Agents In Preterm Infants Research Articles

Human Colostrum and Derived Extracellular Vesicles Prevent Infection by Human Rotavirus and Respiratory Syncytial Virus in Vitro.

It is known that breastfeeding protects the infant from enteric and respiratory infections; however, the antiviral properties of human milk against enteric and respiratory viruses are largely unexplored. To explore the antiviral activity of human preterm colostrum against rotavirus and respiratory syncytial virus and to assess whether the derived extracellular vesicle contribute to this activity. We used a cross-sectional, prospective two-group non-experimental design. Colostra were collected from mothers of preterm newborns (N = 10) and extracellular vesicles were purified and characterized. The antiviral activity of colostra and derived extracellular vesicles were tested in vitro against rotavirus and respiratory syncytial virus and the step of viral replication inhibited by extracellular vesicles was investigated. Each sample of colostrum and colostrum-derived extracellular vesicles had significant antiviral activity with a wide interpersonal variability. Mechanism of action studies demonstrated that extracellular vesicles acted by interfering with the early steps of the viral replicative cycle. We demonstrated the intrinsic antiviral activity of human colostrum against rotavirus and respiratory syncytial virus and we showed that extracellular vesicles substantially contribute to the overall protective effect. Our results contribute to unravelling novel mechanisms underlying the functional role of human milk as a protective and therapeutic agent in preterm infants.

Commentary: Antivascular endothelial growth factor and retinopathy of prematurity.

Commentary: Antivascular endothelial growth factor and retinopathy of prematurity.

Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity.

Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity.

Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity.

Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis in fetal life. Recently, researchers have attempted to use anti-VEGF agents for the treatment of retinopathy of prematurity (ROP), a vasoproliferative disorder. There is currently uncertainty regarding the safety and efficacy of these agents in preterm infants with ROP. To evaluate the efficacy and safety of anti-VEGF drugs when used either as monotherapy, i.e. without concomitant cryotherapy or laser therapy or in combination with planned cryo/laser therapy in preterm infants with type 1 ROP (defined as zone I any stage with plus disease, zone I stage 3 with or without plus disease or zone II stage 2 or 3 with plus disease). We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 1), MEDLINE (1966 to January 1, 2016), EMBASE (1980 to January 1, 2016), CINAHL (1982 to January 1, 2016), conference proceedings, and previous reviews. Randomised or quasi-randomised controlled trials that evaluated the efficacy and safety of administration, or both, of anti-VEGF agents compared with conventional therapy in premature infants with ROP. We used standard Cochrane and Cochrane Neonatal methods for data collection and analysis. Three trials, in which 239 infants participated, fulfilled the inclusion criteria. Two trials compared intravitreal bevacizumab with conventional laser therapy (monotherapy) while the third compared intravitreal pegaptanib plus laser treatment with laser and cryotherapy (combination therapy) in infants with type 1 ROP.Of the two studies that evaluated intravitreal bevacizumab, one randomized infants while the other randomized eyes of the infants to the intervention and control groups. The former did not report any difference in the incidence of complete or partial retinal detachment between the groups (143 infants; RR 1.04, 95% CI 0.21 to 5.13; RD 0.00, 95% CI -0.06 to 0.07; very low quality evidence) but reported a significant reduction in the risk of refractive errors - very high myopia - at 30 months of age (211 eyes; RR 0.06, 95% CI 0.02 to 0.20; RD -0.40, 95% CI -0.50 to -0.30; low quality evidence) and recurrence of ROP by 54 weeks' postmenstrual age (143 infants; RR 0.22, 95% CI 0.08 to 0.62; RD -0.20, 95% CI -0.31 to -0.09; moderate quality evidence) in the bevacizumab group. The study found no difference in the risk of mortality before discharge from the hospital (150 infants; RR 1.50; 95% CI 0.26 to 8.75; RD 0.01; 95% CI -0.04 to 0.07; low quality evidence), mortality at 30 months of age (150 infants; RR 0.86, 95% CI 0.30 to 2.45; RD -0.01; 95% CI -0.10 to 0.08; low quality evidence), corneal opacity requiring corneal transplant (286 eyes; RR 0.34, 95% CI 0.01 to 8.26; RD -0.01; 95% CI -0.03 to 0.02; very low quality evidence), or lens opacity requiring cataract removal (286 eyes; RR 0.15, 95% CI 0.01 to 2.79; RD -0.02; 95% CI -0.05 to 0.01; very low quality evidence). The second trial that randomized eyes of the infants did not find any difference in the risk of complete retinal detachment between the eyes randomized to bevacizumab and those that were randomized to laser therapy (13 eyes; RR 0.33, 95% CI 0.01 to 7.50; RD -0.08, 95% CI -0.27 to 0.11).When used in combination with laser therapy, intravitreal pegaptanib was found to reduce the risk of retinal detachment when compared to laser/cryotherapy alone (152 eyes; RR 0.26, 95% CI 0.12 to 0.55; RD -0.29, 95% CI -0.42 to -0.16; low quality evidence). The incidence of recurrence of ROP by 55 weeks' postmenstrual age was also lower in the pegaptanib + laser therapy group (76 infants; RR 0.29, 95% CI 0.12 to 0.7; RD -0.35, 95% CI -0.55 to -0.16; low quality evidence). There was no difference in the risk of perioperative retinal haemorrhages between the two groups (152 eyes; RR 0.62, 95% CI 0.24 to 1.56; RD -0.05, 95% CI -0.16 to 0.05; very low quality evidence). The risk of delayed systemic adverse effects with either of the drugs is, however, not known. Intravitreal bevacizumab reduces the risk of refractive errors during childhood when used as monotherapy while intravitreal pegaptanib reduces the risk of retinal detachment when used in conjunction with laser therapy in infants with type 1 ROP. Quality of evidence was, however, low for both the outcomes because of the risk of detection and other biases. Effect on other critical outcomes and, more importantly, the long-term systemic adverse effects of the drugs are not known. The insufficient data precludes strong conclusions favouring routine use of intravitreal anti-VEGF agents in preterm infants with type 1 ROP. Further studies are needed to evaluate the effect of anti-VEGF agents on structural and functional outcomes in childhood and delayed systemic adverse effects such as myocardial dysfunction and adverse neurodevelopmental outcomes.

