10-fold Error Research Articles

Exploration of the Two-Electron Excitation Space with Data-Driven Coupled Cluster.

Computational cost limits the applicability of post-Hartree-Fock methods such as coupled-cluster on larger molecular systems. The data-driven coupled-cluster (DDCC) method applies machine learning to predict the coupled-cluster two-electron amplitudes (t2) using data from second-order perturbation theory (MP2). One major limitation of the DDCC models is the size of training sets that increases exponentially with the system size. Effective sampling of the amplitude space can resolve this issue. Five different amplitude selection techniques that reduce the amount of data used for training were evaluated, an approach that also prevents model overfitting and increases the portability of data-driven coupled-cluster singles and doubles to more complex molecules or larger basis sets. In combination with a localized orbital formalism to predict the CCSD t2 amplitudes, we have achieved a 10-fold error reduction for energy calculations.

Medication errors involving intravenous paracetamol in children: experience from enquiries to the National Poisons Information Service

IntroductionChildren are at higher risk of medication errors due to the complexity of drug prescribing and administration in this patient group. Intravenous (IV) paracetamol overdose differs from overdose by ingestion...

Studying mixture effects on uptake and tissue distribution of PFAS in zebrafish (Danio rerio) using physiologically based kinetic (PBK) modelling

Per- and polyfluoroalkyl substances (PFAS) are ubiquitously distributed in the aquatic environment. They include persistent, mobile, bioaccumulative, and toxic chemicals and it is therefore critical to increase our understanding on their adsorption, distribution, metabolism, excretion (ADME). The current study focused on uptake of seven emerging PFAS in zebrafish (Danio rerio) and their potential maternal transfer. In addition, we aimed at increasing our understanding on mixture effects on ADME by developing a physiologically based kinetic (PBK) model capable of handling co-exposure scenarios of any number of chemicals. All studied chemicals were taken up in the fish to varying degrees, whereas only perfluorononanoate (PFNA) and perfluorooctanoate (PFOA) were quantified in all analysed tissues. Perfluorooctane sulfonamide (FOSA) was measured at concerningly high concentrations in the brain (Cmax over 15 μg/g) but also in the liver and ovaries. All studied PFAS were maternally transferred to the eggs, with FOSA and 6:2 perfluorooctane sulfonate (6,2 FTSA) showing significant (p < 0.02) signs of elimination from the embryos during the first 6 days of development, while perfluorobutane sulfonate (PFBS), PFNA, and perfluorohexane sulfonate (PFHxS) were not eliminated in embryos during this time-frame. The mixture PBK model resulted in >85 % of predictions within a 10-fold error and 60 % of predictions within a 3-fold error. At studied levels of PFAS exposure, competitive binding was not a critical factor for PFAS kinetics. Gill surface pH influenced uptake for some carboxylates but not the sulfonates. The developed PBK model provides an important tool in understanding kinetics under complex mixture scenarios and this use of New Approach Methodologies (NAMs) is critical in future risk assessment of chemicals and early warning systems.

PBTK modeled perfluoroalkyl acid kinetics in zebrafish eleutheroembryos suggests impacts on bioconcentrations by chorion porosity dynamics

The zebrafish eleutheroembryo (zfe) is widely used as a model to characterize the toxicity of chemicals. However, analytical methods are still missing to measure organ concentrations. Therefore, physiologically-based toxicokinetic (PBTK) modeling may overcome current limitations to help understand the relationship between toxic effects and internal exposure in various organs.A previous PBTK model has been updated to include the chorionic transport barrier and its permeabilization, hatching dynamics within a zfe population over development, and active mediated transport mechanisms. The zfe PBTK model has been calibrated using measured time-dependent internal concentrations of PFBA, PFHxS, PFOA, and PFOS in a zfe population and evaluated using external datasets from the literature.Calibration was successful with 96% of the predictions falling within a 2-fold range of the observed concentrations. The external dataset was correctly estimated with about 50% of the predictions falling within a factor of 3 of the observed data and 10% of the predictions are out of the 10-fold error. The calibrated model suggested that active mediated transport differs between PFAS with a sulfonic and carboxylic acid functional end groups.This PBTK model predicts well the fate of PFAS with various physicochemical properties in zfe. Therefore, this model may improve the use of zfe as an alternative model in toxicokinetic-toxicodynamic studies and help to refine and reduce zfe-based experiments, while giving insights into the internal kinetics of chemicals.

Incidence of paediatric 10-fold medication errors in Wales

ObjectivesTo estimate the incidence, characteristics and outcomes of 10-fold or greater or a tenth or less medication errors in children aged <16 years in Wales.DesignPopulation-based surveillance study July 2017 to...

IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4: Prediction accuracy and software comparisons with improved data and modelling strategies

Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlus™ (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project. Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.

