Neonatal Drug Therapy Research Articles

Glomerular Filtration Rate Estimation Formulas for Pediatric and Neonatal Use.

Renal function assessment is of the utmost importance in predicting drug clearance and in ensuring safe and effective drug therapy in neonates. The challenges to making this prediction relate not only to the extreme vulnerability and rapid maturation of this pediatric subgroup but also to the choice of renal biomarker, covariates, and glomerular filtration rate (GFR) estimating formula. In order to avoid burdensome administration of exogenous markers and/or urine collection in vulnerable pediatric patients, estimation of GFR utilizing endogenous markers has become a useful tool in clinical practice. Several estimation methods have been developed over recent decades, exploiting various endogenous biomarkers (serum creatinine, cystatin C, blood urea nitrogen) and anthropometric measures (body length/height, weight, muscle mass). This article reviews pediatric GFR estimation methods with a focus on their suitability for use in the neonatal population.

Sharing Data to Accelerate Medicine Development and Improve Neonatal Care: Data Standards and Harmonized Definitions

Sharing Data to Accelerate Medicine Development and Improve Neonatal Care: Data Standards and Harmonized Definitions

The Use of Hemodynamic and Cerebral Monitoring to Study Pharmacodynamics in Neonates.

Drugs acting on the cardiovascular and central nervous system often display relatively fast clinical responses, which may differ in neonates compared to children and adults. Introduction of bedside monitoring tools might be of additional value in the pharmacodynamic (PD) assessment of such drugs in neonates. We aim to provide an overview of the frequently used monitoring tools to assess drug effects on the hemodynamic status as well as the cerebral circulation, oxygenation and cerebral metabolism in neonates. The use of blood pressure measurements, heart rate variability, functional echocardiography, nearinfrared spectroscopy and (amplitude-integrated) electroencephalography in neonates is discussed, as well as new parameters introduced by these tools. Based on the 'brain circulation model', the hemodynamic effects on the brain and their interplay are summarized. In this model, 3 processes (i.e. blood processes, vascular smooth muscle processes and tissue processes) and 3 mechanisms (i.e. autoregulation, blood flow metabolism coupling and cerebral oxygen balance) are distinguished, which all may be influenced by drug administration. Finally, propofol, sevoflurane, midazolam and inotropes are used as examples of which PD has been studied using the available hemodynamic and/or cerebral monitoring tools. The implementation of (non-)invasive monitoring tools to document hemodynamic and cerebral PD effects in neonates is of relevance both in a neonatal research and intensive clinical care setting. We highlight the need to integrate these tools in future PD research. Furthermore, besides short-term drug effects, long-term outcome of drug therapy in neonates also warrants further attention.

Pharmacokinetics and drug therapy in neonates

Pharmacokinetics and drug therapy in neonates

Neonatal drug therapy: The first frontier of therapeutics for children.

Knowledge about the safe and effective use of medicines in neonates has increased substantially but has resulted in few label changes. Drugs developed for use in adults are reshaped and tailored to specific neonatal indications. However, the use of drugs in neonates should not only mirror adult pharmacotherapy, but should be driven by their own specific needs. Therefore, building collaborative networks may assist to develop a newborn-driven research agenda addressing their clinical needs and diseases.

Antimicrobial drug utilization pattern in neonatal sepsis in a tertiary care hospital

Objective: The objective of this study was to determine antimicrobial drug use in newborns at a tertiary care neonatal intensive care unit, to identify educational/research priorities in neonatal drug therapy. Materials and Methods: This prospective observational study included 713 patients of neonatal sepsis over a period of 18 months. Data like name, age, sex, birth weight, gestational age, antibiotics used were recorded in the previously prepared case record form. Results: Number of patients admitted in early neonatal period was 467(65.5%) and number of patients admitted in late neonatal period was 246(34.5%). The mean age of all patients being admitted in NICU was 6.23 ± 5.86 days. The majority of neonates (92.56%) were prescribed 2 to 5 antibiotics and 29.59% of neonates were prescribed 2 antibiotics. Average number of antibiotics of all patients being admitted was 3.74 ± 1.38. Most frequently used antibiotics in decreasing frequency were: Amikacin (97.19%), ampicillin + sulbactam (60.17%), vancomycin (57.64%), ceftazidime (38.71%), cefotaxime (34.22%), ciprofloxacin (26.23%), piperacillin + tazobactam (19.07%). 73% drugs were given by generic name and 53.33% drugs were prescribed from the essential drug list. Mean length of stay in NICU of all patients being admitted was 7.59 ± 5.66 days. Conclusion: The present study provides valuable insight about the overall pattern of antimicrobial drug use profile in patients of neonatal sepsis of a tertiary care hospital. It is intended to be a step in broader evaluation of safety and efficacy of drug prescription in neonatal sepsis patients.

