Wayne R. Snodgrass

Urine fluorescence using a wood's lamp to detect the antifreeze additive sodium fluorescein: A qualitative adjunctive test in suspected ethylene glycol ingestions

Antifreeze ingestions require rapid and accurate differential diagnosis to prevent fatal outcomes. Sodium fluorescein is added to some commercial antifreeze preparations (ethylene glycol) to a final concentration of approximately 20 micrograms/mL as a colorant to aid in detection of automobile cooling-system leaks. For an adult human being, a potentially toxic volume of antifreeze is 30 mL, which contains 0.4 to 0.6 mg sodium fluorescein. Six male volunteers were given a 0.6-mg oral bolus of sodium fluorescein on an empty stomach. Urine was collected at two-hour intervals. Using a Woods lamp, visually detectable fluorescence was seen with 100% reliability for two hours and 60% reliability for four hours. A second group of male volunteers was given the same dose of sodium fluorescein, and fluorescence was measured with a fluorometer during a six-hour period. Detectable fluorescence was present in all samples except the zero time point, including those with no fluorescence present by visual examination. We conclude that exposing urine to a Woods lamp may be a useful adjunctive diagnostic test for early evaluation of patients with suspected antifreeze ingestion while awaiting definitive quantitative analysis of serum ethylene glycol concentration. A prospective clinical trial is needed to evaluate the frequency of false-positives and false-negatives.

Population pharmacokinetic models: Effect of explicit versus assumed constant serum concentration assay error patterns upon parameter values of gentamicin in infants on and off extracorporeal membrane oxygenation

Prior authors had hypothesized (but not clearly found) an increased apparent volume of distribution (Vd) for gentamicin in neonates undergoing extracorporeal membrane oxygenation (ECMO). We chose to study the question in our own clinical setting. To develop population pharmacokinetic models of the drug, we used the nonparametric expectation and maximization population modeling method and data from 11 neonates who received gentamicin on ECMO, including 6 infants who received gentamicin both on and off ECMO for severe respiratory failure. We found an increased Vd for gentamicin on ECMO and attributed much of the difference from prior investigations to our use of an explicitly determined laboratory assay error pattern for the measured serum concentrations rather than using constant weighting of the serum level data points. For six infants, while on ECMO their median Vd was 0.748 L/kg compared with a median Vd of 0.471 L/kg after ECMO was discontinued. The median clearance of gentamicin in the six infants while undergoing ECMO was 0.239 L/h compared with 0.350 L/h after ECMO was discontinued. The median half-time (T1/2) was 9.24 h while on ECMO compared with 3.87 h when off ECMO. We conclude that while undergoing ECMO, neonates have a higher volume of distribution for gentamicin, a lower clearance, and a much longer half-life. Based on these results, for attainment of the desired peak-and-trough plasma gentamicin concentrations for infants undergoing ECMO (i.e., 5–8 and <2.0 μg/ml, respectively), we now recommend a loading dose of ∼4.3 mg/kg of gentamicin and a maintenance dose of ∼3.7 mg/kg to be given at dosing intervals of 18–24 h, followed by monitoring of serum concentrations and appropriate dose adjustments thereafter. To attain alternative goals, the model provides different loading and maintenance doses.