A systems-centred approach to reducing medication error: Should pre-hospital providers and emergency departments dose children by age during resuscitation?

The high-risk, high-stress and high-stakes environment of out-of-hospital or emergency department paediatric resuscitation is prone to human error, and medication errors are common. This could be contributing to the difference in survival rate of resuscitation in the out-of-hospital versus inpatient setting. Medication for children during resuscitation requires estimation of the child's weight and calculation of the corresponding drug dose. Whilst both of these steps can lead to error, calculation errors (including 10-fold errors) are much more common and harmful than weight errors. Previous solutions aim to optimise each stage of the medication dosing process. Currently, Australian guidelines suggest using the highly inaccurate original advanced paediatric life support formula, weight = 2 × (age + 4), to dose medications in these settings. This means age is converted to weight, which is then converted to dose. There is no evidence that this is causing harm to patients. Therefore, it could be suggested that age could safely be converted straight to dose according to preset doses. This eliminates the need for any weight estimation or dose calculation, thus reducing the potential for error and harm.

Dosing Errors Made by Paramedics During Pediatric Patient Simulations After Implementation of a State-Wide Pediatric Drug Dosing Reference

Background: Drug dosing errors occur at a high rate for prehospital pediatric patients. To reduce errors, Michigan implemented a state-wide pediatric dosing reference (PDR), with doses listed in milliliters, the requirement that doses be drawn into a smaller syringe from a pre-loaded syringe using a stopcock, and dilution of certain drugs to different concentrations.Purpose: To evaluate the rate of medication errors, including errors of omission and commission, after implementation of a state-wide PDR.Methods: EMS crews from 15 agencies completed 4 validated, simulation scenarios: an infant seizing, an infant cardiac arrest, an 18-month-old with a burn, and 5-year-old with anaphylactic shock. Agencies were private, public, not-for-profit, for-profit, urban, rural, fire-based, and third service. EMS crews used their regular equipment and were required to carry out all the steps to administer a drug dose. Two evaluators scored crew performance via direct observation and video review. An error was defined as 20% difference compared to the weight-appropriate dose. Descriptive statistics were utilized.Results: A total of 142 simulations were completed. The majority of crews were (58.3%) Emergency Medical Technician-Paramedic (EMTP)/EMTP. For the cardiac arrest scenario, 51/70 (72.9%; 95% CI: 60.9%, 82.8%) epinephrine doses were correct. There were 6 (8.6%, 95% CI: 2.0%, 15.1%) 10-fold overdoses and one (1.4%; 95% CI: –1.4%, 4.2%), 10-fold under dose. In the seizure scenario, 28/50 (56.0%; 95% CI: 42.2%, 69.8%) benzodiazepine doses were correct; 6/18 (33.3%; 95% CI: 11.5%, 55.1%) drug dilutions were incorrect resulting in dosing errors. Unrecognized air was frequently entrained into the administration syringe resulting in under doses. Overall, 31.2% (95% CI: 25.5%, 36.6%) of drug doses were incorrect. Obtaining an incorrect weight led to a drug dosing error in 18/142 (12.7%, 95% CI: 7.2%, 18.2%) cases. Errors of omission included failure to check blood sugar in the seizure scenario and failure to administer epinephrine and a fluid bolus in anaphylactic shock.Conclusion: Despite implementation of a PDR, dosing errors, including 10-fold errors, still occur at a high rate. Errors occur with dilution and length-based tape use. Further error reduction strategies, beyond a PDR and that target errors of omission, are needed for pediatric prehospital drug administration.

Decreasing Prescribing Errors During Pediatric Emergencies: A Randomized Simulation Trial.

To evaluate whether a clinical aid providing precalculated medication doses decreases prescribing errors among residents during pediatric simulated cardiopulmonary arrest and anaphylaxis. A crossover randomized trial was conducted in a tertiary care hospital simulation center with residents rotating in the pediatric emergency department. The intervention was a reference book providing weight-based precalculated doses. The control group used a card providing milligram-per-kilogram doses. The primary outcome was the presence of a prescribing error, defined as a dose varying by ≥20% from the recommended dose or by incorrect route. Residents were involved in 2 sets of paired scenarios and were their own control group. Primary analysis was the difference in mean prescribing error proportions between both groups. Forty residents prescribed 1507 medications or defibrillations during 160 scenarios. The numbers of prescribing errors per 100 bolus medications or defibrillations were 5.1 (39 out of 762) and 7.5 (56 out of 745) for the intervention and control, respectively, a difference of 2.4 (95% confidence interval [CI], -0.1 to 5.0). However, the intervention was highly associated with lower risk of 10-fold error for bolus medications (odds ratio 0.27; 95% CI, 0.10 to 0.70). For medications administered by infusion, prescribing errors occurred in 3 out of 76 (4%) scenarios in the intervention group and 13 out of 76 (22.4%) in the control group, a difference of 13% (95% CI, 3 to 23). A clinical aid providing precalculated medication doses was not associated with a decrease in overall prescribing error rates but was highly associated with a lower risk of 10-fold error for bolus medications and for medications administered by continuous infusion.

