Neonatal Drug Research Articles

Aerosol Deposition in Neonatal Ventilation

Lung deposition of inhaled drugs in ventilated neonates has been studied in models of questionable relevance. With conventional nebulizers, pulmonary deposition has been limited to 1% of the total dose. The objective of this study was to assess lung delivery of aerosols in a model of neonatal ventilation using a conventional and novel electronic micropump nebulizer. Aerosol deposition studies with 99mTc diethylenetriamine pentaacetate (99mTc-DTPA) were performed in four macaques (2.6 kg) that were ventilated through a 3.0-mm endotracheal tube (with neonatal settings (peak inspiratory pressure 12-14 mbar, positive end-expiratory pressure 2 mbar, I/E ratio 1/2, respiratory rate 40/min), comparing a jet-nebulizer MistyNeb (3-mL charge, 4.8 microm), an electronic micropump nebulizer operating continuously [Aeroneb Professional Nebulizer (APN-C); 0.5-mL charge, 4.6 microm], and another synchronized with inspiration [Aeroneb Professional Nebulizer Synchronized (APN-S); 0.5-mL charge, 2.8 microm]. The amount of radioactivity deposited into lungs and connections and remaining in the nebulizer was measured by a gamma counter. Despite similar amounts of 99mTc-DTPA in the respiratory circuit with all nebulizers, both APN-S and APN-C delivered more drug to the lungs than MistyNeb (14.0, 12.6, and 0.5% in terms of percentage of nebulizer charge, respectively; p = 0.006). Duration of delivery was shorter with APN-C than with the two other nebulizers (2 versus 6 and 10 min for the APN-S and the MistyNeb, respectively; p < 0.001). Electronic micropump nebulizers are more efficient to administer aerosols in an animal model of ventilated neonates. Availability of Aerogen's electronic micropump nebulizers offers new opportunities to study clinical efficacy and risks of aerosol therapy in ventilated neonates.

Treatment of Pain and Stress in the Neonate

After completing this article, readers should be able to: 1. Describe the pain assessment tools used for preterm and term neonates. 2. List painful procedures in the neonatal intensive care unit (NICU). 3. Describe nonpharmacologic interventions for alleviating neonatal pain. 4. Describe pharmacologic methods used for neonatal analgesia. 5. Delineate the adverse effects of the common forms of pain relief. Neonates are sensitive to pain and vulnerable to both its short- and long-term effects. However, there is a lack of consistency in both attitudes and practices among NICU staff with regard to pain assessment and management in neonates. Recognition of the clinical importance of neonatal pain and stress has been delayed and hampered by the lack of awareness that newborns are capable of experiencing pain, insufficient knowledge about the developing nervous system, difficulty in assessing neonatal pain, lack of evidence for the safety and efficacy of different modalities available for the treatment of pain, and fears about adverse effects associated with analgesic use. Neonatal pain has been of minimal concern until the last 25 years. For example, at one time, neonates were given paralytic drugs without anesthesia for major surgical procedures because physicians believed that neonates were incapable of interpreting or remembering pain. Further, there was no understanding of the consequences of untreated pain. Newer technologies to sustain life have exposed neonates to multiple invasive procedures and prolonged hospital stays that are associated with acute and chronic pain and stress. In 2001, an international evidence-based group for neonatal pain developed guidelines for the assessment, prevention, and treatment of neonatal pain in an effort to standardize practices for physicians and health care facilities. Within the consensus statement, the group defined general principles to prevent and treat pain and listed the most commonly performed diagnostic, therapeutic, and surgical procedures in the NICU. The guidelines also indicated the …

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

Effects of neonatal alcohol and/or cocaine exposure on stress in juvenile and adult female rats

The effects of neonatal exposure to alcohol and/or cocaine on two measures of stress were studied in juvenile and young adult female rats. After implantation with an intragastric cannula, subjects were artificially reared from postnatal days 4–10. This “brain growth spurt” period is roughly equivalent to CNS development during the third trimester of human pregnancy. There were five treatment groups: alcohol (6 g/kg/day), cocaine (60 mg/kg/day), alcohol/cocaine (6 g/kg/day alcohol and 60 mg/kg/day cocaine), stock (an artificially reared control), and sham (a suckled control). Subjects were tested in open field and forced swim tests beginning at 21 or 60–70 days of age, respectively. Compared to controls, alcohol-exposed females displayed longer latencies to become immobile in the forced swim test as juveniles and cocaine-exposed females showed increased immobility as adults. Increased immobility can be interpreted as hyporesponsiveness to stress. In contrast, very few differences were observed in the open field. Furthermore, the group exposed to alcohol and cocaine in combination did not differ from controls in either paradigm. These findings suggest that the forced swim test may be more sensitive to neonatal drug effects than open field, although these effects may not be consistent across age.