Recent advances in medicines for children and neonates

The European Society for Developmental, Perinatal and Paediatric Pharmacology held its 13th Biennial Congress in Oslo, Norway. The congress was attended by over 100 health professionals from all around the world. The focus of the congress was recent advances in drug therapy in neonates and children. Alongside invited speakers, there were a host of presentations by young investigators which consisted of oral and poster presentations.

Profound changes in drug metabolism enzymes and possible effects on drug therapy in neonates and children

Introduction: There are profound changes that take place in drug metabolism enzymes during fetal and postnatal development. These changes may significantly impact drug therapy in children.Areas covered: A combination of focused and comprehensive literature searches using PubMed and reference lists (from inception to 7 November 2009) is undertaken to identify reports on in vitro and in vivo development of drug metabolism enzymes as well disposition of selected drugs and their effect in children. The article provides an update on development of drug metabolism enzymes and their impact on drug substrate disposition and disease, which may aid to improve clinical practice and optimally design clinical trials in children.Expert opinion: Drug metabolism enzyme activity changes profoundly throughout the continuum of postnatal development and often results in different disposition pathways than in adults. Genetics and co-morbidity interact significantly with these developmental changes. Translation of existing knowledge into age-adjusted dosing guidelines and clinical trial design is highly needed for there to be an improvement in drug therapy in children.

Off-Label Use of Antiepileptic Drugs for the Treatment of Neonatal Seizures

Medically refractory neonatal seizures represent a major therapeutic challenge in neonatal intensive care units. Conventional antiepileptic drugs demonstrate limited efficacy. Previous studies documented a high frequency of off-label drug therapy in neonates. We sought to determine if pediatric neurologists are recommending treatment of neonatal seizures with newer agents, despite a lack of information about their safety or efficacy in this population. Surveys were distributed at the 2007 Annual Meeting of the Child Neurology Society. Responses from 55 pediatric neurologists were analyzed. Seventy-three percent (40/55) recommended treatment of neonatal seizures with one or both of levetiracetam and topiramate; 47% (26/55) recommended levetiracetam; and 55% (30/55) recommended topiramate. Despite an absence of data on neonatal pharmacokinetics of either drug, neurologists made different dosing recommendations for these two drugs (P = 0.003, chi-square test). Respondents considered both agents to be efficacious in the majority of cases; adverse effects were recognized more frequently with topiramate. These results highlight the urgent need for rigorous clinical trials to understand the risks and benefits of new drug therapies for neonatal seizures.

Patterns of Drug Utilization in a Neonatal Intensive Care Unit

The objective of this study was to determine drug use in newborns at an inborn tertiary care neonatal intensive care unit, serving a predominantly African American population, to identify educational/research priorities in neonatal drug therapy. Data on demographics and exposure rates to all drugs from 6839 neonates born between January 1997 and June 2004 were analyzed. Number of drugs used was correlated with race, gender, gestational age, birthweight, and survival status. The contribution of these factors to mean drug use was predicted by multivariate regression analysis. In this population of 80% African Americans, mean drug use was 3.6/infant, with the highest use in the 24- to 27-week gestational age group (11.7/infant). Ampicillin and cefotaxime had the highest exposure rates. Premature infants had high use of surfactant, pressor agents, and diuretics. Caucasians, males, gestational age<28 weeks, and birthweight<1000 g were the risk factors for higher drug exposure. Future research/education must emphasize these therapeutic areas with priority assigned to low-birthweight infants.

