Off-Label Use of Drugs and Adverse Drug Reactions in Pediatric Units: A Prospective, Multicenter Study.

BACKGROUND: Given the growing use of off-label in pediatric practice, there is a growing interest on pharmacovigilance programs monitoring the occurrence of adverse drug reactions related to off-label drug prescription in childhood. PATIENTS AND METHODS: The results of a one-year program of pharmacovigilance issued in the Sicilian Region, Italy, are herein presented. The study involved 6 pediatric and neonatal centres and prospectively reviewed the prescriptions of 5,060 patients, who were stratified for age (newborn, infant, children, adolescents). RESULTS: A total of 14,916 prescriptions were issued for 5,060 patients. Among them, 454 patients [8.97%] received at least one off-label drug. Among the off-label treated patients, 255 [56.2%] were newborns. Anti-infective drugs were the most frequent off-label used drugs, followed by drugs for alimentary tract and metabolism and drugs for blood or blood forming organs. Ninety adverse drug reactions were recorded [1.78% of the total patients]. They occurred after an off-label prescription in 33 out of 90 [36.7%], while those occurring after an on-label prescription were 57 [63.3%]. Patients treated with an off-label drug had a significantly higher risk of adverse drug reactions [7.3% vs. 1.2%; p <0.01]. CONCLUSION: The present study indicates that children admitted to neonatal intensive care units are likely to receive an off-label medication; children who receive an off-label medication are usually more likely to be treated with more medication than the others; adverse drug reactions occur in patients admitted in neonatal intensive care and pediatrics are units are more frequently with off-label than with on-label drugs.

Visfatin: New marker of oxidative stress in preterm newborns.

BACKGROUND: Oxidative stress is involved in several neonatal conditions characterized by an upregulation in the production of oxidative or nitrative free radicals and a concomitant decrease in the availability of antioxidant species. Oxygen, which is obviously vital to survival, can be highly damaging to neonatal tissue which is known to be poorly equipped to neutralize toxic derivatives. Thus, exposure of the newborn infant to high oxygen concentrations during resuscitation at birth increases oxidative damage. Visfatin is an adipocytokine involved in oxidative stress and an important mediator of inflammation that induces dose-dependent production of both pro-inflammatory and anti-inflammatory cytokines. To our knowledge, the diagnostic value of visfatin as a marker of oxidative stress in preterm newborns has not been investigated. OBJECTIVE: The aim of this study was to evaluate visfatin levels in preterm neonates resuscitated with different concentrations of oxygen in the delivery room. PATIENTS: Fifty-two preterm newborns with gestational age less than 32 weeks, resuscitated randomly with different oxygen concentrations (40%, 60%, or 100%) were enrolled at the University Hospital of Messina, over a 12-month period to evaluate serum visfatin levels at T0 (within 1 h after birth), T24 h, T72 h, and T168 h of life. RESULTS: At T72 h and T168 h, higher serum visfatin values in the high-oxygen group compared to the low- and mild-oxygen subjects (P=0.002 and P<0.001, respectively) were noted. CONCLUSION: The results of this study suggest that visfatin could be a new marker of oxidative stress in preterm newborns.

Sterol Regulatory Element Binding Transcription Factor-1 Gene Variation and Medication Load Influence White Matter Structure in Schizophrenia.