A pioneer of chemical dependency treatment: Dr Mondanaro takes no prisoners.

A pioneer of chemical dependency treatment: Dr Mondanaro takes no prisoners.

Clinical utilization of atypical antipsychotics in pregnancy and lactation.

To analyze the available literature regarding the safety of atypical antipsychotics in pregnancy and lactation in order to recommend evidence-based strategies for pharmacologic management of psychosis in these conditions. We summarized the results from articles identified via MEDLINE/PubMed/TOXNET (1993-January 31, 2004), using the key terms pregnancy, lactation, breast-feeding, human milk, psychotropic drugs, atypical antipsychotics, olanzapine, quetiapine, risperidone, clozapine, ziprasidone, and aripiprazole. Retrospective studies, clinical observations, and case reports regarding the 6 atypical antipsychotics mentioned above were selected and analyzed. Extensive manual review of pertinent journals and textbooks was also performed. Reviewed studies show that olanzapine and clozapine apparently do not increase the teratogenic risk if administered to pregnant women, while evidence on quetiapine, risperidone, aripiprazole, and ziprasidone is still limited. In contrast, available information is not able to exclude unwanted serious effects associated with the use of all atypical antipsychotics on mother-infant dyads. Furthermore, more than a few studies suggest increased hyperglycemic risk for pregnant women related to atypical antipsychotic therapy during gestation. Finally, published evidence about the effects on long-term infant neurodevelopment of drug exposure through both placenta and breast milk is represented only by sporadic case reports. It is well known that potential consequences of an untreated psychotic episode may be severe and may lead to the mother attempting suicide and/or infanticide. For these reasons, clinicians need to help mothers weigh both fetal and neonatal risks of exposure to drugs against the potential risk they and their infant may incur if the psychiatric illness is not treated. On the other hand, atypical antipsychotics in pregnancy and breast-feeding do not show evident advantages in safety when compared with typical neuroleptic agents. Therefore, we suggest that the most relevant parameters for selecting the best clinical option for pregnant and breast-feeding women with schizophrenia and related disorders remain strongly related to 3 main points: (1). cautious evaluation of the risk/benefit ratio of fetal and neonatal drug exposure, (2). degree of severity of maternal psychiatric illness, and (3). careful preliminary choice of drugs characterized by a balanced safety/efficacy profile.

Neural and hormonal consequences of neonatal 5,7-dihydroxytryptamine may not be associated with serotonin depletion

The neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) is often used in neonatal rats to induce specific, rapid, and permanent depletion of brain serotonin (5-HT). One assumed benefit of using this drug in neonates is that it is well-tolerated, with pups exhibiting few side effects normally attributed to 5-HT depletion. Here, we present evidence that 5,7-DHT administered neonatally induces seizure-like behavior, decreases weight gain, and increases plasma corticosterone without depletion of brain 5-HT.

Antifungals in systemic neonatal candidiasis.

