Does protocol miconazole administration improve mortality and morbidity on surgical necrotizing enterocolitis?

PURPOSE: Our previous clinical pilot study reported that miconazole (MCZ) prevented morbidity from surgical necrotizing enterocolitis (NEC). The present study re-investigated this effect in a long-term cohort over 20 years. METHODS: We conducted a retrospective cohort study from April 1998 to March 2020. A total of 1169 extremely low-birth-weight infants (ELBWIs) admitted to our neonatal intensive care unit, including 45 with NEC (3.8%), underwent surgery. Since 2002, protocol MCZ administration for 3 weeks has been applied for neonates born before 26 weeks' gestation or weighing under 1000 g. We compared the background characteristics and clinical outcomes between patients with and without MCZ administration. RESULTS: The morbidity rate decreased after applying the MCZ protocol, but no improvement in mortality was seen. A propensity score-matched analysis indicated that treated patients by MCZ showed a delay in developing surgical NEC by 12 days. The MCZ protocol also helped increase body weight at surgery. Prophylactic MCZ administration did not improve the neurological development of the language-social and postural-motor domains in the surgical NEC patients. But cognitive-adaptive domain caught up by a chronological age of 3 years old. CONCLUSIONS: Revising the protocol to extend the dosing period may improve the outcomes of surgical NEC after the onset.

Association between gastrointestinal perforation and patent ductus arteriosus in extremely-low-birth-weight infants: a retrospective study of our decade-long experience.

PURPOSE: Management of persistently patent ductus arteriosus (PDA) in extremely low-birth-weight infants (ELBWIs) requires attention due to the risk of tissue hypoperfusion. We investigated the association between PDA and gastrointestinal perforation. METHODS: We performed a retrospective chart review from 2012 to 2021. Preterm (≤ 32 weeks) ELBWIs with PDA after birth who developed necrotizing enterocolitis (NEC), focal intestinal perforation (FIP), and idiopathic gastric perforation were included; ELBWIs with congenital heart disease were excluded. Data were analyzed using chi-squared tests with Yates; correction, and Student's t test. RESULTS: Five hundred thirty-five preterm ELBWIs were analyzed, including 20 with NEC, 22 with FIP, and 1 with gastric perforation. In NEC and FIP, the ductus arteriosus remained open in 40% (4/10) and 63.6% (14/22) of cases, respectively, and cyclo-oxygenase inhibitor treatment showed poor efficacy (p = 0.492 and 0.240). The incidence of perforation in NEC (4/9 vs. 6/11, p = 0.653), mortality in NEC (3/4 vs. 3/6, p = 0.895) and FIP (6/14 vs. 3/8, p = 0.838) did not differ according to whether the PDA persisted or resolved. CONCLUSION: The presentation of PDA did not affect the mortality or morbidity of ELBWIs. However, it is essential to consider the possibility of gastrointestinal perforation due to decreased organ blood flow caused by ductal steal.

Predictive factors of bowel resection for midgut volvulus based on an analysis of bi-center experiences in southern Japan.

PURPOSE: Midgut volvulus is an urgent disease often occurring in neonates. This study clarified the clinical features of midgut volvulus and evaluated predictors to avoid bowel resection. METHODS: This bi-center retrospective study enrolled 48 patients who underwent surgery for intestinal malrotation between 2010 and 2022. Patients' background characteristics and preoperative imaging findings were reviewed. RESULTS: Midgut volvulus was recognized in 32 patients (66.7%), and 6 (12.5%) underwent bowel resection. Based on a receiver operating curve analysis of bowel resection, the cut-off value of the body weight at birth and at operation were 1984 g [area under the curve (AUC) 0.75, 95% confidence interval (CI) 0.52-0.99] and 2418 g (AUC 0.70, 95% CI 0.46-0.94), respectively. The cut-off value of intestinal torsion was 540° (AUC 0.76, 95% CI 0.57-0.95), and that of the time from the onset to the diagnosis was 12 h (AUC 0.85, 95% CI 0.72-0.98). For midgut volvulus with an intestinal torsion > 540°, the most sensitive preoperative imaging test was ultrasonography (75%) Patients with bloody stool tended to undergo bowel resection. CONCLUSIONS: Patients with a low body weight and bloody stool should be confirmed to have whirlpool sign by ultrasonography and scheduled for surgery as soon as possible.