Brain Injury and Development in Preterm Infants Exposed to Fentanyl.

Fentanyl is commonly used in preterm infants. Relatively little is known regarding the neurodevelopmental outcomes of preterm infants exposed to fentanyl. To investigate the association between cumulative fentanyl dose and brain injury and diameters in a cohort of preterm infants. Data on demographics, perinatal course, and neonatal course, including total fentanyl exposure prior to term equivalent age, were retrospectively evaluated for 103 infants born at ≤30 weeks gestational age (mean gestational age 26.9 ± 1.8 weeks) who underwent magnetic resonance imaging at term equivalent age. Magnetic resonance images were evaluated for brain injury and regional brain diameters. Developmental testing was conducted at term equivalent and 2 years of age. Seventy-eight infants (76%) received fentanyl (median cumulative dose 3 µg/kg, interquartile range 1-441 µg/kg). Cumulative fentanyl dose in the first week of life correlated with the incidence of cerebellar hemorrhage after correction for covariates (odds ratio 2.1, 95% confidence interval 1.1-4.1). Cumulative fentanyl dose before term equivalent age correlated with reductions in transverse cerebellar diameter after correction for covariates, including the presence of cerebellar hemorrhage (r = 0.461, P = 0.002). No correlation was detected between cumulative fentanyl dose and development at 2 years of age. Higher cumulative fentanyl dose in preterm infants correlated with a higher incidence of cerebellar injury and lower cerebellar diameter at term equivalent age. Our findings must be taken with caution, but emphasize the need for future prospective trials examining the risks and benefits of commonly used analgesic agents in preterm infants.