BACKGROUND: Diffusion tensor imaging (DTI) studies have shown a widespread disruption of white matter (WM) microstructure in schizophrenia. Furthermore, higher fractional anisotropy (FA) has been consistently correlated with the severity of psychotic symptoms. Antipsychotic drugs (APDs) affect lipid homeostasis. Gene polymorphisms in sterol regulatory element binding transcription factor (SREBF)-1 and SREBF-2 have been associated with schizophrenia. METHODS: In a sample of 65 patients affected by chronic schizophrenia, we investigated the effect of ongoing APD medication, SREBF-1 rs11868035 polymorphism and SREBF-2 rs1052717 polymorphism on the WM microstructure, using tract-based spatial statistics with threshold-free cluster enhancement. RESULTS: We reported increased FA associated with the risk rs11868035 G/G genotype in several WM tracts, mainly located in the left hemisphere, and opposite effects of the APD medication load, with reduced FA and generally increased diffusivity. These opposite effects overlapped in the forceps minor, cingulum, uncinate fasciculus, the superior and inferior longitudinal fasciculi, the corticospinal tract, inferior fronto-occipital fasciculus and the anterior thalamic radiation. CONCLUSION: We suggest that changes of WM structure could be an as yet poorly explored biomarker of the effects of APDs, to be further investigated in prospective studies correlating long-term clinical effects with changes of DTI measures in specific WM tracts contributing to the functional integrity of the brain. © 2015 S. Karger AG, Basel.

Noninvasive ventilation strategies for early treatment of RDS in preterm infants: an RCT.

BACKGROUND AND OBJECTIVES: There is evidence that new methods of noninvasive ventilation (NIV) support have significantly changed respiratory distress syndrome (RDS) management in preterm infants. Further perspectives for neonatologists involve the assessment of different NIV strategies in terms of availability, effectiveness, and failure. This study evaluates the efficacy of 2 different NIV strategies for RDS treatment in very low birth weight (VLBW) infants: nasal synchronized intermittent positive pressure ventilation (NSIPPV), which is a modality of conventional ventilation with intermittent peak inspiratory pressure, and bilevel continuous positive airway pressure (BiPAP), not synchronized, with 2 alternate levels of continuous positive airway pressure. METHODS: We conducted a 2-center randomized control study in 124 VLBW infants (<1500 g and <32 weeks of gestational age) with RDS who received NIV support (NSIPPV, n = 62; BiPAP, n = 62) within 2 hours of birth. We evaluated the performance of NIV strategies by selected primary outcomes (failure rate and duration of ventilation) and secondary outcomes. RESULTS: The number of failures and duration of ventilation support did not differ between NSIPPV and BiPAP strategies (P > .05 for both). Moreover, no differences between groups were found regarding secondary outcomes (P > .05 for all). CONCLUSIONS: The present data show no statistically significant differences between NSIPPV and BiPAP strategies in terms of duration of ventilation and failures, suggesting that both NIV techniques are effective in the early treatment of RDS in VLBW infants. Further randomized investigations on wider populations are needed to evaluate the effect of NIV techniques on long-term outcomes.

A new formula for premature infants: effects on growth and nutritional status.

OBJECTIVE: Nutritional management influences immediate survival as well as subsequent growth and development of low birth weight and very low birth weight infants. Preterm infant formula (PTF) is used when there is an inadequate supply of mother's milk or when the mother is unable to breastfeed and donor breast milk is unavailable. The purpose of this prospective multicenter study was to evaluate short-term effects on nutritional status (auxological and biochemical parameters) in a population of premature infants who received a preterm infant formula. METHODS: Ninety-seven preterm infants with a birth weight between 500 g and 2000 g and a gestational age of 25-34 weeks postmenstrual age were randomly assigned to received a new preterm infant formula (Nutribèn Pre), and their nutritional status were compared to 75 fortified human milk (FHM) fed infants. RESULTS: No significant differences were observed between FHM and Nutribèn Pre fed infants in terms of growth, feeding tolerance and biochemical profiles. CONCLUSION: Nutribèn Pre is a valid, effective and safe alternative for the nutrition of preterm infants.

Oxidative stress-mediated aging during the fetal and perinatal periods.

Oxidative stress is worldwide recognized as a fundamental component of the aging, a process that begins before birth. There is a critical balance between free radical generation and antioxidant defenses. Oxidative stress is caused by an imbalance between the production of free radicals and the ability of antioxidant system to detoxify them. Oxidative stress can occur early in pregnancy and continue in the postnatal period; this damage is implicated in the pathophysiology of pregnancy-related disorders, including recurrent pregnancy loss, preeclampsia and preterm premature rupture of membranes. Moreover, diseases of the neonatal period such as bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and periventricular leukomalacia are related to free radical damage. The specific contribution of oxidative stress to the pathogenesis and progression of these neonatal diseases is only partially understood. This review summarizes what is known about the role of oxidative stress in pregnancy and in the pathogenesis of common disorders of the newborn, as a component of the early aging process.

