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.

Incubator humidity and temperature control in infants born at 22-23 weeks' gestation.

BACKGROUND: Preterm infants, especially those born at ≤23 gestational weeks (GW), present with extremes in insensible water loss (IWL) and changes in water balance. AIMS: To prevent water loss from the skin and achieve skin maturation without infection, we investigated transepidermal water loss (TEWL), IWL from the skin (IWL-s), and electrolyte balance with differences in high incubator humidity and temperature control from birth to postnatal 1 month in 22-23 GW and 24-25 GW infants. STUDY DESIGN: Prospective cohort study. SUBJECTS: Extremely preterm infants born at 22-23 GW (n = 11) and 24-25 GW (n = 11), admitted to the neonatal intensive care unit between September 2018 and October 2019. OUTCOME MEASURES: Total fluid intake (TFI), fluid output volume, TEWL, IWL-s, and electrolyte balance were compared between the two groups with controlled incubator humidity and temperature, gradually decreasing the humidity and ambient temperature from 95% to 50% and from 37.0 to 34.0 °C, respectively, while maintaining the central body temperature at 36.5-37.5 °C. RESULTS: TEWL and IWL-s between the 22-23 and 24-25 GW was not significantly different for infants at postnatal age. No significant difference in electrolyte imbalance was noted between the two groups, within the first 7 days. Differences in TEWL and IWL-s were eliminated with corresponding humidity and temperature adjustments. CONCLUSIONS: Incubator humidity and temperature control should aid management of 22-23 GW infants to reduce IWL, facilitate skin maturation, and prevent infection.

Potential predictors of the onset of focal intestinal perforation in extremely low birth weight infants based on an analysis of coagulation and fibrinolysis markers at birth: A case-control study based on ten years of experience at a single institution.

PURPOSE: We aimed to investigate potential predictors of focal intestinal perforation (FIP) in extremely low birth weight infants (ELBWIs) among coagulation and fibrinolysis markers at birth. METHODS: We reviewed the medical records of FIP patients and their coagulation and fibrinolysis markers at birth between 2010 and 2019, and matched patients according to gestational age. FIP was diagnosed based on macroscopic intestinal perforation with a punched-out lesion without necrosis. Patient characteristics and blood test results, including coagulation and fibrinolysis marker levels, were compared between the groups. RESULTS: Two hundred forty ELBWIs were enrolled in this study (FIP, n = 18; controls, n = 222). In the FIP group, the gestational age at birth was significantly younger (p = 0.023) and the birth weight was significantly lower (p = 0.007) in comparison to the control group. Furthermore, the FIP group showed significantly lower levels of fibrinogen (p = 0.027) and factor XIII (F-XIII) (p = 0.007). The receiver operating characteristics curves for fibrinogen and F-XIII revealed that the 95% confidence intervals of fibrinogen and F-XIII were 0.530-0.783 (p = 0.027), and 0.574-0.822 (p = 0.007), respectively. CONCLUSIONS: This is the first report focusing on coagulation and fibrinolysis markers in FIP patients at birth. The fibrinogen and F-XIII values at birth are potential predictors of FIP in ELBWIs. TYPE OF STUDY: Study of Diagnostic Test (Case Control Study) LEVEL OF EVIDENCE: : Level IV.

Risk Factors for Mortality and Neurodevelopmental Impairment among Neonates Born at 22-23 Weeks' Gestation.