305 Dopamine Reduces White Matter Injury in Hypoxic-Ischaemia in the Preterm Lamb

BackgroundDopamine is frequently used as inotropic agent in preterm infants. Its cardiovascular actions, as well as effects on neurovascular interactions may be neuroprotective during hypoxic-ischaemic events. Using a preterm lamb...

Use of prokinetics in the preterm infant

Functional gastrointestinal dysmotility is a common condition that affects premature infants. Delay in achievement of full enteral nutrition results in dependence on prolonged parenteral nutrition, predisposing to adverse outcomes. Studies in recent years show apparently conflicting results regarding the use of prokinetic agents in preterm infants. This review aims to evaluate these studies to determine whether use of these agents in premature infants is beneficial and justified. Randomized controlled trials in recent years have been performed to investigate the effectiveness of erythromycin in the treatment of nonobstructive gastrointestinal dysmotility in preterm infants. Overall, neither low-dose regimes nor prophylactic trials have been shown to be useful. High-dose regimes used as rescue therapy of infants with established gastrointestinal dysmotility have consistently shown clinical benefit. Theoretical risks of prolonged antibiotic use, such as emergence of antibiotic resistance and abnormal intestinal microbiota, have not been fully evaluated. Judicious use of high-dose erythromycin in premature infants as rescue therapy is probably justifiable. Further research in this area is warranted to develop newer prokinetic agents which may improve the safety profile of therapy.

Neuroprotective effects of erythropoietin in preterm infants

The dramatic increase in survival of extremely premature infants has been associated with a growing population of individuals with neurodevelopmental disabilities. To date, clinical trials of neuroprotective agents in preterm infants have been limited, but new data suggest that erythropoietin might have important neuroprotective effects in these vulnerable infants.

Erythromycin for the prevention and treatment of feeding intolerance in preterm infants

Functional immaturity of gastrointestinal motility predisposes preterm infants to feeding intolerance. Erythromycin is a motilin agonist that exerts its prokinetic effect by stimulating propagative contractile activity in the interdigestive phase. To evaluate the efficacy of erythromycin in the prevention and treatment of feeding intolerance in preterm infants. Systematic literature search was performed according to the Cochrane Neonatal Collaborative Review Group search strategy. Randomized controlled trials of erythromycin in preterm infants to promote gastrointestinal motility were identified from the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), MEDLINE (1966 - December 2007), EMBASE (1980 - December 2007), CINAHL (1982 - December 2007), cross-references, abstracts, and journal hand searching. The initial selection criteria limited the review to studies using erythromycin at 3 - 12 mg/kg/day in preterm infants less than 36 weeks gestational age with feeding tolerance. However, a significant number of studies using erythromycin at a higher dose (> 12 mg/kg/day) or as prophylaxis for those at risk of feeding intolerance were identified. A post hoc decision was made to include these studies in the review. Studies were categorized into prevention and treatment studies, and data from each category were analyzed separately. Within each category, subgroup analyses were performed based on low (3 to 12mg/kg/day) and high doses (> 12mg/kg/day) of erythromycin. Primary outcome was days to full enteral feeding. Secondary outcomes included adverse effects associated with erythromycin, duration of total parenteral nutrition (TPN), weight gain, necrotizing enterocolitis (NEC), and length of hospital stay. Ten randomized controlled studies (three prevention and seven treatment studies) were included. Studies varied greatly in the definition of feeding intolerance and how outcomes were measured, analyzed and reported, so meta-analysis of most outcomes was impossible. It was observed, however, that the studies using erythromycin at higher treatment doses (40 to 50 mg/kg/day) or in infants > 32 weeks' GA reported more positive effects in improving feeding intolerance.Meta-analysis of high dose prevention studies showed no significant difference in NEC (typical RR 0.59, 95% CI 0.11, 3.01; typical RD -0.021, 95% CI -0.087, 0.045). Meta-analysis of high dose treatment studies showed no significant difference in septicemia (typical RR 0.83, 95% CI 0.47, 1.45; typical RD -0.04, 95% CI -0.17, 0.08). There is insufficient evidence to recommend the use of erythromycin in low or high doses for preterm infants with or at risk of feeding intolerance. Future research is needed to determine if there is a more precise dose range where erythromycin might be effective as a prokinetic agent in preterm infants > 32 weeks' GA.