Melatonin and atopy: role in atopic dermatitis and asthma.

Melatonin may have important immunostimulatory actions in allergic diseases, in addition to its well-known antioxidant and cytoprotective effects in several inflammatory conditions. The activation of the immune system leads to free radical production associated with decreased melatonin levels and depressed antioxidant enzyme activities in several inflammatory diseases. Many skin disorders, including atopic dermatitis, are accompanied by infiltration and activation of mast cells, which release vasoactive and proinflammatory mediators. Experimental data suggest that melatonin inhibits development of atopic eczema and reduces serum total IgE and IL-4. Allergic asthma is a condition characterized by bronchial hyperresponsiveness and the presence of IgE antibodies in response to inhaled allergens; often there is also enhanced total serum IgE levels. Melatonin regulates smooth muscle tone and influences the immune response. Melatonin may, however, act as a pro-inflammatory agent in asthma leading to bronchial constriction. The safety of melatonin as a sleep-inducing agent has been confirmed in asthmatic subjects, but its routine use is not recommended in bronchial asthma. This review summarizes what is known about the role of melatonin as an immunomodulatory agent in asthma and atopic eczema.

Neonatal liver abscesses associated with candidemia: three cases and review of literature.

BACKGROUND: Our aim was to identify risk factors for the development of neonatal Candida liver abscess and to find useful information to better manage this potentially fatal complication. METHODS: A computerized search was conducted using PubMed. Overall, three articles describing the history of seven infants were finally considered. The characteristics of these seven cases were analyzed together with those of three new cases that we treated in the recent past. RESULTS: All the neonates were premature. Previous antibiotic use was reported in all the cases, umbilical venous catheterization in 9/10 and total parenteral nutrition in 8/10. Candida albicans was isolated in 9/10. All the patients presented with aspecific signs of sepsis. Liver abscesses were described as "microabscesses" or "miliary abscesses" in three cases, as solitary lesion in two cases. In one case two lesions and in one four lesions were reported. Three infants died. CONCLUSIONS: Liver ultrasonography should be performed in all the neonates with signs of sepsis, especially in the presence of candidemia and/or hepatomegaly and/or significant change in liver enzymes. Umbilical venous catheter should be removed, and peripheral IV access should be used until there is documented clearance from the blood with three or more negative blood cultures.

An extra mouth in a newborn: a unique case of facial duplication.

An accessory mouth is a very rare condition, with approximately 15 cases reported in the literature to date. We describe another unique case and discuss its possible embryopathogenesis.

Protective role of melatonin in neonatal diseases.

Oxidative stress contributes to the severity of several newborn conditions to the extent that Saugstad coined the phrase "oxygen radical diseases of neonatology." In order to counteract free radicals damage many strategies to augment antioxidant status in ill-term and preterm infants have been proposed and several medications have been experimented with mixed results. Several studies have tested the efficacy of melatonin to counteract oxidative damage in diseases of newborns such as chronic lung disease, perinatal brain injury, necrotizing enterocolitis, and retinopathy of prematurity, giving promising results. The peculiar perinatal susceptibility to oxidative stress indicates that prophylactic use of antioxidants as melatonin could help to prevent or at least reduce oxidative stress related diseases in newborns. However, more studies are needed to confirm these beneficial effects.

Human milk feeding prevents retinopathy of prematurity (ROP) in preterm VLBW neonates.