INTRODUCTION: We aimed to evaluate the risk factors for mortality and neurodevelopmental impairment (NDI) among infants of 22-23 weeks' gestational age, which currently remain unclear. METHODS: This retrospective case-control study included 104 infants delivered at 22-23 weeks' gestation at Kagoshima City Hospital from 2006 to 2015. We compared 65 and 34 cases of survival to discharge and postnatal in-hospital death (5 excluded), respectively, and 26 and 35 cases with and without NDI, respectively, using maternal, prenatal, and postnatal records. A high rate of survivors' follow-up (61/65) was achieved in this study. RESULTS: The survival rate was 75.0% (21/28) and 62.0% (44/71) among infants born at 22 and 23 weeks' gestation, respectively. Infants who died weighed less (525.5 vs. 578 g, p = 0.04) and their intrauterine growth retardation (IUGR) rate (<5th percentile) was higher (14.7 vs. 1.5%, p = 0.02). Mortality was associated with an increased incidence of bradycardia on fetal heart rate monitoring (11.8 vs. 1.5%, p = 0.046), periventricular hemorrhagic infarction (PVHI; 32.4 vs. 6.2%, p = 0.001), necrotizing enterocolitis (NEC, surgery or drain tube; 14.7 vs. 0.0%, p = 0.004), and tension pneumothorax (29.4 vs. 6.2%, p = 0.004). There were significant differences in the proportion of PVHI (15.4 vs. 0%, p = 0.03) between infants with and without NDI. CONCLUSIONS: IUGR, bradycardia, PVHI, NEC, and tension pneumothorax were associated with neonatal mortality among infants born at 22-23 weeks' gestation. NDI at 36-42 months' chronological age was associated with PVHI.

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.

Safety, speed, and effectiveness of air transportation for neonates.

BACKGROUND: In Japan, 44.3% of neonates are delivered in private clinics without an attending pediatrician. Obstetricians in the clinics must resuscitate asphyxiated neonates in unstable condition, such as respiratory failure, and they are frequently transferred to tertiary perinatal medical centers. There has been no study comparing the physiological status and prognosis of neonates transported by ambulance with those transported by helicopter. METHODS: Medical and transport records were used to compare the physiological status of neonates transported to Kagoshima City Hospital by land and those transported by air between January 1, 2013, and December 31, 2017. RESULTS: Data from 425 neonates transferred by land and 143 by air were analyzed. There were no significant differences between the two groups in mean gestational age, mean birthweight, fetal blood pH, Apgar score, or the Score for Neonatal Acute Physiology with Perinatal Extension-II (SNAPPE-II) on arrival to the tertiary center (16.3 ± 15.4 [95% confidence interval (CI): 13.2-17.7] vs 16.4 ± 15.4 [95% CI: 13.9-19.0], respectively; P = 0.999); both groups had SNAPPE-II score 10-19, indicating no difference in mortality risk. The times to starting first aid and to admission to the intensive care unit were significantly reduced in neonates transported by air than by land. In subgroup analysis of patients of a gestational age ≤28 weeks, all cases of severe intraventricular hemorrhage (IVH) were observed in the land transportation group. CONCLUSIONS: Neonatal transportation by air is as safe as land transportation, and time to first aid and intensive care are significantly reduced by transportation by air than by land. Air transport could also contribute to the prevention of IVH in neonatal transportation.

Assessment of risk factors for cystic periventricular leukomalacia.

AIM: Periventricular leukomalacia (PVL) is an important cause of cerebral palsy in premature infants, and cystic PVL is the most serious form of the disease. The risk factors for cystic PVL in singleton fetuses at a gestational age of <35 weeks are unclear. METHODS: This study included 2013 singleton birth infants delivered at a gestational age of <35 weeks in Kagoshima City Hospital between 2006 and 2017. The findings for 30 infants with cystic PVL were compared with those for 63 matched control infants by gestational age and birth weight. RESULTS: The cystic PVL was associated with increased incidence of recurrent late deceleration (L/D) (43.4% vs. 15.9%, P = 0.004) and loss of variability (LOV) (10.0% vs. 0.0%, P = 0.03) in fetal heart rate monitoring and late-onset circulatory dysfunction (LCD) (33.3% vs. 11.1%, P = 0.02). Logistic regression analysis revealed that recurrent L/D (odds ratio [OR] = 3.57, 95% confidence interval [CI]: 1.29-10.15, P = 0.01) and LCD (OR = 3.41, 95% CI: 1.09-11.04, P = 0.03) were risk factors associated with cystic PVL. LOV was not included in the multivariate analysis as there were too few cases in both the cystic PVL and control groups. CONCLUSION: Recurrent L/D, LOV and LCD are strongly associated with cystic PVL. In cases of fetal acidosis related to recurrent L/D or loss of variability, cystic PVL may occur.

Extracorporeal membrane oxygenation in 61 neonates: Single-center experience.