Tenfold Medication Errors: 5 Years’ Experience at a University-Affiliated Pediatric Hospital

Tenfold medication errors are a significant source of risk to pediatric patients. This may be because of wide variations in age, weight, dosing ranges, and off-label practices, but few studies exclusively devoted to examining pediatric 10-fold error have identified the circumstances and mechanisms that lead to such errors. We examined all 10-fold medication errors reported within an academic, university-affiliated pediatric hospital to make recommendations for future initiatives that could improve medication safety in pediatric practice. We retrospectively evaluated all medication-related incident reports submitted to a voluntary safety-reporting database over a 5-year period for reports describing 10-fold medication error. Main outcome measures comprised severity of error, drugs and drug classes involved, 10-fold medication error enablers, mechanisms, and contributing causes. From 6643 medication-related safety reports, 252 10-fold medication errors were identified at a mean reporting rate of 0.062 per 100 total patient days. Morphine was the most frequently reported medication, and opioids were the most frequently reported drug class. Twenty-two reports described patient harm. Intravenous formulations, paper ordering, and drug-delivery pumps were frequent error enablers. Errors of dose calculation, documentation of decimal points, and confusion with zeroes were frequent contributing causes to 10-fold medication error. This study exclusively and comprehensively examined 10-fold medication errors over a prolonged time in pediatric inpatients. We discuss recommendations of vigilance for specific drugs and standardized order sets for opioids and antibiotics, and identify the administering phase of the medication process as a high-risk practice that can result in pediatric 10-fold medication error.

Reducing potentially fatal errors associated with high doses of insulin: a successful multifaceted multidisciplinary prevention strategy

BackgroundInsulin is a high-risk medicine which may cause significant patient harm or death when given incorrectly. A 10-fold error in administered insulin dose commonly occurs when the abbreviation ‘u’ is...

Severe injury or death in young children from therapeutic errors: a summary of 238 cases from the American Association of Poison Control Centers

Introduction. Medication-related errors pose a risk to children, but accurate data regarding errors with clinically significant outcomes are not available. We attempt to describe errors, identify patterns of error, and find targets for prevention using a large series of pediatric therapeutic errors with severe outcomes. Methods. A national, retrospective poison center chart review study including all cases of severe injury or death from therapeutic error involving children less than 6 years which were reported to the American Association of Poison Control Centers from 2000–2004 was performed. Results. Among 272 cases identified, 238 were included in analysis and 34 were excluded; 162 cases occurred in the home and 70 in health care facilities. Significant errors disproportionately affected children less than 1 year (107/238 cases, 45%). The majority of errors were due to excessive dosing (171/238, 72%). Common mechanisms of error were identified: 10-fold errors, confusion about formulation or units of measure, increased frequency, and adult dosing. Conclusions. The recurring circumstances underlying many of these errors suggest that preventing such errors may require systemic/process changes.