Is anemia frequently recognized in gastroschisis compared to omphalocele? A multicenter retrospective study in southern Japan.

PURPOSE: We compared cases of anemia in gastroschisis versus omphalocele and investigated this clinical question. METHODS: A multicenter study of five pediatric surgery departments in southern Japan was planned. Sixty patients were collected between 2011 and 2020, with 33 (gastroschisis: n = 19, omphalocele: n = 14) who met the selection criteria ultimately being enrolled. Anemia was evaluated before discharge and at the first outpatient visit. RESULTS: Despite gastroschisis cases showed more frequent iron administration during hospitalization than omphalocele (p = 0.015), gastroschisis cases tended to show lower hemoglobin values at the first outpatient visit than omphalocele cases (gastroschisis: 9.9 g/dL, omphalocele: 11.2 g/dL). Gastroschisis and the gestational age at birth were significant independent predictors of anemia at the first outpatient visit, (gastroschisis: adjusted odds ratio [OR] 19.00, p = 0.036; gestational age at birth: adjusted OR 0.341, p = 0.028). A subgroup analysis for gastroschisis showed that the ratio of anemia in the 35-36 weeks group (8/10, 80.0%) and the > 37 weeks group (6/6, 100%) was more than in the < 34 weeks group (0/3, 0.0%). CONCLUSIONS: Gastroschisis may carry an increased risk of developing anemia compared with omphalocele due to the difference of direct intestinal exposure of amnion fluid in utero.

How should we treat representative neonatal surgical diseases with congenital heart disease?

PURPOSE: Representative neonatal surgical diseases are often complicated by congenital heart disease (CHD). We reviewed our decade of experience from the perspective of the prognosis and report on the management of infants with CHD. METHODS: Cases with and without CHD between 2011 and 2020 were retrospectively compared. Qualitative data were analyzed using a chi-square test with Yates' correction, and quantitative data were compared using Student's t-test. RESULTS: Of the 275 neonatal surgical cases, 36 had CHD (13.1%). Ventricular septal defect was the most common cardiac anomaly, followed by atrial septal defect. Esophageal atresia showed the highest complication rate of CHD (43.8%, 14/32) followed by duodenal atresia (38.5%, 10/26). The mortality rates of patients with and without CHD (22.2% [8/36] vs. 1.3% [3/239]) were significantly different (χ2 = 30.6, p < 0.0001). Of the eight deaths with CHD, six patients had cyanotic complex CHD. Notably, four of these patients died from progression of inappropriate hemodynamics in the remote period after definitive non-cardiac surgery. CONCLUSION: Considering its high-mortality, the presence of CHD, especially cyanotic heart disease, is an important issue to consider in the treatment of neonatal surgical diseases. Pediatric surgeons should be alert for changes in hemodynamics after surgery, as these may affect mortality.

Prophylactic efficacy of enteral antifungal administration of miconazole for intestinal perforation, especially for necrotizing enterocolitis: a historical cohort study at a single institution.

PURPOSE: Despite improvements in neonatal intensive care, the outcomes of extremely-low-birth-weight infants (ELBWIs) with surgical diseases remain to be improved. We started administering enteral miconazole (MCZ) to ELBWIs from 2002 to prevent fungal infection. Since then, the incidence of intestinal perforation has significantly decreased. We investigated this prophylactic effect of MCZ against necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) and explored a new prophylactic concept against intestinal perforation. METHODS: We designed a historical cohort study to evaluate the effect of MCZ for intestinal perforation in ELBWIs who underwent treatment in our neonatal intensive-care unit between January 1998 and December 2005. We divided these cases into two groups: the Pre-MCZ group and the Post-MCZ group. We compared the morbidity, clinical outcomes and pathological features of NEC and FIP. RESULTS: The rate of intestinal perforation with NEC was significantly reduced after the introduction of MCZ (p = 0.007, odds ratio; 3.782, 95% confidence interval; 1.368-12.08). The pathological findings of NEC specimens showed that the accumulation of inflammatory cells was significantly reduced in the Post-MCZ group when compared with the Pre-MCZ group (p < 0.05). CONCLUSIONS: The efficacy of the enteral administration of MCZ on intestinal perforation with NEC highlights a new prophylactic concept in the clinical management of ELBWIs.