BACKGROUND: There have been few reports on the outcome of extracorporeal membrane oxygenation (ECMO) in newborn Japanese infants. METHODS: A review was carried out of 61 neonates with ECMO between January 1995 and December 2015 at a single center. ECMO was used in neonates with oxygenation index >20 after conventional treatment. Background factors, such as etiology, vascular access mode (veno-venous [VV] or veno-arterial [VA]), number of days with ECMO, and early ECMO (within 24 h after birth), were analyzed in relation to outcome with respect to survival to hospital discharge (SHD). RESULTS: Survival to hospital discharge was achieved in 35 infants (57%), while the remaining 26 died during hospital stay. Gestational age at birth was significantly higher and number of days with ECMO was significantly lower in SHD infants compared with those with adverse outcome (median, 4.0 vs 5.5 days, respectively; P = 0.008). The SHD rate was significantly higher for those with VV than VA vascular access mode (78%, 18/23 vs 45%, 17/38, respectively; P = 0.016), and for those with than without early ECMO (72%, 28/39 vs 32%, 7/22, respectively; P = 0.003). The SHD rate was relatively high in neonates with meconium aspiration syndrome (86%, 12/14), persistent pulmonary hypertension associated with hypoxic ischemic encephalopathy (75%, 6/8), and emphysema (80%, 4/5). On stepwise logistic regression analysis two independent factors of SHD were identified: early ECMO (OR, 9.63; 95%CI: 2.47-37.6) and ECMO length <8 days (OR, 8.05; 95%CI: 1.94-33.5). CONCLUSIONS: Neonates with early ECMO and those with ECMO duration <8 days may benefit from ECMO with respect to SHD.

Polymyxin B-immobilized fiber column direct hemoperfusion and continuous hemodiafiltration in premature neonates with systemic inflammatory response syndrome.

BACKGROUND: There have been no previous studies regarding whether combined use of Polymyxin B-immobilized fiber column direct hemoperfusion (PMX-DHP) and continuous hemodiafiltration (CHDF) is helpful in the treatment of preterm infants with systemic inflammatory response syndrome (SIRS) and hypercytokinemia. METHODS: A retrospective review was carried out of 18 SIRS infants born at gestational week 24-28. Eight with blood interleukin (IL)-6 ≥ 1000 pg/mL were treated actively with 2 h PMX-DHP followed by 2 h PMX-DHP and CHDF. Ten with IL-6 < 500 pg/mL were treated conventionally (with neither PMX-DHP nor CHDF) and served as controls. RESULTS: Demographic characteristics were similar except for IL-6, arterial-to-alveolar oxygen tension ratio (a/APO2 ), and number of immature neutrophils between the two groups. Baseline a/APO2 was significantly lower in infants with than without active treatment (0.44 vs 0.67, respectively, P = 0.002). After 4 h treatment, the IL-6 decreased to < 500 pg/mL in all eight infants, and a/APO2 improved significantly to 0.62 (P = 0.006). Bronchopulmonary dysplasia occurred in a similar proportion (63%, 5/8 vs 80%, 8/10, respectively), but the number of days on inhaled oxygen (30 vs 47 days, respectively, P = 0.033) and tracheal intubation (36 vs 51 days, respectively, P = 0.040) was significantly lower in infants with than without active treatment. Prevalence of adverse events was similar (13%, 1/8 vs 50%, 5/10 for active vs conventional treatment, respectively). CONCLUSION: Active treatment with PMX-DHP and CHDF was helpful in the reduction of days on inhaled oxygen and tracheal intubation in preterm SIRS infants with hypercytokinemia. Further prospective randomized studies are warranted.

Effects of infant flow Bi-NCPAP on apnea of prematurity.

