Gastrointestinal decontamination in the acutely poisoned patient

ObjectiveTo define the role of gastrointestinal (GI) decontamination of the poisoned patient.Data sourcesA computer-based PubMed/MEDLINE search of the literature on GI decontamination in the poisoned patient with cross referencing of sources.Study selection and data extractionClinical, animal and in vitro studies were reviewed for clinical relevance to GI decontamination of the poisoned patient.Data synthesisThe literature suggests that previously, widely used, aggressive approaches including the use of ipecac syrup, gastric lavage, and cathartics are now rarely recommended. Whole bowel irrigation is still often recommended for slow-release drugs, metals, and patients who "pack" or "stuff" foreign bodies filled with drugs of abuse, but with little quality data to support it. Activated charcoal (AC), single or multiple doses, was also a previous mainstay of GI decontamination, but the utility of AC is now recognized to be limited and more time dependent than previously practiced. These recommendations have resulted in several treatment guidelines that are mostly based on retrospective analysis, animal studies or small case series, and rarely based on randomized clinical trials.ConclusionsThe current literature supports limited use of GI decontamination of the poisoned patient

Riding (High) into the Danger Zone: A Review of Potential Differences in Chemical Exposures in Fighter Pilots Resulting from High Altitude and G-Forces

Full Article Figures & data References Citations Metrics Reprints & Permissions Get access ABSTRACT Introduction: When in flight, pilots of high performance aircraft experience conditions unique to their profession. Training flights, performed as often as several times a week, can expose these pilots to altitudes in excess of 15 km (~50,000 ft, with a cabin pressurized to an altitude of ~20,000 ft), and the maneuvers performed in flight can exacerbate the G-forces felt by the pilot. While the pilots specifically train to withstand these extreme conditions, the physiologic stress could very likely lead to differences in the disposition of chemicals in the body, and consequently, dangerously high exposures. Unfortunately, very little is known about how the conditions experienced by fighter pilots affects chemical disposition. Areas covered: The purpose of this review is to present information about the effects of high altitude, G-forces, and other conditions experienced by fighter pilots on chemical disposition. Using this information, the expected changes in chemical exposure will be discussed, using isopropyl alcohol as an example. Expert opinion: There is a severe lack of information concerning the effects of the fighter pilot environment on the pharmacokinetics and pharmacodynamics of chemicals. Given the possibility of exposure prior to or during flight, it is important that these potential effects be investigated further

Antibiotic Dosing in Pediatric Critically Ill Patients

Despite being some of the most frequently utilized drugs in children, caregivers still commonly prescribe antibiotics in neonates and children based on dosing regimens linearly extrapolated from adults. Although this practice is not limited to antibiotics, specific concerns related to dosing inaccuracy for antibiotics are treatment failure, antimicrobial resistance, and maturational toxicity. In this chapter, we first discuss the simultaneous impact of maturation and critical illness on pediatric pharmacokinetics (PK), including the specific impact of major burns and extracorporeal equipment. Both aspects (maturation and critical illness) will play a significant role in the final, phenotypic PK in a given child. Second, a section on pharmacodynamics (PD) focuses on the developmental safety of antibiotics. Developmental PD aspects may result in differences in risk rate, or altogether different risks compared to adult observations. Third, some compound-specific PK/PD observations (aminoglycosides, vancomycin, meropenem) in neonates and children are discussed to further illustrate the complex interaction between physiology and pathophysiology, including the limitations of the currently available guidance. In the final part of the chapter, the contribution of PK modeling and simulation and advanced therapeutic drug monitoring is explored as a tool towards tailored pharmacotherapy in pediatric critically ill patients

