestinal injury was scored blindly by four investigators and classified as no/minor injury (score 0 or 1) or NEC (score ≥2). RESULTS: mtDNA is significantly increased in gut and blood of NEC mice (p < 0.05). Furthermore, mtDNA increases in intestine and blood proportionally to the degree of intestinal injury as indicated by a positive correlation with histological scoring and inflammation (r = 0.6; p < 0.05) (expression of IL-6 and TNF-α). CONCLUSION: Following NEC intestinal injury, mtDNA is released from the intestine into circulation. The blood level of mtDNA is related to the degree of intestinal injury. mtDNA can be a novel marker of intestinal injury and can be useful for monitoring the progression of NEC.

Vasoactive intestinal peptide decreases inflammation and tight junction disruption in experimental necrotizing enterocolitis.

BACKGROUND AND PURPOSE: Excessive inflammatory cell infiltration and accumulation in the intestinal mucosa are pathological features of necrotizing enterocolitis (NEC) leading to intestinal barrier disruption. Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent that regulates intestinal epithelial barrier homeostasis. We previously demonstrated that VIP-ergic neuron expression is decreased in experimental NEC ileum, and this may be associated with inflammation and barrier compromise. We hypothesize that exogenous VIP administration has a beneficial effect in NEC. METHODS: NEC was induced in C57BL/6 mice by gavage feeding, hypoxia, and lipopolysaccharide administration between postnatal day (P) 5 and 9. There were four studied groups: Control (n = 6): Breast feeding without stress factors; Control + VIP (n = 5): Breast feeding + intraperitoneal VIP injection once a day from P5 to P9; NEC (n = 9): mice exposed to NEC induction; NEC + VIP (n = 9): NEC induction + intraperitoneal VIP injection. Terminal ileum was harvested on P9. NEC severity, intestinal inflammation, (IL-6 and TNFα), and Tight junctions (Claudin-3) were evaluated. RESULTS: NEC severity and intestinal inflammation were significantly decreased in NEC + VIP compared to NEC. Tight junction expression was significantly increased in NEC + VIP compared to NEC. CONCLUSION: VIP administration has a beneficial therapeutic effect in NEC by reducing inflammation and tight junction disruption.

Safety and usefulness of plastic closure in infants with gastroschisis: a systematic review and meta-analysis.

PURPOSE: Recently, plastic closure of abdominal defect in infants with gastroschisis has been used. Timing of gastroschisis closure can be mainly divided into two groups: primary closure and delayed closure after silo forming. Safety and usefulness of plastic closure in gastroschisis remains unclear. We aimed to evaluate the current evidence for plastic closure in infants with gastroschisis. METHODS: The analysis was done for primary closure as well as closure after silo. Outcomes were mortality, wound infection, duration of ventilation, time to feeding, and length of hospital stay (LOS). The quality of evidence was summarized using the GRADE approach. RESULTS: In the "primary" group, there was no significant difference in mortality, time to feeding initiation and LOS. In the "silo" group, wound infection was significantly lower in plastic closure (Odds ratio 0.24, 95%CI 0.09-0.69, p = 0.008). Duration of ventilation, time to feeding initiation and LOS were significantly shorter after plastic closure (Ventilation; mean difference (MD) - 5.76, p = 0.03. Feeding initiation; MD - 9.42, p < 0.0001. LOS; MD - 14.06, p = 0.002). Quality of evidence was very low for all outcomes. CONCLUSIONS: Current results suggest that plastic closure may be beneficial for infants with gastroschisis requiring silo formation. However, this evidence is suboptimal and further studies are needed.

Post-operative paralysis and elective ventilation reduces anastomotic complications in esophageal atresia: a systematic review and meta-analysis.

AIM OF STUDY: The repair of esophageal atresia (EA) carries an increased risk of anastomotic leak and stricture formation, especially in patients with anastomotic tension. To minimize this risk, pediatric surgeons perform elective post-operative muscle paralysis, positive-pressure ventilation, and head flexion (PVF) to reduce movement and tension at the anastomosis. We systematically reviewed and analyzed the effect of post-operative PVF on reducing anastomotic complications. METHODS: Embase, MEDLINE, Web of Science, and PubMed databases were used to conduct searches. Articles reporting pediatric EA undergoing primary anastomosis, anastomotic complications, and comparisons between patients who received post-operative PVF to those who did not were included. Odds ratios (OR) for all post-operative anastomotic complications were calculated using random effects modelling. MAIN RESULTS: Three of the 2268 papers retrieved met inclusion criteria (all retrospective cohort studies). There were no randomized controlled trials. Post-operative PVF showed a significant reduction in anastomotic leak (OR 0.07; 95% CI 0.01-0.35) when compared to no PVF. Stricture formation was not statistically different between groups. Potential sources of bias include patient allocation. CONCLUSIONS: Based on available data, our analysis indicates PVF may reduce anastomotic post-operative leak. To confirm these results, a prospective study with clearer definitions of treatment allocation should be performed.