BACKGROUND: Infant flow biphasic nasal continuous positive airway pressure (Bi-NCPAP) and regular NCPAP (Re-NCPAP) are equally useful with respect to the rate of successful weaning from mechanical ventilation. It remains unclear, however, whether Bi-NCPAP or Re-NCPAP is more effective for reducing apnea of prematurity (AOP). METHODS: A multicenter randomized controlled study was conducted of 66 infants assigned to receive Bi-NCPAP and 66 assigned to receive Re-NCPAP for respiratory support after extubation. Primary outcome was the number of AOP events during the 48 h observation period after successful extubation, defined as no reintubation and no adverse events associated with the use of NCPAP during the observation period. The secondary outcome was successful extubation. Reintubation was at the discretion of the attending physician. RESULTS: Baseline characteristics were similar between the two groups. The number of AOP events during the 48 h observation period was significantly lower in infants with Bi-NCPAP than in those with Re-NCPAP (5.2 ± 6.5 vs 10.3 ± 10.9 per infant, respectively; P = 0.002). The rate of successful extubation tended to be greater in those with Bi-NCPAP than in those with Re-NCPAP (92.4%, 61/66 vs 80.3%, 53/66, respectively; P = 0.074). Adverse events occurred in only one of 132 infants: erosive dermatitis developed on the nose after application of Re-NCPAP. The risk of reintubation did not differ significantly between the two groups (7.6%, 5/66 for Bi-NCPAP vs 18.2%, 12/66 for Re-NCPAP; P = 0.117). CONCLUSIONS: Bi-NCPAP was superior to Re-NCPAP for reduction of AOP following extubation.

Outcome of infants with hypoxic ischemic encephalopathy treated with brain hypothermia.

AIM: The aim of this study was to determine perinatal factors associated with cerebral palsy (CP) in infants treated with brain hypothermia (BHT). MATERIAL AND METHODS: We carried out a retrospective review of 23 infants with hypoxic ischemic encephalopathy in whom BHT was applied within 6 h after birth. Outcome regarding the presence or absence of CP was assessed at the age of 18 months. Oxygen extraction fraction (OEF) was measured before, during and after BHT at the jugular sinus. RESULTS: Three infants died and 12 developed CP (poor outcome group). The remaining eight infants did not have CP at 18 months old (favorable outcome group). There were no differences in gestational age, birthweight, pH, base deficit, or lactate level between infants with favorable and poor outcomes. Infants with flat trace on electroencephalography on admission were less likely to have favorable outcome (0.0% [0/8] vs 53% [8/15], respectively, P = 0.02), while those with Apgar score at 10 min ≥5 (57% [8/14] vs 0.0% [0/9], P = 0.007) or ≥6 (70% [7/10] vs 7.7% [1/13], P = 0.002), OEF ≥ 13.3% during BHT (64% [7/11] vs 8.3% [1/12], P = 0.009), and OEF ≥ 18.5% after BHT (73% [8/11] vs 0.0% [0/12], P = 0.002) were more likely to have favorable outcome compared with those with counterpart characteristics. CONCLUSION: Infants with an Apgar score at 10 min ≥5, activity on electroencephalography on admission, and higher OEF during and after BHT were likely to have a favorable outcome.

Predicting onset of chronic lung disease using cord blood cytokines.

BACKGROUND: Applicability of cord blood interleukin-6 (IL-6) and interleukin-8 (IL-8) as markers for early prediction of the onset of chronic lung disease (CLD) due to intrauterine infection was investigated in the present study. METHODS: Eighty very low-birthweight infants with chorioamnionitis were divided into two groups: the CLD group (42 patients) and the non-CLD group (38 patients), according to the presence or absence of CLD, and the clinical background and cord blood IL-6 and IL-8 levels in each group were compared and investigated. RESULTS: The CLD group had significantly longer duration of mechanical ventilation and hospitalization (P < 0.05) and significantly higher IL-6 and IL-8 (P < 0.01) than the non-CLD group. Using the receiver operating characteristic curves of CLD onset for both IL-6 and IL-8, the cut-off value of IL-6 for predicting onset of CLD was 48.0 pg/mL, and its sensitivity and specificity were 76% and 96%, respectively. The cut-off value for IL-8 was 66.0 pg/mL, and its sensitivity and specificity were 71% and 82%, respectively. CONCLUSION: The cord blood levels of both IL-6 and IL-8 were significantly higher in the CLD group, indicating that both IL-6 and IL-8 are useful predictors of onset of CLD.

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.

An induced pluripotent stem cell-mediated and integration-free factor VIII expression system.