Antibiotic dosing in pediatric critically ill patients

Despite being some of the most frequently utilized drugs in children, caregivers still commonly prescribe antibiotics in neonates and children based on dosing regimens linearly extrapolated from adults. Although this practice is not limited to antibiotics, specific concerns related to dosing inaccuracy for antibiotics are treatment failure, antimicrobial resistance, and maturational toxicity. In this chapter, we first discuss the simultaneous impact of maturation and critical illness on pediatric pharmacokinetics (PK), including the specific impact of major burns and extracorporeal equipment. Both aspects (maturation and critical illness) will play a significant role in the final, phenotypic PK in a given child. Second, a section on pharmacodynamics (PD) focuses on the developmental safety of antibiotics. Developmental PD aspects may result in differences in risk rate, or altogether different risks compared to adult observations. Third, some compound-specific PK/PD observations (aminoglycosides, vancomycin, meropenem) in neonates and children are discussed to further illustrate the complex interaction between physiology and pathophysiology, including the limitations of the currently available guidance. In the final part of the chapter, the contribution of PK modeling and simulation and advanced therapeutic drug monitoring is explored as a tool towards tailored pharmacotherapy in pediatric critically ill patients

Additional file 1 of Re-expressing coefficients from regression models for inclusion in a meta-analysis

Additional file 1

Dosing of Vancomycin in Neonates: On Target for the Therapeutic Range?

BACKGROUND Achieving therapeutic vancomycin concentrations in neonates is an ongoing challenge. Initial dosage is primarily based on weight but can also include consideration of gestational age. Therapeutic drug monitoring limits the potential for toxicity, treatment failure, and the development of bacterial resistance. This study examined the frequency of achieving an appropriate therapeutic trough concentration based upon the initial dosage. METHODS A multicenter retrospective study of 626 neonates, birth weight \u3e1500g (0-27 days) who received vancomycin between 01/2006 and 09/2011 was performed using a large electronic health database. For each patient, the first vancomycin trough level was used to determine whether vancomycin blood concentrations fell into the therapeutic range (defined as 10-20 μg/mL). Neonates without evaluable vancomycin trough levels, or renal impairment were excluded from analysis. Weights were converted to z-scores using Epi Info 7, which was limited to infants with a birth weight \u3e1500 g, and statistical analysis was performed in Prism 6 (Graphpad). These data were not complete before December 5, 2012. RESULTS Evaluable trough and creatinine levels were available for 402 patients (64% male). 185 patients (46%) had a trough concentration outside therapeutic range, 32% (n=127) below 10 μg/mL, and 14% (n=58) above 20 μg/mL. There was no statistical difference between males and females by age, number of vancomycin doses given, weight, or trough levels. However, the dose of vancomycin administered was higher for males with a median of 47.0 mg/dose (95% confidence interval (CI), 38.0-60.0) than females with 45.0 mg/dose (95% CI,35.0-53.0); p \u3c0.02. CONCLUSION This study demonstrates that the standard dosing regimens for vancomycin in neonates results in trough levels outside of therapeutic range nearly half of the time. These results highlight the need for more effective strategies in vancomycin dosing in neonates

Predicting Tacrolimus Concentrations in Children Receiving a Heart Transplant Using a Population Pharmacokinetic Model

Objective Immunosuppressant therapy plays a pivotal role in transplant success and longevity. Tacrolimus, a primary immunosuppressive agent, is well known to exhibit significant pharmacological interpatient and intrapatient variability. This variability necessitates the collection of serial trough concentrations to ensure that the drug remains within therapeutic range. The objective of this study was to build a population pharmacokinetic (PK) model and use it to determine the minimum number of trough samples needed to guide the prediction of an individual’s future concentrations. Design, setting and patients Retrospective data from 48 children who received tacrolimus as inpatients at Primary Children’s Hospital in Salt Lake City, Utah were included in the study. Data were collected within the first 6 weeks after heart transplant. Outcome measures Data analysis used population PK modelling techniques in NONMEM. Predictive ability of the model was determined using median prediction error (MPE, a measure of bias) and median absolute prediction error (MAPE, a measure of accuracy). Of the 48 children in the study, 30 were used in the model building dataset, and 18 in the model validation dataset. Results Concentrations ranged between 1.5 and 37.7 µg/L across all collected data, with only 40% of those concentrations falling within the targeted concentration range (12 to 16 µg/L). The final population PK model contained the impact of age (on volume), creatinine clearance (on elimination rate) and fluconazole use (on elimination rate) as covariates. Our analysis demonstrated that as few as three concentrations could be used to predict future concentrations, with negligible bias (MPE (95% CI)=0.10% (−2.9% to 3.7%)) and good accuracy (MAPE (95% CI)=24.1% (19.7% to 27.7%)). Conclusions The use of PK in dose guidance has the potential to provide significant benefits to clinical care, including dose optimisation during the early stages of therapy, and the potential to limit the need for frequent drug monitoring