The value of mechanical bowel preparation prior to pediatric colorectal surgery: a systematic review and meta-analysis.

PURPOSE: The use of mechanical bowel preparation (MBP) before pediatric colorectal surgery remains the standard of care for many pediatric surgeons, though the value of MBP remains unclear. The aim of this study was to systematically review and analyze the effect of MBP on the incidence of postoperative complications; anastomotic leakage, intra-abdominal infection, and wound infection, following colorectal surgery in pediatric patients. METHODS: Embase, MEDLINE, Web of Science, and CINAHL databases were searched to compare the effect of MBP versus no MBP prior to elective pediatric colorectal surgery on postoperative complications. After critical appraisal of included studies, meta-analyses were conducted using a random-effect model. RESULTS: 1731 papers were retrieved; 2 randomized controlled trials and 4 retrospective cohort studies met the inclusion criteria. The overall quality of evidence was low. MBP before colorectal surgery did not significantly decrease the occurrence of anastomotic leakage, intra-abdominal infection, or wound infection compared to no MBP. CONCLUSIONS: On the basis of the existing evidence, the use of MBP before colorectal surgery in children seems not to decrease the incidence of postoperative complications compared to no MBP. To overcome confounding factors such as antibiotic prophylaxis, age and type of operation, a multicentre prospective study is suggested to validate these results.

Value of abdominal ultrasound in management of necrotizing enterocolitis: a systematic review and meta-analysis.

PURPOSE: Necrotizing enterocolitis (NEC) remains a life-threatening disease among infants in the NICU. Early diagnosis and careful monitoring are essential to improve outcomes. Abdominal ultrasound (AUS) seems a promising addition to current diagnostic modalities, but its clinical utility is uncertain. The aim of this study was to identify AUS features associated with definite NEC (i.e. Bell stage ≥ II), failed medical treatment, surgery, and death. METHODS: Embase, MEDLINE, Web of Science and CINAHL databases were searched for studies that addressed any NEC-related AUS feature in relation to any of the four outcomes. After critical appraisal of relevant study methods, meta-analyses were conducted using a random-effect model. RESULTS: 15 out of 1215 studies were included. All AUS features had sensitivities below 70% and specificities largely above 80% for diagnosing definite NEC; several AUS features were significantly associated with failed medical treatment and surgery. Substantial heterogeneity, poor reporting quality and uncertain risk of bias were found. CONCLUSIONS: While clear associations of AUS features with failed medical treatment exist and AUS may detect definite NEC, substantial heterogeneity, poor reporting quality and an uncertain risk of bias impair the use of AUS for clinical decision making. A prospective, well-designed validation study is needed.

Development of Nerve Fibre Diameter in Young Infants With Hirschsprung Disease.

OBJECTIVES: Finding thickened nerve fibres is one of the key elements in the diagnosis of Hirschsprung disease (HD); however, its value at different ages remains uncertain. Nerve fibre diameters <40 µm can be observed in infants younger than 8 weeks, despite the presence of HD. The aim of this study was to identify a change in maximum nerve fibre diameter in HD patients, measured before and after 8 weeks of age. METHODS: Nerve fibre diameter was retrospectively evaluated in tissue of 20 infants treated for definite HD. Rectal suction biopsies (RSBs) obtained within the first 8 weeks of life (T1) and resected bowel obtained during primary surgery at an average of 24.7 weeks (T2), were assessed. The 2 thickest nerve fibre diameter recordings at T1 and T2 were compared in each subject, to examine changes in nerve trunk diameter with increasing age. RESULTS: In 13 cases (65%), nerve fibre diameters were ≥40 µm at T1 and T2. Six subjects (30%) had nerve trunk diameters <40 µm at T1; however, they experienced diameter increases to ≥40 µm by T2. Thus, at T2, 19 subjects (95%) had diameter recordings ≥40 µm. Nerve fibre diameter in the remaining case (5%) stayed consistent at <40 µm at T1 and T2, despite the presence of HD. CONCLUSIONS: After the first 8 weeks of life, nerve fibre measurements appear to be associated with HD. Measuring the 2 thickest nerve fibres can support typical HD diagnosis criteria beyond 8 weeks of age, but is not superior to histopathological confirmation of aganglionosis.