Human artificial chromosome (HAC) has several advantages as a gene therapy vector, including stable episomal maintenance and the ability to carry large gene inserts. Induced pluripotent stem (iPS) cells also have a great potential for gene therapy, which can be generated from an individual's own tissues and contribute to any tissues when reintroduced. A Sendai virus (SeV) vector with reprogramming factors is a powerful tool for generating iPS cells because of the high infection efficiency without the risk of integration into host chromosomes. In this study, we developed an iPS cell-mediated and integration-free coagulation factor VIII (FVIII) expression system using non-integrating SeV- and HAC-vectors. Multiple human FVIII genes, which were under the control of the megakaryocyte-specific platelet factor-4 (PF4) promoter for development of a treatment for hemophilia A, were inserted into a HAC vector (PF4-FVIII-HAC). The PF4-FVIII-HAC was introduced into SeV vector-mediated iPS cells derived from a mouse model of hemophilia A. After in vitro differentiation of iPS cells with the PF4-FVIII-HAC into megakaryocytes/platelets, the PF4-FVIII-HAC resulted in expression of FVIII. This study has developed the iPS cell-mediated PF4-driven FVIII expression system using two non-integrating vectors; therefore, this system may be a promising tool for safer gene- and cell-therapy of hemophilia A.

Integration-free and stable expression of FVIII using a human artificial chromosome.

Human artificial chromosome (HAC) has several advantages as a gene therapy vector, including stable episomal maintenance that avoids insertional mutations and the ability to carry large gene inserts. To examine the copy number effect on the gene expression levels and its stability for a long-term culture for a future application in gene therapy, we constructed a HAC vector carrying the human factor VIII (FVIII) complementary DNA, FVIII-HAC in Chinese hamster ovary (CHO) cells. One and more copies of FVIII gene on the HAC were expressed in the copy-number-dependent manner in the CHO cells. The HAC with 16 copies of FVIII, FVIII (16)-HAC, was transferred from CHO hybrids into a human immortalized mesenchymal stem cell using microcell-mediated chromosome transfer. The expression levels of HAC-derived FVIII transgene products were compared with transfected FVIII plasmids. The former showed expression levels consistent with those of the original clones, even after 50 population doublings, whereas the latter showed a remarkable decrease in expression despite unvarying DNA content, indicating that the gene on the HAC is resistant to gene silencing. These results suggest that the HAC-mediated therapeutic gene-expression system may be a powerful tool for stable expression of transgenes, and possibly for industrial production of gene products.

Complete genetic correction of ips cells from Duchenne muscular dystrophy.

Human artificial chromosome (HAC) has several advantages as a gene therapy vector, including stable episomal maintenance that avoids insertional mutations and the ability to carry large gene inserts including the regulatory elements. Induced pluripotent stem (iPS) cells have great potential for gene therapy, as such cells can be generated from the individual's own tissues, and when reintroduced can contribute to the specialized function of any tissue. As a proof of concept, we show herein the complete correction of a genetic deficiency in iPS cells derived from Duchenne muscular dystrophy (DMD) model (mdx) mice and a human DMD patient using a HAC with a complete genomic dystrophin sequence (DYS-HAC). Deletion or mutation of dystrophin in iPS cells was corrected by transferring the DYS-HAC via microcell-mediated chromosome transfer (MMCT). DMD patient- and mdx-specific iPS cells with the DYS-HAC gave rise to differentiation of three germ layers in the teratoma, and human dystrophin expression was detected in muscle-like tissues. Furthermore, chimeric mice from mdx-iPS (DYS-HAC) cells were produced and DYS-HAC was detected in all tissues examined, with tissue-specific expression of dystrophin. Therefore, the combination of patient-specific iPS cells and HAC-containing defective genes represents a powerful tool for gene and cell therapies.

Withdrawal symptom after discontinuation of transdermal fentanyl at a daily dose of 0.6 mg.

Neurophysiologic disorders developed in three patients after discontinuation of transdermal fentanyl (TDF) at a daily dose of 0.6 mg (2.5 mg per a patch), although direct removal of a 2.5 mg patch is permitted by the manufacturer as the formulation has the lowest fentanyl content among all the commercially available patch formulations. These observations indicate that the discontinuation of TDF carries a risk for developing withdrawal symptoms even when using a 2.5 mg patch. To avoid such adverse events, we considered the necessity of gradual reduction in the daily fentanyl requirements. For this purpose, we covered part of the application surface of the patch with an insulating tape, and then increased the covered area in a stepwise manner. There were no apparent withdrawal signs during the procedure described above.