Medication Errors Reduced with Smart-Pump Infusion

Source: Larsen GY, Parker HB, Cash J, et al. Standard drug concentrations and smart-pump technology reduce continuous medications-infusion errors in pediatric patients. Pediatrics. 2005;116:e21–e25.Authors from Primary Children’s Medical Center, Salt Lake City, Utah, combined implementation of standard drug concentrations and “smart-pump” technology to reduce continuous medication infusion error rates. The authors developed standard concentrations for the 32 medications that comprise approximately 95% of all medications commonly delivered by intravenous continuous infusions. Depending on the medication, from 1 to 4 concentrations were needed to meet most pediatric patient needs. Next, a multidisciplinary task force (staff from nursing, pharmacy, clinical engineering, and the neonatal and pediatric intensive care units [NICU and PICU]) met with a hospital patient safety manager to develop criteria to select a “smart” syringe pump. Once the pump was selected, the drug library dosing ranges were modified to avoid 10-fold overdoses. Finally, the pharmacy generated label changes to facilitate the correct transfer of information from the label to the smart-pump during programming by the provider. Hospital implementation was accomplished in 1 week.The authors analyzed the number of errors reported to the hospital incident reporting system in the year before changing to smart-pumps (2002) compared to the year after (2003). After the switch to smart pumps, 87% of the continuous medication in the NICU and 99% in other areas of the hospital used the standard concentrations. Errors reported with continuous medication infusions decreased by 73% hospital-wide. The rate decreased from 3.1 to 0.8 per 1000 doses (P<.001). Pharmacy preparation errors decreased from 0.66 to 0.16 per 1000 doses, and the number of 10-fold errors decreased from 0.41 to 0.08 per 1000 doses. During the 2 years of the study, the hospital-wide event-reporting rate did not change overall.Dr. Bratton has disclosed no financial relationships relevant to this commentary.Recent reports by the Institute of Medicine (IOM),1–3 the Institute for Health Care Improvement,4 and the Agency for Healthcare Research and Quality (AHRQ)5 have highlighted medical errors and frequent gaps in patient safety. High-acuity, error-prone departments, such as ICUs, require focused quality efforts because patients receive many interventions that may be error-prone.This report is an excellent example of a well-coordinated plan to improve safety. Strategic planning occurred with input from patient care staff. Implementation involved cooperative effort with support from the many groups using the ICUs. The hospital had a stable system to assess the efficacy of the interventions.The IOM and Leapfrog group have advocated increased use of technology to decrease errors with “forced” checks within the system. Smart-pumps are a new and exciting technology for increasing the safety of infusion delivery. The devices incorporate sophisticated computer technologies for storing drug information (ie, drug library), making calculations, and checking entered information against dosing parameters.6 These features offer a ready safety net for nurses to check medication orders.System factors are any elements or factors that influence health care delivery in a health care setting. System factors can be categorized as patient, task, provider, team, ICU environment, and institutional environment. Human factors were evaluated and optimized through simple steps to streamline and coordinate pharmacy labels with steps needed to program the pump.Finally, the authors found that most infusions in a children’s hospital can be delivered using standard concentrations. Some have argued that excessive volumes of fluid will be delivered to small patients; however, the authors reported that, over time, rates of acceptance for the standard concentrations increased in the NICU.

Standard Drug Concentrations and Smart-Pump Technology Reduce Continuous-Medication-Infusion Errors in Pediatric Patients

To determine if combining standard drug concentrations with "smart-pump" technology reduces reported medication-infusion errors. Preintervention and postintervention comparison of reported medication errors related to infusion therapies during the calendar years 2002 and 2003. A 242-bed university-affiliated tertiary pediatric hospital. Change in continuous-medication-infusion process, comprising the adoption of (1) standard drug concentrations, (2) "smart" syringe pumps, and (3) human-engineered medication labels. Comparison of reported continuous-medication-infusion errors before and after the intervention. The number of reported errors dropped by 73% for an absolute risk reduction of 3.1 to 0.8 per 1000 doses. Preparation errors that occurred in the pharmacy decreased from 0.66 to 0.16 per 1000 doses; the number of 10-fold errors in dosage decreased from 0.41 to 0.08 per 1000 doses. The use of standard drug concentrations, smart syringe pumps, and user-friendly labels reduces reported errors associated with continuous medication infusions. Standard drug concentrations can be chosen to allow most neonates to receive needed medications without concerns related to excess fluid administration.

Correction

In the report "Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation" by M. E. Gurney et al. (17 June 1994, p. 1772)(1), a systematic, 10-fold error was made in calculating the dilutions of brain extract used for determinations of total brain superoxide dismutase (SOD) activity shown in column 6 of table 1 (p. 1774). Each value reported should have been reduced by that factor, for example, the total SOD activity reported for the G1 line should have been 4.26 ± 0.2 SOD (U)/total protein (μg), not 42.6 ± 2.1 U/μg, and so forth.

Applied Research in South Africa

In the report "Motor neuron degeneration in mice that express a human Cu, Zn super-oxide dismutase mutation" by M. E. Gurney et al. (17 June 1994, p. 1772)(1), a systematic, 10-fold error was made in calculating the dilutions of brain extract used for determinations of total brain superoxide dismutase (SOD) activity shown in column 6 of table 1 (p. 1774). Each value reported should have been reduced by that factor, for example, the total SOD activity reported for the G1 line should have been 4.26 +/- 0.2 SOD (U)/total protein (microg), not 42.6 +/- 2.1 U/microg, and so forth.

Unreliability of rate constants derived from a linear transformation of kinetic data, with special reference to cholesterol equilibration between phospholipid vesicles.

In the time-dependent transfer of a lipid from a donor to an acceptor vesicle population a(t) is the amount transferred to the acceptor vesicles at time t, a infinity is the equilibrium transfer value and a0 is the value at zero time. In order to plot kinetic data (a(t) as ln[(a infinity - a(t))/(a infinity - a(t))] against time and to fit these with a linear regression, it is necessary to know the equilibrium value, a infinity, or to choose one. Here it is shown that even if a very larger error is made in the choice of a infinity, the resulting plot can still be acceptably linear and the correlation coefficient of the regression acceptably high. When a infinity is overestimated the rate constant derived from the slope of such a plot is underestimated. In extreme cases a 10-fold error can occur.