Discrepancy between the survival rate and neuropsychological development in postsurgical extremely low-birth-weight infants: a retrospective study over two decades at a single institution.

PURPOSE: Necrotizing enterocolitis (NEC), focal intestinal perforation (FIP), and meconium-related ileus (MRI) are major diseases that cause gastrointestinal disorders in extremely low-birth-weight infants (ELBWIs). We conducted a review to compare the postoperative outcomes of ELBWIs with these diseases in our neonatal intensive-care unit. METHODS: A retrospective chart review of ELBWIs surgically treated for NEC (n = 31), FIP (n = 35), and MRI (n = 16) in 2001-2018 was undertaken. This period was divided into early (2001-2005), middle (2006-2010), and late (2011-2018) periods. Data were analyzed with the Cochran-Armitage test. Statistical significance was defined as p < 0.05. RESULTS: The survival rates in ELBWIs with NEC (early/middle/late: 36.4%/42.9%/61.5%; p = 0.212) and FIP (20%/50%/70.6%; p = 0.012) improved over time; all patients with MRI survived. The neuropsychological development of 24 cases was assessed with the Kyoto Scale of Psychological Development in the Postural-Motor, Cognitive-Adaptative, and Language-Social domains. The mean developmental quotient of all domains was 68.4 (range 18-95) at corrected 1.5 years of age and 69.1 (range 25-108) at chronological 3 years of age, both were considered as poor development. There was no improvement over time (p = 0.899). CONCLUSION: Ideal neuropsychological development was not observed with the improvement of survival rate. Less-invasive surgical intervention and adequate postoperative care are required to encourage further development.

Oral diatrizoate acid for meconium-related ileus in extremely preterm infants.

BACKGROUND: Intestinal disorders are common in very low-birthweight infants. The purpose of this study was to evaluate the impact of prophylactic oral Gastrografin® (diatrizoate acid) on meconium-related ileus (MRI) in extremely preterm infants. METHODS: This was a retrospective case-control study of infants born extremely preterm at <28 weeks of gestation and treated with diatrizoate acid (prophylactic group) or not (control group) in the periods 2007-2014 and 2000-2009, respectively. In the 2007-2014 period, 120 infants received prophylactic diatrizoate acid solution. From the 165 infants in the control group, we selected 120 infants matched for gestational age. Cases of death before 72 h of life or congenital abnormalities were excluded. Intestinal disorders, time until full enteral feeding, duration of hospital stay, mortality rate, and neurodevelopmental outcome were compared. RESULTS: MRI occurred in six infants in the control group and in none of the infants in the prophylactic group (P = 0.039). Median time until full enteral feeding was 25 versus 22 days (P < 0.01), hospital stay was 142 versus 126 days (P < 0.01), and mortality rate for infants aged 24-27 weeks was 8.2% versus 0% (P = 0.021), respectively. CONCLUSIONS: Prophylactic oral diatrizoate acid reduced MRI in extremely preterm infants without side-effects and decreased the mortality rate of infants born at 24-27 weeks, and is thus beneficial in extremely preterm infants.

Prophylactic efficacy of enteral miconazole administration for neonatal intestinal perforation and its potential mechanism.

PURPOSE: Intestinal perforation (IP) is a fatal complication in extremely low birth weight infants (ELBWI). We started administrating enteral miconazole (MCZ) to ELBWI in 2002. Since then, the incidence of IP has significantly decreased. The aim of this study was to elucidate the prophylactic effect of MCZ for the treatment of neonatal IP, and to establish a new prophylactic concept for this disease. METHODS: In in vivo experiments, the effects of MCZ were examined histopathologically using a mouse model of intestinal ischemia. In in vitro experiments, the cytoprotective effect of MCZ against hypoxia was evaluated using Caco-2 intestinal cells, and its anti-inflammatory potential using a co-culture model of Caco-2 and HL60 cells. RESULTS: MCZ showed a tissue protective effect against intestinal ischemia. MCZ reduced high mobility group-box 1 (HMGB1) release in Caco-2 cells under hypoxic stress and attenuated the potential to activate co-cultured HL60 leukocytes with Caco-2 cells by suppressing interleukin-8 (IL-8). CONCLUSION: MCZ may have preventive roles in the clinical management of IP in ELBWI by the suppression of IL-8 and HMGB-1.