BACKGROUND: Retinopathy of prematurity (ROP) is a multifactorial disease, but little is known about its relationships with neonatal nutritional policies. Human, maternal milk is the best possible nutritional option for all premature infants, including those at high risk for severe complications of prematurity, such as ROP. OBJECTIVE: This is a secondary analysis of data collected during two multicenter RCTs performed consecutively (years 2004 through 2008) by a network of eleven tertiary NICUs in Italy. The two trials aimed at assessing effectiveness of fluconazole prophylaxis (Manzoni et al., N Engl J Med 2007 Jun 14;356(24):2483-95), and of bovine lactoferrin supplementation (Manzoni et al., JAMA 2009 Oct 7;302(13):1421-8), in prevention of invasive fungal infection, and of late-onset sepsis in VLBW infants, respectively. We tested the hypothesis that exclusive feeding with fresh maternal milk may prevent ROP of any stage - as defined by the ETROP study - in VLBW neonates, compared to formula feeding. METHODS: We analyzed the database from both trials. Systematic screening for detection of ROP was part of the protocol of both studies. The definition of threshold ROP was as defined by the ETROP study. Univariate analysis was performed to look for significant associations between ROP and several possible associated factors, and among them, the type of milk feeding (maternal milk or formula for preterms). When an association was indicated by p < 0.05, multiple logistic regression was used to determine the factors significantly associated with ROP. RESULTS: In both trials combined, 314 infants received exclusively human maternal milk (group A), and 184 a preterm formula because their mothers were not expected to breastfeed. The clinical, demographical and management characteristics of the neonates did not differ between the two groups, particularly related to the presence of the known risk factors for ROP. Overall, ROP incidence (any stage) was significantly lower in infants fed maternal milk (11 of 314; 3.5%) as compared to formula-fed neonates (29 of 184; 15.8%) (RR 0.14; 95% CI 0.12-0.62; p = 0.004). The same occurred for threshold ROP (1.3% vs. 12.3%, respectively; RR 0.19; 95% CI 0.05-0.69; p = 0.009). At multivariate logistic regression controlling for potentially confounding factors that were significantly associated to ROP (any stage) at univariate analysis (birth weight, gestational age, days on supplemental oxygen, systemic fungal infection, outborn, hyperglycaemia), type of milk feeding retained significance, human maternal milk being protective with p = 0.01. CONCLUSIONS: Exclusive human, maternal milk feeding since birth may prevent ROP of any stage in VLBW infants in the NICU.

N-SIPPV versus bi-level N-CPAP for early treatment of respiratory distress syndrome in preterm infants.

OBJECTIVE: Non-invasive ventilation (NIV) for RDS in extremely/very low birth-weight infants represents the new challenge for neonatologists. In this regard, data comparing the effectiveness of Bi-Level-NCPAP (BiPAP) versus nasal synchronized intermittent positive pressure ventilation (NSIPPV) as primary mode of treatment for RDS are lacking. STUDY DESIGN: We conducted a retrospective study from December 2007 to December 2010 in seventy-eight infants, who received NIV (N-SIPPV: 33; BiPAP: 45). The primary outcomes were the length and failure of NIV. Secondary outcomes were adverse short-long term pulmonary outcomes, multiple doses of surfactant and others. RESULTS: There were no significant differences (p > 0.05) between the two different NIV modes. CONCLUSION: The present findings suggest that N-SIPPV and BiPAP gives similar results in the RDS treatment. We did not find a benefit of one over the other ventilation mode and both could be constitute a valid option to conventional mechanical ventilation. The theoretical benefits of these two different methods of NIV are tidal volume enhancement, improvements of the functional residual capacity and of the mean airway pressure and reducing apnea episodes. Further randomized studies to assess the advantages and the efficacy of different methods of NIV for the treatment of the RDS are needed.

High endogenous melatonin levels in critically ill children: a pilot study.