Analysis of chlorpyrifos exposure and human health: Expert panel report

This report summarizes the deliberations of an eight-member panel of scientists convened by Dow AgroSciences in cooperation with the U.S. Environmental Protection Agency (EPA). The panel was charged with evaluating the scientific literature on the health effects potentially associated with exposure to the insecticide chlorpyrifos. Specifically, the panel was asked to (1) evaluate human experience data available and address the adequacy of the available current literature; (2) develop a list of recommendations for epidemiology studies, including appropriate endpoints and study populations, and strengths and weaknesses of each approach; and (3) draft a report to summarize its recommendations. The panel assessed the quality of the existing epidemiologic literature on chlorpyrifos and specific outcomes such as neuropathy (including organophosphate induced delayed neurotoxicity), behavior (cognition and affect), immunologic, and multiple complaints (also referred to as multiple chemical sensitivities). The majority of panel members (five members) agreed that the literature reviewed provided little or no scientific evidence that chlorpyrifos exposure causes harm to human health other than its known cholinergic effects associated with acute poisoning. Those panel members voting in the minority (three members) agreed that the studies reviewed provided inadequate evidence to preclude the possibility of adverse effects to human health from chlorpyrifos exposure at levels associated with its manufacture or professional application. Those voting in the minority suggested further investigation of cohort(s) of workers engaged in either the manufacture or the professional application of chlorpyrifos, or both. Compared to the general population, these groups have relatively high levels of exposure to chlorpyrifos. The primary health outcomes recommended for study were cognitive and affective disorders, with consideration of the assessment of peripheral neuropathy also suggested for at least a subset of the cohort.

Population Pharmacokinetic Models

SummaryThe availability of personal computer programs for individualising drug dosage regimens has stimulated interest in modelling population pharmacokinetics. Appropriate use of population models requires knowledge of the distribution of their pharmacokinetic parameter values. If non-Gaussian, it is imperative not to assume that the arithmetic mean is the best measure of central tendency. This has important consequences for therapeutic drug monitoring and for individualising drug dosage regimens.Utilising a new nonparametric expectation maximisation (NPEM) population modelling program and retrospective data from 129 preterm infants who received gentamicin in our own clinical setting, we developed 2 population models. The NPEM algorithm showed that both had significant non-Gaussian distributions of their parameter values (e.g. the mean value for the volume of distribution exceeded the 75th percentile).Although the median parameter values demonstrated only slightly better predictive accuracy than the mean, its choice as the measure of central tendency was associated with excellent agreement between the goal and the subsequently observed average initial peak serum gentamicin concentrations (i.e. 6.0 vs 6.2 mg/L). In contrast, simulation using the mean parameter values predicted an average concentration 30% greater than the goal (i.e. 8.0 vs 6.0 mg/L). Thus, for this group of patients, the median proved a better measure of central tendency.

Accidental Hydrocarbon Ingestion Cases Telephoned to a Regional Poison Center

One hundred eighty-four telephone calls to the Texas State Poison Center concerning accidental hydrocarbon ingestion were reviewed in an attempt to define the risk of developing any subsequent medical problem requiring therapeutic intervention. Special attention was given to changing symptom severity in an attempt to evaluate its usefulness in predicting future complications. One hundred twenty patients (65%) had no initial symptoms and remained asymptomatic throughout an 18-hour follow-up period. Sixty-two (34%) of patients had symptoms initially but quickly became asymptomatic. Two (1%) developed significant complications (one chemical pneumonitis, one death). These data suggest that the risk of significant complications after accidental hydrocarbon ingestion is low (approximately 1% of patients at risk). Patients who are asymptomatic or who quickly become asymptomatic can be watched safely at home, and referral of asymptomatic patients to a hospital may be unwarranted.

Role of indomethacin in ductus closure: an update evaluation

Patent ductus arteriosus (PDA) in premature infants is a current challenge to pediatricians. Pharmacological closure of PDA with indomethacin, a prostaglandin synthetase inhibitor is an effective drug therapy, along with usual medical treatment. Administration of indomethacin may decrease mortality and morbidity (e.g. bronchopulmonary dysplasia) among very small premature infants (less than 1,000 g). Co-administration of furosemide with indomethacin may lessen the transient renal side effects of indomethacin. The therapeutic efficacy of indomethacin in closure of PDA depends largely on understanding and manipulation of the pharmacokinetic characteristics of the drug in preterm infants. Maintaining a therapeutic level of the drug in plasma is essential to achieve an optimal therapeutic response. Compared to surgical ligation, indomethacin is a noninvasive, less expensive and safer therapy for ductus closure.