Summary Proceedings From the Cardiology Group on Cardiovascular Instability in Preterm Infants

The appropriate determination of adequate tissue perfusion and the best approach to treatment of perceived abnormalities in blood pressure in the neonate remain controversial. There is no consensus regarding the actual definition of hypotension in the neonate or how best to raise perceived low blood pressure. In addition, there is no direct and prospectively collected information available on the result of treatment of a "low" blood pressure on neonatal morbidity and mortality. It also has not been clearly demonstrated that bringing systemic blood pressure to a "normal" range improve outcomes. However, it is widely accepted by clinicians that early and aggressive treatment of hypotension leads to improved neurologic outcome and survival in the neonate. Commonly used therapeutic maneuvers to correct systemic hypotension in the neonate include volume expansion, inotropic agents, and corticosteroids. Although there is a paucity of research on the cardiovascular response to these commonly used agents in neonates, among the commonly used inotropic drugs dopamine has been shown to be more effective than dobutamine in raising blood pressure in the neonate. The cardiology group focused on the use of inotropes, particularly dopamine and dobutamine, to treat very low birth weight infants with cardiac instability and neonatal postoperative cardiac patients. The cardiology group identified key issues that must be considered when designing studies of inotropic agents in preterm infants and proposed 2 clinical-trial designs: (1) a placebo-controlled trial with rescue for symptomatic infants; and (2) a targeted-blood pressure study. The first trial design would answer questions concerning efficacy of treatment with inotropic agents in this population. The second trial design would address concerns related to the lack of knowledge on normal blood pressure ranges in this population. The group identified specific design elements that would need to be addressed for the complicated trial design to study inotropic agents in neonates.

Gastroesophageal Reflux in the Preterm Neonate

After completing this article, readers should be able to: 1. Describe the epidemiology and pathophysiology of gastroesophageal reflux (GER) in preterm neonates. 2. Delineate the associations of GER with apnea, chronic lung disease, behavior, and growth of preterm infants. 3. Review the investigations used to evaluate GER in preterm infants. 4. Describe nonpharmacologic and pharmacologic therapies for GER. Gastroesophageal reflux (GER) is a normal physiologic event occurring across the age spectrum. It may contribute to a variety of disorders, including esophagitis, feeding problems, and airway disease in all age groups. (1) A large number of symptoms and signs have been purported to be caused by GER despite a lack of data showing a clear association between a specific symptom and GER. In preterm infants, empiric therapy often is administered using agents of unproven efficacy and safety to treat symptoms that likely are unrelated to GER. In a survey on management practices for GER in preterm infants, common treatment strategies included positioning (98%) and slopes (96%), histamine 2 (H 2) receptor antagonists (100%), feed thickeners (98%), antacids (96%), prokinetics (79%), proton pump inhibitors (PPIs) (65%), and dopamine receptor antagonists (53%). (2)(3) The safety, efficacy, and appropriate dosing recommendations for most medical therapies remain uncertain in neonates. In this review, we attempt to summarize the current literature regarding physiology, pathophysiology, and diagnostic and management strategies for GER pertinent to the neonate, with an emphasis on the preterm infant. GER describes the retrograde movement of stomach contents (air or feeding, liquid or semisolid, acid or alkaline, enzymes or bile salts) into the esophagus. GER disease (GERD) occurs when GER causes symptoms or signs such as pain, poor weight gain, esophagitis, hematemesis, and airway symptoms, including apnea, aspiration, recurrent pneumonia, chronic lung disease (CLD), or large airway inflammation. However, any of these symptoms or signs …