OBJECTIVE: To evaluate the serum melatonin levels in critically ill pediatric patients and to test the effect of light on the melatonin's circadian rhythm. Data on melatonin secretion in critically ill pediatric subjects are lacking. STUDY DESIGN: We investigated the serum melatonin levels of 16 sedated and mechanically ventilated patients in a pediatric intensive care unit. Children (mean age, 5.1 ± 3.1 years) were randomly assigned to a dark-exposed or to a light-exposed group to evaluate the effects of light on serum melatonin concentrations. Blood samples for serum melatonin analysis were collected at 10 p.m., 1 a.m., 3 a.m., 5 a.m., 8 a.m., and 12 p.m. RESULTS: The melatonin circadian rhythm was severely disrupted in critically ill children; light exposure lowered serum melatonin even in a context of highly altered circadian cycle; melatonin peaks were greater for healthy age-matched children. CONCLUSION: The high melatonin levels in the critically ill children may be a response to counteract the elevated oxidative stress associated with serious diseases. Whether these elevated melatonin levels confer any beneficial effects in pediatric critically ill patients remains unknown.

Lithium and GSK3-ß promoter gene variants influence white matter microstructure in bipolar disorder.

Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-ß (GSK3-ß). The less active GSK3-ß promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-ß gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-ß promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-ß rs334558*C gene-promoter variants, and the long-term administration of the GSK3-ß inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-ß inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.

Oxidative stress and persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide and different oxygen concentrations.

OBJECTIVES: The aim of this study was to determine the effects of inhaled NO with different oxygen concentrations on the inflammatory cascade in newborns with hypoxic respiratory failure secondary to persistent pulmonary hypertension. METHODS: 60 newborns received iNO and 30 of them received an initial oxygen concentration of 45% (group 1), while the other 30 newborns received an initial oxygen concentration of 80% (group 2). The levels of inflammatory cytokines (IL-6, IL-8, TNF-α) were measured. The clinical outcome was also recorded. RESULTS: The findings show that interleukin concentrations (IL-6, IL-8, TNF-α) were significantly decreased between 0 and 72 hours (p < 0.01) in the newborns exposed to initial oxygen concentration of 45% and significantly increased in the other group. CONCLUSIONS: When inhaled, NO was co-administered with concentration of O(2) <45%, anti-inflammatory responses occurred, in accord with evidence in the published literature. The benefits of iNO on the clinical outcome in the current study demonstrate that inhaled NO in both groups was associated with improved short-term oxygenation.

Acetaldehyde oral self-administration: evidence from the operant-conflict paradigm.

BACKGROUND: Acetaldehyde (ACD), ethanol's first metabolite, has been reported to interact with the dopaminergic reward system, and with the neural circuits involved in stress response. Rats self-administer ACD directly into cerebral ventricles, and multiple intracerebroventricular infusions of ACD produce conditioned place preference. Self-administration has been largely employed to assess the reinforcing and addictive properties of most drugs of abuse. In particular, operant conditioning is a valid model to investigate drug-seeking and drug-taking behavior in rats. METHODS: This study was aimed at the evaluation of (i) the motivational properties of oral ACD in the induction and maintenance of an operant-drinking behavior; (ii) ACD effect in a conflict situation employing the punishment-based Geller-Seifter procedure; and (iii) the onset of a relapse drinking behavior, following ACD deprivation. The lever-pressing procedure in a sound-attenuated operant-conditioning chamber was scheduled into 3 different periods: (i) training-rewarded responses with a fixed ratio 1; (ii) conflict-rewarded responses periodically associated with a 0.2 mA foot-shock; and (iii) relapse-rewarded lever presses following 1-week ACD abstinence. RESULTS: Our results show that oral self-administrated ACD induced: a higher rate of punished responses in Geller-Seifter procedures; and the establishment of a relapse behavior following ACD deprivation. CONCLUSIONS: In conclusion, our results indicate that ACD is able to induce an operant-drinking behavior, which is also maintained besides the conflict procedure and enhanced by the deprivation effect, supporting the hypothesis that ACD itself possesses motivational properties, such as alcohol and other substances of abuse.

Pain in neonatal intensive care: role of melatonin as an analgesic antioxidant.