Herbal products: Risks and benefits of use in children

Background: The use of herbal products in children is a concern because little information is available concerning the benefits and risks of these products in the pediatric population. Objective: This article defines herbal products and reviews the reasons for using such products, the most commonly used herbal products in the United States, their use during pregnancy and breast-feeding, and the adverse effects, drug interactions, and regulatory issues associated with herbal products. Methods: A literature search was conducted using MEDLINE and references from journal articles. Results: Many of the herbal products that are being given to children in the United States currently do not meet the standards of good manufacturing practices. No high-quality studies have been conducted to determine the efficacy of these products. Their concentrations of active ingredients are unpredictable, their labeling is inadequate, and they can cause toxicity. Conclusions: The benefit-risk ratio of most herbal products remains unknown. Greater efforts and resources should be devoted to high-quality research to determine the effectiveness and tolerability of these widely used herbal products.

Use of medication data to validate an association in community-based symptom prevalence studies.

A chemical spill from an oil refinery in Texas City, Texas, exposed the community to more than 40,000 lbs (18,144 kg) of highly toxic and corrosive hydrofluoric acid. A symptom prevalence study indicated an association between symptom reports, most notably breathing symptoms, and hydrofluoric acid exposure. Although verification of self-reported symptoms by checking medical records or performing clinical tests is theoretically possible, it is not a feasible alternative in dealing with an entire community. Open-ended data on medication use collected in the prevalence study were coded by organ system and analyzed by cross-classification techniques and log linear models. Results showed that the reported use of medication for hydrofluoric acid-related problems was associated with the exposure; medication use for problems unrelated to hydrofluoric acid exposure was uniform across the exposure categories. Moreover, medication use was significantly associated with the severity of breathing-related problems for each exposure category. Medication use, however, may have been under-reported because it seems difficult to conjure up the names of medications that were not taken or medications not taken recently may not be recalled. Nonetheless, open-ended medication data may be a useful surrogate approach to validating an association between an exposure and health outcomes.

Diagnosis and Treatment of Poisoning Due to Pesticides

Publisher Summary This chapter covers diagnosis and management of both acute and chronic pesticide poisoning, which presents a significant challenge to current clinical capabilities. There are increasing attempts to carry out prospective clinical studies to answer clinically significant challenges to improve the outcome of patients poisoned by pesticides. Pesticides may be categorized by major agricultural classes of insecticides, herbicides, and fungicides. Additional groupings are rodenticides, nematocides, molluscides, acaricides, larvacides, miticides, pediculicides, scabicides, attractants (pheromones), defoliants, desiccants, plant growth regulators, and repellants. Greater risk rates of pesticide poisonings may be expected in countries with fewer regulatory controls where pesticides may be used extensively. Organophosphates and N-methyl carbamates are the pesticides that most commonly cause systemic illness. Acute severe organophosphate poisoning is one of the most life-threatening human poisonings, but it is also treatable (atropine plus pralidoxime), often with a good outcome if treatment is begun promptly and early in the time course of poisoning. With careful attention to the details of exposure history and clinical findings in each individual patient, coupled with knowledge of the specific pesticide involved, an individualized management plan can be formulated that should be beneficial for most patients.

Pharmacotherapy and pregnancy

1Indiana University School of Medicine, PREGMED, The Indiana University Center for Pharmacogenetics and Therapeutics Research in Maternal and Child Health, Indianapolis, Indiana, USA 2University of Texas Medical Branch, Galveston, Texas, USA 3University of Washington School of Medicine, Seattle, Washington, USA 4Food and Drug Administration, Washington, D.C., USA 5Indiana University Center for Bioethics, Indianapolis, Indiana, USA 6SickKids Hospital, Motherisk, Toronto, Ontario, Canada, USA 7The National Institute of Child Health and Human Development, Washington, D.C., USA Correspondence: DM Haas (dahaas@iupui.edu). Reprints not available from authors. DOI: 10.1111/j.1752-8062.2009.00079.x Pharmacotherapy and Pregnancy