Erythromycin as a Prokinetic Agent in Preterm Infants

The macrolide antibiotic erythromycin is a prokinetic agent that stimulates gastrointestinal motility. The aim of the study was to determine the effect of erythromycin on the gastrointestinal motility of preterm infants. Erythromycin 10 mg/kg, 8 hourly or a placebo, was given orally for 7 days in a double-blind randomized, crossover study of 20 preterm infants with a median gestational age of 32 weeks (range, 26-34 weeks). Antral contractility was determined by using ultrasonography to measure the decrease in the gastric antral cross-sectional area after a feed. The whole gut transit time was assessed by timing the transit of carmine red through the gut. Antral contractility lasted for a shorter period of time during erythromycin treatment than during placebo treatment (mean [standard deviation], 31 minutes [9.9 minutes] vs. 70 minutes [13 minutes]; P < 0.01). Whole gut transit time was also shorter during erythromycin treatment (mean, 23.1 hours [12.9 hours] vs. 49.3 hours [29 hours]; P < 0.01). All infants tolerated the drug well. Oral erythromycin in food-intolerant preterm infants enhances both antral contractility and whole gut transit time.

Erythromycin as a Prokinetic Agent in Preterm Infants

ABSTRACTBackgroundThe macrolide antibiotic erythromycin is a prokinetic agent that stimulates gastrointestinal motility. The aim of the study was to determine the effect of erythromycin on the gastrointestinal motility of preterm infants.MethodsErythromycin 10 mg/kg, 8 hourly or a placebo, was given orally for 7 days in a double‐blind randomized, crossover study of 20 preterm infants with a median gestational age of 32 weeks (range, 26–34 weeks). Antral contractility was determined by using ultrasonography to measure the decrease in the gastric antral cross‐sectional area after a feed. The whole gut transit time was assessed by timing the transit of carmine red through the gut.ResultsAntral contractility lasted for a shorter period of time during erythromycin treatment than during placebo treatment (mean [standard deviation], 31 minutes [9.9 minutes] vs. 70 minutes [13 minutes];P &lt; 0.01). Whole gut transit time was also shorter during erythromycin treatment (mean, 23.1 hours [12.9 hours] vs. 49.3 hours [29 hours];P &lt; 0.01). All infants tolerated the drug well.ConclusionsOral erythromycin in food‐intolerant preterm infants enhances both antral contractility and whole gut transit time.

Clinical pharmacokinetics of antibacterial agents in pre-term infants

Antimicrobial agents are the most frequently used drugs in neonatal intensive care units because bacterial infections continue to be a major cause of morbidity and mortality in preterm infants admitted to these units. This extensive use of antibiotics underscores the necessity to perform pharmacokinetic and pharmacodynamic studies in this unique patient population which will lead to optimal therapy and minimize drug-related toxicity and cost of therapy. It is apparent that maturation of organ-system function and changes in body composition during gestation, and during the neonatal period, have a significant effect on the disposition of drugs. Previous or concomitant exposure to other drugs, hypoxaemia or the severity of the pathological status of the infant may further influence drug disposition. This review presents the information currently available on the clinical pharmacokinetics of antibacterial agents in the pre-term infant. The ontogeny of the disposition of each drug is reviewed, and the currently recommended dosage regimens are given. Possible alternative dosing regimens are provided which take into account developmental changes and their impact on drug disposition. It is emphasized that prospective evaluations are needed to validate these proposed alternative dosing regimens.

Nebulized sodium cromoglycate in preterm infants—protection against water challenge-induced bronchoconstriction

Nebulized water is an effective bronchoprovocative agent in asthmatic adults and children. The aim of this study was to assess the bronchoconstrictor effect of this agent in preterm infants studied at follow-up and if their response to it was altered by pre-treatment with nebulized sodium cromoglycate. Lung function, thoracic gas volume and airway resistance, was measured by whole body plethysmography and specific conductance (SGAW) calculated. Measurements were made before and after nebulized saline, nebulized water (first water challenge), nebulized sodium cromoglycate and again nebulized water (second water challenge). There was no significant change in SGAW following either normal saline or sodium cromoglycate. In nine infants SGAW deteriorated by more than 16% (twice the coefficient of variation of the measurement) after the first water challenge but only in one after the second water challenge (P < 0.01). We conclude that nebulized water is an effective bronchoconstrictor in preterm infants and that sodium cromoglycate can protect against this challenge.