Endotracheal intubation is a common painful procedure in newborn care. Neonates are more sensitive to pain than older infants, children, and adults, and this hypersensitivity is further exacerbated in preterm neonates. The aim of this study was to evaluate the analgesic activity of melatonin during endotracheal intubation of the newborn by using the Neonatal Infant Pain Scale (NIPS) and Premature Infant Pain Profile (PIPP) score. Secondary outcome was an evaluation of melatonin as inflammatory responses. This was performed by measuring the levels of pro- and anti-inflammatory cytokines implicated in the pain. Sixty preterm infants were enrolled in the study and were randomly divided into two groups: 30 infants treated with melatonin plus common sedation and analgesia recommended by Italian Society of Neonatology (group 1) and 30 infants treated with only common sedation and analgesia. The sedative and analgesic drugs included atropine, fentanyl, and vecuronium. The reduction in pain score (NIPS) was similar in both groups at an early phase, while it (PIPP score) was lower in melatonin-treated group infants than the other newborns at a late phase, during intubation and mechanical ventilation. The differences were statistically significant at 12, 24, 48, and 72 hr (P < 0.001). Pro-inflammatory and anti-inflammatory cytokines (IL-6, IL-8, IL-10 and IL-12) were higher in the common sedation and analgesia group than in melatonin-treated infants at 24, 48, 72 hr and 7 days (P < 0.001). This study suggests the use of melatonin as an adjunct analgesic therapy during procedural pain, especially when an inflammatory component is involved.

Stress response and procedural pain in the preterm newborn: the role of pharmacological and non-pharmacological treatments.

UNLABELLED: Repeated invasive procedures occur routinely in neonates who require intensive care, causing pain at a time when it is developmentally unexpected. Multiple lines of evidence suggest that repeated and prolonged pain exposure alters their subsequent pain processing, long-term development, and behaviour. Primary outcome of this study was to evaluate the reduction of procedural pain induced by "heel-lances" in preterm newborns with three different treatment [administration of fentanyl (FE, 1-2 µg/kg), facilitated tucking (FT), sensorial saturation (SS)]. Secondary outcome was the measurement of the levels of cytokines as markers of stress correlated to pain. A prospective randomized controlled trial (RCT) comparing three different pharmacological or non-pharmacological treatments was performed involving 150 preterm newborn (gestational age 27-32 weeks). No other analgesic treatment was performed during the study. CRIES score was used to evaluate the procedural pain. The results showed that the reduction in the pain score was greater in FE and SS groups than FS group. The differences were statistically significant (p < 0.01). The levels of IL-6, IL-8, and TNF-α were higher in the FT individuals than in the FE or SS-treated infants at 1 day (p < 0.01), at 3 days (p < 0.01), and at 7 days (p < 0.01) of life. CONCLUSIONS: The findings of this study suggest that FE and SS provide a superior analgesia in preterm neonates during procedural pain. In particular, sensorial saturation seems to be an important non-pharmacological alternative treatment to prevent and reduce the procedural pain in preterm newborn.

Potential utility of melatonin as an antioxidant during pregnancy and in the perinatal period.

Reactive oxygen species (ROS) play a critical role in the pathogenesis of various diseases during pregnancy and the perinatal period. Newborns are more prone to oxidative stress than individuals later in life. During pregnancy, increased oxygen demand augments the rate of production of ROS and women, even during normal pregnancies, experience elevated oxidative stress compared with non-pregnant women. ROS generation is also increased in the placenta during preeclampsia. Melatonin is a highly effective direct free-radical scavenger, indirect antioxidant, and cytoprotective agent in human pregnancy and it appears to be essential for successful pregnancy. This suggests a role for melatonin in human reproduction and in neonatal pathologies (asphyxia, respiratory distress syndrome, sepsis, etc.). This review summarizes current knowledge concerning the role for melatonin in human pregnancy and in the newborn. Numerous studies agree that short-term melatonin therapy is highly effective in reducing complications during pregnancy and in the neonatal period. No significant toxicity or treatment-related side effects with long-term melatonin therapy in children and adults have been reported. Treatment with melatonin might result in a wide range of health benefits, including improved quality of life and reduced healthcare costs.