Fungal infections are common in the newborn period, especially among premature neonates, and are responsible for considerable morbidity and mortality. Currently, three classes of antifungals are commonly used in the treatment of systemic fungal infections in neonates: the polyene macrolides (e.g. amphotericin B [deoxycholate and lipid preparations]); the azoles (e.g. fluconazole); and the fluorinated pyrimidines (e.g. flucytosine). The echinocandins (e.g. caspofungin and micafungin) are a newer class of antifungals which shows promise in this population.The available kinetic data on amphotericin B deoxycholate in neonates are derived from very small studies and exhibit considerable variability. There are no kinetic data available for the use of lipid preparations in this population and, again, much has been inferred from adult studies. The information available for flucytosine is also limited but appears similar to what is observed in adults. Fluconazole has the most neonatal pharmacokinetic data, which show slightly less variability than the other antifungals. Genomic factors which affect the metabolism of amphotericin B and fluconazole may explain some of the observed variability. Most of the data for the efficacy of antifungal drugs in neonates are derived from retrospective studies and case reports. The data for amphotericin B deoxycholate and flucytosine are limited. There are more data for the liposomal and lipid complex preparations of amphotericin B and for fluconazole in this population. These support the use of these drugs in neonates, but because of their largely noncomparative nature they can not define the optimal dosage or duration of therapy. Amphotericin B deoxycholate is primarily nephrotoxic. It also induces electrolyte abnormalities and is to a lesser degree cardiotoxic. This toxicity in neonates appears similar to published data in older children and adults. While the lipid preparations of amphotericin B owe their existence to a presumed decrease in toxicity, the observed toxicity in neonates appears to be equal to that seen with the deoxycholate, although it should be noted that the lipid preparations are usually given at much higher dosages. Fluconazole toxicity appears to be milder and less frequent in this population than is seen with amphotericin B. In the final analysis, we do not have sufficient data to define the pharmacokinetic profiles, optimal dose or duration of therapy, or toxicity for any of these compounds in neonates. Further studies are necessary if the optimisation of antifungal therapy in this population is to continue.

Protein binding ability of various antimicrobial drugs in neonates

Protein binding ability of various antimicrobial drugs in neonates

Concerns regarding lamotrigine and breast-feeding

Purpose. Many women with epilepsy who are planning a pregnancy are treated with lamotrigine (LTG), resulting in greater fetal exposure to the drug. Current care guidelines suggest that mothers with epilepsy breast-feed their children. These recommendations are made without regard to how nursing newborns metabolize medication. Lamotrigine is extensively metabolized by glucuronidation, which is immature in neonates and may lead to accumulation of medication. This article reports LTG levels in full-term nursing newborns born to mothers with epilepsy on lamotrigine monotherapy. Methods. Serum LTG levels were obtained in nursing mothers and their neonates on Day 10 of life. Maternal LTG clearance during pregnancy and postpartum was determined and correlated with levels. Results. Four mothers with partial epilepsy on LTG monotherapy were evaluated. Serum LTG levels in nursing newborns ranged from <1.0 to 2.0 μg/mL on Day 10 of life. Three babies had LTG levels >1.0 μg/mL. After excluding one child with an undetectable level, the LTG levels in newborns were on average 30% (range 20–43%) of the maternal drug level. No decline was noted in two children with repeat levels at 2 months. Conclusion. Serum concentrations of LTG in breast-fed children were higher than expected, in some cases reaching “therapeutic” ranges. These high levels may be explained by poor neonatal drug elimination due to inefficient glucuronidation. Our observation that not all newborns had a high LTG level suggests considerable genetic variability in metabolism. Our limited data suggest monitoring blood levels in nursing children and the need for individual counseling for women with epilepsy regarding breast-feeding.

New Methods for Neonatal Drug Screening

After completing this article, readers should be able to: 1. Describe perinatal and neonatal complications of maternal use of cocaine, alcohol, opiates, and barbiturates in pregnancy. 2. List established cutoffs of conventional immunoassays of urine for common substances of abuse. 3. List the advantages of using meconium testing for substances of abuse. 4. Describe the role of fatty acid ethyl esters in detecting prenatal alcohol exposure. Maternal substance use during pregnancy can have direct consequences on both the developing fetus and the mother and is a significant public health concern. The prevalence of gestational use of drugs of abuse varies, depending on the study population and method of detection, but it generally ranges from 1% to 15%. (1) One of the largest epidemiologic studies conducted in the United States documented that although most pregnant women decrease the use of substances as the pregnancy progresses, a significant proportion of them remain regular users, even in the third trimester (eg, ethanol [13%], cannabis [9.3%], cocaine [10%], and heroin [1%]). (2) Various perinatal and neonatal complications can result from prenatal exposure to common drugs of abuse. (3) The use of cocaine during pregnancy is associated with increased risks of preterm labor, intrauterine growth retardation, and neurobehavioral abnormalities. Heavy alcohol use during pregnancy leads to fetal alcohol spectrum disorder, which is characterized by an array of congenital malformations, central nervous system abnormalities, and neurodevelopmental deficits. Neonates exposed to opiates, alcohol, and barbiturates in utero are at risk of developing neonatal abstinence syndrome, which is characterized by irritability, gastrointestinal dysfunction, respiratory distress, and other nonspecific symptoms. (1) Data in the literature conflict regarding adverse events in the immediate postnatal period that can be attributed to prenatal exposure to other illicit drugs. Thus, early identification of neonates in whom substance exposure is suspected is important for appropriate treatment intervention and …

Dopamine agonists for cocaine dependence.