Optimal Surgical Method and Timing for Low-birth-weight Esophageal Atresia Babies: Multi-institutional Observational Study.

AIM OF THE STUDY: Previous research has shown that low birth weight is one of the risk factors for esophageal atresia. However, there remains a paucity of evidence on the timing and the treatment method. METHOD: Data were collected using a multi-institutional observational study in 11 hospitals that performed surgeries on esophageal atresia babies whose birth weights were ≤1500 g from 2001 to 2020. RESULTS: Of the 46 patients analyzed, median birth weight was 1233 (IQR 1042-1412) g. Within 46 cases, 19 (41%) underwent definitive esophageal anastomosis at the median of age in 8 (IQR 2-101) days. Thirteen out of 19 experienced either closure of tracheoesophageal fistula, gastrostomy, or esophageal banding at the first operation, followed by esophageal anastomosis. Seven infants, including four cases of <1000 g, underwent anastomosis after one month of age to wait for weight gain (variously 2-3000 g). Twenty-one out of 27 infants (78%) who did not receive anastomosis died within one year of age, including 21 (78 %) with major cardiac anomalies and 24 (89%) with severe chromosomal anomalies (trisomy 18). Six survivors in this group, all with trisomy 18, lived with palliative surgical treatments. CONCLUSION: In our study, the definitive esophageal anastomosis was effective either at the first operation or as a later treatment after gaining weight. Although having severe anomalies, some infants receive palliative surgical treatments, and the next surgery was considered depending on their condition. EVIDENCE LEVEL: II.

Comparison of Transumbilical Laparoscopy-Assisted Appendectomy with Conventional Three-Port Laparoscopic Appendectomy Performed by Pediatric Surgeons in Training for Appendicitis in Children.

Background: Transumbilical laparoscopy-assisted appendectomy (TULAA) is the technique of choice for all types of appendicitis. However, the technique is challenging for trainees to learn in comparison with performing conventional three-port laparoscopic appendectomy (CTPLA) in children. We aimed to compare the surgical outcomes of children with appendicitis treated by TULAA versus CTPLA performed by pediatric surgeons in training (PSITs). Materials and Methods: This retrospective study analyzed pediatric patients with acute appendicitis treated with CTPLA or TULAA between April 2016 and December 2022. Operative time (OT: minutes), pneumoperitoneum time (PT: minutes), blood loss (milliliter), length of hospital stay (days), and surgical site infection rate were compared between the two groups. Operative outcomes were also analyzed according to type of appendicitis such as uncomplicated and complicated cases. Results: Two hundred twenty-five laparoscopic appendectomies were performed by CTPLA (n = 94) or TULAA (n = 131). All cases were performed by PSITs and there was no open conversion cases. TULAA had a shorter OT (67.0 ± 28.4 versus 78.3 ± 21.7; P < .01) and PT (26.1 ± 17.4 versus 52.5 ± 22.1 min; P < .01). The surgical site infection rate was slightly higher in the TULAA group, but the difference was not statistically significant. In uncomplicated appendicitis (n = 164), significant differences between the CTPLA and TULAA groups were observed in OT (CTPLA versus TULAA: 70.7 ± 14.9 versus 59.1 ± 21.6, P < .01) and PT (CTPLA versus TULAA: 43.6 ± 13.1 versus 20.4 ± 13.6, P < .01). With regard to postoperative complications, only surgical site infection was significantly different between the CTPLA and TULAA groups (CTPLA: 0.0% versus TULAA: 8.2%, P < .05). In complicated cases (n = 61), there were significant differences between the groups in PT (CTPLA versus TULAA: 73.4 ± 24.9 versus 42.3 ± 17.2, P < .01) and length of hospital stay (CTPLA versus TULAA: 7.0 ± 1.3 versus 8.9 ± 4.7, P < .05). Conclusions: TULAA had a shorter OT and PT than CTPLA. TULAA for PSITs shows similar safety and feasibility to CTPLA for not only uncomplicated cases but also complicated cases.

Notable Clinical Differences Between Neonatal and Post-Neonatal Intestinal Malrotation: A Multicenter Review in Southern Japan.