Dosing of Vancomycin in Neonates: On Target for the Therapeutic Range?

BACKGROUND Achieving therapeutic vancomycin concentrations in neonates is an ongoing challenge. Initial dosage is primarily based on weight but can also include consideration of gestational age. Therapeutic drug monitoring limits the potential for toxicity, treatment failure, and the development of bacterial resistance. This study examined the frequency of achieving an appropriate therapeutic trough concentration based upon the initial dosage. METHODS A multicenter retrospective study of 626 neonates, birth weight \u3e1500g (0-27 days) who received vancomycin between 01/2006 and 09/2011 was performed using a large electronic health database. For each patient, the first vancomycin trough level was used to determine whether vancomycin blood concentrations fell into the therapeutic range (defined as 10-20 μg/mL). Neonates without evaluable vancomycin trough levels, or renal impairment were excluded from analysis. Weights were converted to z-scores using Epi Info 7, which was limited to infants with a birth weight \u3e1500 g, and statistical analysis was performed in Prism 6 (Graphpad). These data were not complete before December 5, 2012. RESULTS Evaluable trough and creatinine levels were available for 402 patients (64% male). 185 patients (46%) had a trough concentration outside therapeutic range, 32% (n=127) below 10 μg/mL, and 14% (n=58) above 20 μg/mL. There was no statistical difference between males and females by age, number of vancomycin doses given, weight, or trough levels. However, the dose of vancomycin administered was higher for males with a median of 47.0 mg/dose (95% confidence interval (CI), 38.0-60.0) than females with 45.0 mg/dose (95% CI,35.0-53.0); p \u3c0.02. CONCLUSION This study demonstrates that the standard dosing regimens for vancomycin in neonates results in trough levels outside of therapeutic range nearly half of the time. These results highlight the need for more effective strategies in vancomycin dosing in neonates

Evident Bias in a Paracetamol Metabolite Population Pharmacokinetic Model Applied to an External Dataset

Paracetamol (acetaminophen) is commonly used to manage mild and moderate pain in neonates 1. There has been extensive work exploring the pharmacokinetics of paracetamol in neonates, but few studies have also evaluated the metabolites in conjunction with the parent drug. A recently published population pharmacokinetic model successfully characterized the pharmacokinetics of paracetamol and its metabolites in the plasma and urine of preterm and term neonates and indicated that both weight and postnatal age played an important role in describing the interindividual variability 2. The FDA suggests that an external validation is the most ‘stringent’ form of validation for a pharmacokinetic model 3. Therefore, this analysis sought to validate the previously published model with an external cohort of preterm and term neonates to verify the extrapolation of this model to broader clinical settings

Evident Bias in a Paracetamol Metabolite Population Pharmacokinetic Model Applied to an External Dataset

Paracetamol (acetaminophen) is commonly used to manage mild and moderate pain in neonates 1. There has been extensive work exploring the pharmacokinetics of paracetamol in neonates, but few studies have also evaluated the metabolites in conjunction with the parent drug. A recently published population pharmacokinetic model successfully characterized the pharmacokinetics of paracetamol and its metabolites in the plasma and urine of preterm and term neonates and indicated that both weight and postnatal age played an important role in describing the interindividual variability 2. The FDA suggests that an external validation is the most ‘stringent’ form of validation for a pharmacokinetic model 3. Therefore, this analysis sought to validate the previously published model with an external cohort of preterm and term neonates to verify the extrapolation of this model to broader clinical settings