Cocaine dependence is a common and serious condition, which has become nowadays a substantial public health problem. There is a wide and well documented range of consequences associated to chronic use of this drug, such as medical, psychological and social problems, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure. Therapeutic management of the cocaine addicts includes an initial period of abstinence from the drug. During this phase the subjects may experience, besides the intense craving for cocaine, symptoms such as depression, fatigue, irritability, anorexia, and sleep disturbances. It was demonstrated that the acute use of cocaine may enhance dopamine transmission and chronically it decreases dopamine concentrations in the brain. Pharmacological treatment that affects dopamine could theoretically reduce these symptoms and contribute to a more successful therapeutic approach. To evaluate the efficacy and acceptability of dopamine agonists for treating cocaine dependence. Electronic searches of Cochrane Library, EMBASE, MEDLINE, PsycLIT, Biological Abstracts and LILACS; reference searching; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence, was performed for the primary version of this review in 2001. Another search of the electronic databases was done in December of 2002 for this update. The specialised register of trials of the Cochrane Group on Drugs and Alcohol was searched until February 2003. The inclusion criteria for all randomised controlled trials were that they should focus on the use of dopamine agonists on the treatment of cocaine dependence. The reviewers extracted the data independently and Relative Risks, weighted mean difference and number needed to treat were estimated. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. Seventeen studies were included, with 1224 participants randomised. Amantadine, bromocriptine, and pergolide were the drugs evaluated. The main outcomes evaluated were positive urine sample for cocaine metabolites, for efficacy, and retention in treatment, as an acceptability measure. There were no significant differences between interventions, and in trials where participants had primary cocaine dependence or had additional diagnosis of opioid dependence and/or were in methadone maintenance treatment. Current evidence does not support the clinical use of dopamine agonists in the treatment of cocaine dependence. Given the high rate of dropouts in this population, clinicians may consider adding other supportive measures aiming to keep patients in treatment.

Hyperphagia, weight gain and neonatal drug withdrawal

Hyperphagia, a classical feature of neonatal drug withdrawal, has been reported not to lead to excessive weight gain, but this is contrary to our clinical experience. The aim of this study was to determine whether infants with neonatal drug withdrawal suffered excessive weight gain because of hyperphagia and, if so, to determine the risk factors. The study population comprised 48 infants consecutively admitted to the neonatal intensive care unit, 11 of whom gained weight by more than 20 g kg‐1 d‐1 for at least 10 d (excessive weight gain). All 11 infants were hyperphagic (&gt;200 ml/kg) for at least part of the excessive weight gain period. During the perinatal period, the 11 infants had a greater fluid intake (p &gt; 0.01) but similar weight gain to gestational‐age‐matched, neonatal drug‐withdrawal infants who did not suffer any excessive weight gain. Compared to the rest of the cohort, the infants with excessive weight gain were more likely to require treatment with morphine/chlorpromzaine (p &gt; 0.05) and had a higher maximum withdrawal score (p &gt; 0.01). Conclusion: Hyperphagia can lead to excessive weight gain in infants with neonatal drug withdrawal. Our results suggest that hyperphagia occurs in those who require treatment for severe withdrawal.