Patterns of drug utilization in a neonatal intensive care unit

Background/Aims Pharmacological agents are extensively used in neonatal intensive care settings but their utilization rates in neonates including premature infants is an area that has not been studied in great detail. This study determined the types, patterns and frequency of drug use in sick newborns to identify educational and research priorities in neonatal drug therapy. Methods Data that had been prospectively collected in 6860 neonates admitted to the neonatal intensive care unit (ICU) / progressive care nursery (PCN) at a maternity hospital between 1997 and 2003 were analyzed retrospectively. Results A total of 107 different drugs used in a predominantly African-American (~80%) population were studied. Mean length of ICU/PCN stay was 15±24 days, birthweight (BW) 2494±1002 grams and gestational age (GA) 35±5 weeks. Drug exposure rates (fig 1) were highest for antibiotics. The highest average drug usage was in the 24–27 week GA group at 12.4/infant followed by the <23 week GA category at 10.5/infant. Factors associated with increased risk of drug exposure by multivariate analysis were: Caucasian ethnicity, male gender, GA <28 week and BW <1000 grams. Conclusions Antibiotics are the most commonly used drugs, far outweighing any other category, with >90% of infants being exposed to them. Future research and educational efforts should be directed to areas of appropriate antibiotic therapy in neonates with priority assigned to very low birth weight infants. Clinical Pharmacology & Therapeutics (2005) 77, P30–P30; doi: 10.1016/j.clpt.2004.12.007

The incidence of acute and remote seizures in children with intraventricular hemorrhage.

Seizures are a well-known complication of intraventricular hemorrhage (IVH) in premature infants; however, the rate at which they occur is not known. The authors decided, therefore, to investigate both the incidence of acute and remote seizures in infants with IVH and the association with the grade of hemorrhage. One hundred and three infants with IVH were identified and their records were reviewed for acute seizures, remote seizures, and associated morbidity and mortality. The average gestational age of these infants was 29 weeks (range, 23-40 weeks). Of the 103 infants, 32 (31%) developed grade 4 IVH; 19 (18%), grade 3 IVH; and 52 (50%), grades 1 and 2 IVH. Seventeen (17%) patients had acute seizures during their first month of life. Six of the 61 patients (10%) who survived the neonatal period and for whom follow-up data were available had remote seizures. Infants with grade 4 IVH had significantly more acute seizures than infants with grades 1 and 2. In this cohort, only infants with grades 3 and 4 IVH developed remote seizures. Furthermore, among infants with grade 4 IVH acute seizures were a significant risk factor for development of remote seizures. The use of long-term antiepileptic drug therapy in neonates with a history of acute seizures is not established. These results suggest that antiepileptic drug therapy beyond the neonatal period should be reserved for infants with grade 4 IVH with history of acute seizures.

Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (Part II).

Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions for many drugs remain poorly understood. The ontogeny of drug absorption, distribution, metabolism, and elimination are addressed in this review. Drug absorption from any site depends upon both the physicochemical properties of the drug and a variety of patient factors. Absorption of orally administered drugs may be affected by changes in gastric acidity and emptying time as well as by bile salt pool size, bacterial colonisation, and extraintestinal disease states such as congestive heart failure. Factors affecting drug absorption following intramuscular, percutaneous, and rectal administration are also discussed. Drug distribution in the neonate is influenced by a variety of important and predictable age-dependent factors. The developmental aspects of protein binding and body water compartments are described. Additionally, hepatic drug metabolism assumes an important role in understanding the pharmacokinetic and pharmacodynamic properties of many compounds. Certain biotransformation pathways, including hydroxylation by the P450 mono-oxygenase system and glucuronidation, demonstrate only limited activity at birth, while other pathways, such as sulphate or glycine conjugation, appear very efficient at birth. Elimination of drugs excreted unchanged in the urine is dramatically reduced in the newborn, compared with older infants and children, due to immaturity of both glomerular filtration and tubular secretory processes. The glomerular filtration rate remains markedly reduced prior to 34 weeks gestational age, increasing as a function of post-conceptual age until adult values are achieved by approximately 2.5 to 5 months of age. Tubular secretory capacity is also limited at birth, approaching adult values by approximately 7 months of age. Published reports describing the pharmacokinetics and pharmacodynamics of commonly used drugs in the neonatal period, as well as differences in drug biodisposition among premature infants, full term neonates, and older infants and children, are reviewed. Our recommendations for neonatal drug therapy are based upon a critical interpretation of these data, an understanding of fetal development and maturational processes, and an understanding of how disease states may affect drug biodisposition in the neonate.

Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (Part I).

Rational pharmacotherapy is dependent upon an understanding of the clinical pharmacokinetic and pharmacodynamic properties of the drugs employed. Although the available data on drug biodisposition and action in the neonate have increased considerably in the last few years, pharmacokinetic-pharmacodynamic interactions for many drugs remain poorly understood. The ontogeny of drug absorption, distribution, metabolism, and elimination are addressed in this review. Drug absorption from any site depends upon both the physicochemical properties of the drug and a variety of patient factors. Absorption of orally administered drugs may be affected by changes in gastric acidity and emptying time as well as by bile salt pool size, bacterial colonisation, and extraintestinal disease states such as congestive heart failure. Factors affecting drug absorption following intramuscular, percutaneous, and rectal administration are also discussed. Drug distribution in the neonate is influenced by a variety of important and predictable age-dependent factors. The developmental aspects of protein binding and body water compartments are described. Additionally, hepatic drug metabolism assumes an important role in understanding the pharmacokinetic and pharmacodynamic properties of many compounds. Certain biotransformation pathways, including hydroxylation by the P450 mono-oxygenase system and glucuronidation, demonstrate only limited activity at birth, while other pathways, such as sulphate or glycine conjugation, appear very efficient at birth. Elimination of drugs excreted unchanged in the urine is dramatically reduced in the newborn, compared with older infants and children, due to immaturity of both glomerular filtration and tubular secretory processes. The glomerular filtration rate remains markedly reduced prior to 34 weeks gestational age, increasing as a function of post-conceptual age until adult values are achieved by approximately 2.5 to 5 months of age. Tubular secretory capacity is also limited at birth, approaching adult values by approximately 7 months of age. Published reports describing the pharmacokinetics and pharmacodynamics of commonly used drugs in the neonatal period, as well as differences in drug biodisposition among premature infants, full term neonates, and older infants and children, are reviewed. Our recommendations for neonatal drug therapy are based upon a critical interpretation of these data, an understanding of fetal development and maturational processes, and an understanding of how disease states may affect drug biodisposition in the neonate.

Neonatal bilirubin toxicity. A review of kernicterus and the implications of drug-induced bilirubin displacement.

Kernicterus, the primary manifestation of neonatal bilirubin toxicity, remains an important complication of unconjugated hyperbilirubinaemia despite advances made with phototherapy and exchange transfusions. It results from the penetration of bilirubin into neuronal tissues of the CNS with subsequent damage to the mitochondrion. A number of factors may modify or potentiate bilirubin toxicity, including drugs administered to the infant. The importance of drug-bilirubin interactions in the pathogenesis of kernicterus was first realised quite inadvertently in the 1950s, and the potential risk for significant drug-bilirubin interactions has since become an important consideration in neonatal drug therapy. All drugs intended for use in newborn infants should be evaluated for their capacity to displace bilirubin. A number of techniques have been developed which have facilitated investigation of the mechanisms mediating the bilirubin-displacing effects of drugs and the pharmacokinetics of drug-bilirubin interactions. Further, the clinical risk for inducing kernicterus has been investigated for many of the drugs to which neonates may be exposed by direct administration, transplacentally, or through breast milk. This review summarises the available knowledge concerning the physicochemical properties and toxicities of bilirubin, reviews the methodologies used in evaluating drug-bilirubin interactions, and focuses on the mechanisms, pharmacokinetics and clinical significance of the bilirubin displacing effects of antibiotics, anticonvulsants, diuretics, and other important drug classes used in the treatment of neonates.