BACKGROUND: Most cases of intestinal malrotation appear in neonates with bilious vomiting due to midgut volvulus, whereas in cases that develop beyond infancy, the initial symptoms vary. This study investigated the clinical features of these two populations and identified issues that should be considered in daily practice. METHODS: A retrospective chart review was conducted from January 1, 2010, to December 31, 2022. Data on patients with intestinal malrotation were collected in an anonymized fashion from five pediatric surgical hub facilities in the Southern Kyushu and Okinawa areas of Japan. RESULTS: Of the 80 subjects, 57 (71.3%) were neonates (Group N) and 23 (28.7%) were infants and schoolchildren (Group I). The frequencies of initial symptoms, such as abdominal distention (Group N: 19.3% vs. Group I: 13.0%), bilious vomiting (59.6% vs. 43.5%), and hematochezia (8.8% vs. 21.7%), were not skewed by the age of onset (p = 0.535, 0.087, and 0.141, respectively). Midgut volvulus was significantly more frequent in Group N (71.9% [41/57] vs. 34.8% [8/23]; p = 0.005), while the degree of torsion was greater in group I (median 360° [interquartile range: 180-360°] vs. 450° [360-540°]; p = 0.029). Although the bowel resection rate was equivalent (7.0% [4/57] vs. 4.3% [1/23]; p = 1.000), half of the patients in Group N presented with 180° torsion. The neonatal intestine has been highlighted as being more susceptible to ischemia than that in older children. CONCLUSIONS: The incidence of midgut volvulus is higher in neonates than in older children. Even relatively mild torsion can cause ischemic bowel changes during the neonatal period. LEVEL OF EVIDENCE: LEVEL III.

Micafungin versus fluconazole for prophylaxis against fungal infections in premature infants.

BACKGROUND: We conducted a comparative clinical study to evaluate the prophylactic effects of micafungin (MCFG) and fluconazole (FLCZ) on the incidence of fungal infections in extremely low-birthweight infants who were born at a gestational age of less than 26 weeks and weighed less than 1000 g. METHODS: With a combination of enteral administration of miconazole (6 mg/kg/day), FLCZ and MCFG were administered intravenously at a dose of 5 mg/kg/day and 3 mg/kg/day, respectively. The prophylaxis was classified as a failure when fungal infections were identified within the first 21 days after birth. RESULTS: The prophylaxis was successful in seven of 18 cases (39%) in the FLCZ group and 15 of 21 cases (71%) in the MCFG group, indicating that the success rate was significantly higher in the latter group. CONCLUSION: MCFG was superior to FLCZ as prophylaxis against fungal infections in extremely low-birthweight infants.

Extracellular high mobility group box chromosomal protein 1 is a coupling factor for hypoxia and inflammation in arthritis.

OBJECTIVE: Tissue hypoxia is closely associated with arthritis pathogenesis, and extracellular high mobility group box chromosomal protein 1 (HMGB-1) released from injured cells also has a role in arthritis development. This study was thus undertaken to investigate the hypothesis that extracellular HMGB-1 may be a coupling factor between hypoxia and inflammation in arthritis. METHODS: Concentrations of tumor necrosis factor alpha, interleukin-6, vascular endothelial growth factor, lactic acid, lactate dehydrogenase, and HMGB-1 were measured in synovial fluid (SF) samples from patients with inflammatory arthropathy (rheumatoid arthritis and pseudogout) and patients with noninflammatory arthropathy (osteoarthritis). The localization of tissue hypoxia and HMGB-1 was also examined in animal models of collagen-induced arthritis (CIA). In cell-based experiments, the effects of hypoxia on HMGB-1 release and its associated cellular events (i.e., protein distribution and cell viability) were studied. RESULTS: In SF samples from patients with HMGB-1-associated inflammatory arthropathy (i.e., samples with HMGB-1 levels >2 SD above the mean level in samples from patients with noninflammatory arthropathy), concentrations of HMGB-1 were significantly correlated with those of lactic acid, a marker of tissue hypoxia. In CIA models in which the pathologic phenotype could be attenuated by HMGB-1 neutralization, colocalization of HMGB-1 with tissue hypoxia in arthritis lesions was also observed. In cell-based experiments, hypoxia induced significantly increased levels of extracellular HMGB-1 by the cellular processes of secretion and/or apoptosis-associated release, which was much more prominent than the protein release in necrotic cell injury potentiated by oxidative stress. CONCLUSION: These findings indicate that tissue hypoxia and its resultant extracellular HMGB-1 might play an important role in the development of arthritis.