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

The therapeutic and toxic effects of amikacin are known to depend on its concentration in plasma, but the pharmacokinetics of this drug in neonates, infants, and children and the influences of clinical and biological variables have been only partially assessed. Therapeutic drug monitoring data collected from 155 patients (49 neonates, 77 infants, and 29 children) receiving amikacin were analyzed by a nonparametric population-based approach, the nonparametric maximum-likelihood method. We assessed the effects of gestational and postnatal age, weight, Apgar score, and plasma creatinine and urea concentrations on pharmacokinetic parameters. There is no specific formulation of amikacin for neonates and infants. We therefore used an error model to account for errors due to dilution during preparation of the infusion. The covariates that reduced the variance of clearance from plasma and the volume of distribution by more than 10% were postnatal age (43 and 28%, respectively) and body weight (30.4 and 17.4%, respectively). The expected reduction of clearance was about 10% for the plasma creatinine concentration. The other covariates studied (Apgar scores, plasma urea concentration, gestational age, sex) were found to have little effect. Simulations showed that a smaller percentage of patients had a maximum concentration in plasma/MIC ratio greater than 8 with a regimen of 7.5 mg/kg of body weight twice daily than with a regimen of 15 mg/kg once a day for MICs of 1 to 8 mg/liter.

Carbamazepine for cocaine dependence.

Cocaine dependence has become a substantial public health problem, developing a significant number of medical, psychological and social problems, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and neonatal drug exposure. Although there is no consensus regarding how to treat cocaine dependence, effective pharmacotherapy has a potentially major role to play as part of a broader treatment milieu. The anti-convulsant carbamazepine, a tricyclic medication that is widely used to treat a variety of neurological and psychiatric disorders, has also been used for treatment of cocaine dependence, although its effectiveness has not been established. To determine whether carbamazepine (CBZ) is effective for the treatment of cocaine dependence. We searched: the Cochrane Controlled Trials Register (Cochrane Library issue 1, 1999), MEDLINE (from 1966 - October 1997), EMBASE (from 1980 - October 1997), PsycLIT (from 1974 - July 1997), Biological Abstracts and LILACS (from 1982 - 1997); scan of reference list of relevant articles; personal communication; conference abstracts; unpublished trials from pharmaceutical industry; book chapters on treatment of cocaine dependence. The inclusion criteria for all randomised controlled trials were that they should focus on the use of carbamazepine drugs versus placebo on the treatment of cocaine dependence. Trials including patients with additional diagnosis such as opiate dependence were also eligible. The reviewers extracted the data independently and Odds Ratios, weighted mean difference and number needed to treat were estimated. Qualitative assessments of the methodology of eligible studies were carried out using validated checklists. The reviewers assumed that people who died or dropped out had no improvement and tested the sensitivity of the final results to this assumption. Where possible analysis was carried out according to the "intention to treat" principles. 5 studies were included in the review, with 455 people randomised. No differences were found regarding positive urine sample for cocaine metabolites. Scores on Spielberg State Anxiety Inventory slightly favoured carbamazepine, but didn't reach statistical significance. Dropouts were high in both groups up to 70% in the placebo group. Less dropout occurred in the carbamazepine group (RR 0.87 95%CI 0.71-1.06). When no retention in treatment was due to side effects no differences were found. The number of participants presenting at least one side effect, reported in Kranzler (Kranzler 1995), was higher in the carbamazepine group (RR 4.33 95% CI 1.45-12.91). There is no current evidence supporting the clinical use of CBZ in the treatment of cocaine dependence. Larger randomised investigation must be considered taking into account that these time-consuming efforts should be reserved for medications showing more relevant and promising evidence.

Review: therapeutic drug monitoring in pediatrics.

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug concentrations in biologic fluids to assess whether they correlate with the patient’s clinical condition and whether the dosage or dosage intervals need to be changed. This is done to optimize the management of patients receiving drug therapy for the alleviation or prevention of disease. Therapeutic drug monitoring is a relatively new service in the clinical pharmacology and toxicology laboratory and has evolved from being a luxury to a necessity. The principles of TDM were developed in the 1960s. Advances in research and knowledge and increasingly sophisticated laboratory methods led to an expansion of TDM (1–3). A drug must meet the following criteria to be eligible for monitoring: There should be a clinically interpretable correlation between the serum drug concentration and its pharmacologic effect. This usually implies a clinically significant correlation between the serum drug concentration and its concentration in the target tissue (1). There should be a better correlation between the plasma drug concentration and the pharmacologic effect than between the drug dosage and the pharmacologic effect. A narrow margin should exist between serum concentrations that cause toxic effects and concentrations that produce therapeutic effects. The serum concentration resulting from a given drug dose is unpredictable as a result of inter- and intraindividual differences in drug absorption, distribution, and elimination. Such poor correlation between serum concentration and drug dosage has been shown with clomipramine used in treatment of enuresis (2). The pharmacologic effects of drugs are not readily measurable (e.g., suppression of seizure activity is difficult to monitor clinically when administering anticonvulsant drugs). There must be a rapid and reliable method for the analysis of the drug. The criteria for monitoring drugs in children are the same as those for adults (6), but several additional factors must be considered. Neonates, infants, and children undergo major and rapid age-related physiologic and biochemical changes, especially during the first year of life, resulting in different clinical pharmacokinetic and pharmacodynamic parameters from adults (Table 1). Recent indications are that approximately 12% of all drugs prescribed in the United States are for children age 9 years and younger (4). Further, review of drug-dosing habits in neonatal intensive care units has shown that the average number of drugs administered to premature infants weighing less than 1,000 g varies from institution to institution but is usually in the range of 15 to 20 drugs; infants weighing more than 2,500 g usually receive 4 to 10 drugs during their hospital stay. Obviously, drug concentrations in many of these patients need to be monitored by the laboratory, and the possibility of drug interactions needs to be considered. Thus, it is important to have a clear understanding of not only the principles of TDM but also the additional factors inherent in and specific to pediatric clinical pharmacology. Table 1 Pharmacokinetic parameters of drugs commonly used in children When administering drugs to children, age-related differences in drug absorption, distribution, metabolism, and clearance should be taken into account to optimize drug efficacy and to avoid toxicity. There are major differences not only between adults and children but also between neonates and pre- and postpubertal children. The following are some important differences between adults and children: Changes in gastric pH and gastric emptying time during the neonatal period lead to variation in the absorption of many drugs. Differences in body composition (neonates are composed of less body fat and more water) lead to differences in the apparent volume of distribution between neonates, children, and adults (Table 2). Table 2 Some factors affecting drug distribution and disposition Slow total drug clearance in premature infants and neonates is due to immature hepatic and renal function. Immaturity of the hepatic microsomal enzyme system produces slow biotransformation of many drugs in premature infants and neonates, requiring a lower mg/kg dosage to achieve therapeutic concentrations. Greater microsomal enzyme activity in prepubertal children than in postpubertal children and adults necessitates a higher mg/kg dosage to achieve similar serum concentrations of some drugs.

Understanding drug testing in the neonate and the role of meconium analysis.

The use of illicit drugs during pregnancy is a problem that affects a significant number of pregnant women or women of childbearing age. For many reasons, the identification of the drug exposed mother and her infant is a necessary, albeit difficult, task. This article will discuss drug testing to detect the antenatal exposure of the newborn infant to illicit drugs and review the different laboratory methods that are used and the role of meconium analysis in neonatal drug testing.

Neonatal hepatic drug elimination.

After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood flow and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.

Exposición prenatal a drogas y efectos en el neonato

Objetivematernal drug use during pregnancy may result in various neonatal complications: miscarriage, premature deliveries, smallfor-gestational-age, malformations, fetal distress, neonatal drug withdrawal, neonatal vertical infections,… The acute withdrawal syndrome is the most important by frecuency. Methodsto assess the clinical background and treatment in case of prenatal drug exposure and particularly in the acute withdrawal syndrome. Ressultsthe signs of withdrawal include evidence of central nervous system (irritability, tremulousness, hypertonia,…), gastrointestinal (vomiting, diarrhea, poor feeding,…) and autonomic (sweating, fever, mottling,…) dysfunction. The treatment is supportive and pharmacologic. Conclusionsthe decision to use drug therapy must be individualized. This children must be addmitted in neonatal services in order to control and study the posibility of others complications associated.

PERFORMING AND INTERPRETING THE BLEEDING TIME IN THE NEONATAL INTENSIVE CARE UNIT

In summary, the bleeding time is a helpful clinical tool to detect and investigate certain hemostatic defects in neonates and to evaluate the adequacy of treatments. A prolonged bleeding time alone is sometimes not sufficient to diagnose specific conditions requiring further investigations. Platelet hyporeactivity in the first days of life, gestational age, platelet dysfunction secondary to various neonatal or maternal pathologic conditions, neonatal or maternal drug administration, and hematocrit must be considered for the correct interpretation of the bleeding time test in neonates. In addition, reliable test results can be ensured only by the scrupulous execution of the procedure.