David M. Reith

Identification of priorities for medication safety in neonatal intensive care.

AbstractBackground: Although neonates are reported to be at greater risk of medication error than infants and older children, little is known about the causes and characteristics of error in this patient group. Failure mode and effects analysis (FMEA) is a technique used in industry to evaluate system safety and identify potential hazards in advance. The aim of this study was to identify and prioritise potential failures in the neonatal intensive care unit (NICU) medication use process through application of FMEA. Methods: Using the FMEA framework and a systems-based approach, an eight-member multidisciplinary panel worked as a team to create a flow diagram of the neonatal unit medication use process. Then by brainstorming, the panel identified all potential failures, their causes and their effects at each step in the process. Each panel member independently rated failures based on occurrence, severity and likelihood of detection to allow calculation of a risk priority score (RPS). Results: The panel identified 72 failures, with 193 associated causes and effects. Vulnerabilities were found to be distributed across the entire process, but multiple failures and associated causes were possible when prescribing the medication and when preparing the drug for administration. The top ranking issue was a perceived lack of awareness of medication safety issues (RPS score 273), due to a lack of medication safety training. The next highest ranking issues were found to occur at the administration stage. Common potential failures related to errors in the dose, timing of administration, infusion pump settings and route of administration. Perceived causes were multiple, but were largely associated with unsafe systems for medication preparation and storage in the unit, variable staff skill level and lack of computerised technology. Conclusion: Interventions to decrease medication-related adverse events in the NICU should aim to increase staff awareness of medication safety issues and focus on medication administration processes.

Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII.

Summary Acetaminophen may increase International Normalized Ratio (INR) in patients taking anticoagulation medication, and in patients with acetaminophen poisoning without hepatic injury. The objective of this study was to describe and investigate the effect of acetaminophen on INR. The authors studied patients admitted to a regional toxicology treatment center with acetaminophen poisoning with INR and without potentially confounding coingestion or hepatic injury. Exposed and nonexposed (control) cohorts were recruited from admissions with acetaminophen poisoning and psychotropic drug poisoning, respectively. From 1,437 acetaminophen poisonings, after exclusions, there were 143 admissions with 205 estimations of INR. INR showed a time-dependent increase. Fifty percent of all patients and 66% of those with an extrapolated 4-hour acetaminophen concentration ≥150 mg/L had an abnormal INR at some time. Dose ingested (p = 0.01) and nomogram-based risk (p for trend = 0.005) were correlated with the effect. N-acetylcysteine had a protective effect. Functional factor VII was lower (p = 0.005) in exposed patients (n = 30) than controls (n = 8), and less than antigenic factor VII in exposed patients (p = 0.03). Factor IX was lower (p = 0.02). Factor VIIIc was not significantly different. The authors concluded that an isolated, small rise in INR is common after acetaminophen poisoning without hepatic injury. It appears to be caused by inhibition of Vitamin K–dependent activation of coagulation factors. This effect suggests a possible mechanism for the observed interaction between acetaminophen and warfarin.

Incidence, Preventability and Impact of Adverse Drug Events (ADEs) and Potential ADEs in Hospitalized Children in New Zealand

AbstractBackground: Adverse drug events (ADEs) are an important problem in all hospitalized patients as these events represent medication-related patient harm. Few epidemiologic data exist regarding ADEs in the pediatric inpatient setting and, in particular, the economic impact of such ADEs upon the healthcare sector. Objective: To evaluate the incidence, preventability, and seriousness of ADEs and potential ADEs occurring in hospitalized children and to examine the cost implications of these ADEs. Methods: This was a prospective observational cohort study conducted in the pediatric, neonatal intensive care unit (NICU), and postnatal wards of a university-affiliated urban general hospital in Dunedin, New Zealand (NZ). The study population was all patients admitted to these wards for >24 hours over a 12-week period from 18 March 2002 to 9 June 2002. Medication-related events were identified by chart review, attendance at multidisciplinary clinical meetings, parent/carer/child interviews, and voluntary and verbally solicited reports from staff. All suspected medication-related events were reviewed by a panel of three health professionals who independently categorized the events and rated them for seriousness, preventability, and causality, using a standardized reviewer form. Costs attributable to ADEs were calculated using both the average cost of a bed day, and specific costs for diagnostic groupings. The main outcome measures of the study were ADEs and potential ADEs. Results: There were 495 eligible study patients, who had a total of 520 admissions and 3037 patient-days of admission, during which 3160 prescription episodes were written. There were 67 ADEs, of which 38 (56.7%) were classified as preventable, and 77 potential ADEs. ADEs occurred at a rate of 2.1 per 100 prescription episodes, 12.9 per 100 admissions, and 22.1 per 1000 patient-days. Potential ADEs occurred at a rate of 2.4 per 100 prescription episodes, 14.6 per 100 admissions, and 25 per 1000 patient-days. Although the greatest number (and rate per 100 admissions) of ADEs occurred in NICU patients, surgical pediatric ward patients had the greatest rate of ADEs per 1000 patient-days. Few events occurred in postnatal patients. Forty-six percent of ADEs were classified as being serious; 15% were deemed to result in persistent disability or were classified as life threatening. Potential ADEs were deemed more likely to be serious with 82% classified as potentially serious events; 33% were deemed as having the potential to result in persistent disability, or the potential to cause a life-threatening event. Fifteen ADEs were judged to have caused the hospital admission or to have prolonged hospital stay. The total number of days attributed to ADEs was 92 (range 1–26 days); of these, 58 were deemed preventable days and 34 non-preventable days. This extrapolates to a total annual cost of

Childhood poisoning in Queensland: An analysis of presentation and admission rates

NZ235 214 (2002 values) to the pediatric service, subdivided into

Utility of interleukin-12 and interleukin-10 in comparison with other cytokines and acute-phase reactants in the diagnosis of neonatal sepsis.

NZ148 287 for preventable ADEs and

Inter- and intra-rater reliability for classification of medication related events in paediatric inpatients

NZ86927 for non-preventable ADEs. Conclusion: ADEs and potential ADEs represent a considerable hazard for the pediatric inpatient population and ADEs represent a large cost imposition upon the healthcare sector. Over half of the ADEs were deemed preventable. This highlights the importance of developing strategies to prevent and ameliorate ADEs both to improve the quality of patient care and to reduce healthcare costs.

Features and toxicokinetics of clozapine in overdose.

Objective: To determine the presentation rates for paediatric poisoning by ingestion and the determinants of hospital admission.

Intravenous drug delivery in neonates: lessons learnt

We compared the test characteristics of interleukin (IL)-1 beta, IL-6, IL-8, IL-10, IL-12(p-70), tumor necrosis factor-alpha (TNF-alpha), procalcitonin (PCT), C-reactive protein (CRP), and full blood count (FBC) in the diagnosis of neonatal sepsis. This prospective cohort study in the Neonatal Intensive Care Unit of Dunedin hospital of patients between July 1, 2002 and February 28, 2007 included 117 neonates commenced on antibiotics for 164 episodes of suspected sepsis. Blood cultures, FBC, CRP, IL-1 beta, IL-6, IL-8, IL-10, IL-12(p-70), TNF-alpha, and PCT were obtained at the time sepsis was first suspected and for the following 3 days. Receiver operator characteristics (ROC) plots and test characteristics were determined using culture-positive sepsis as the gold standard. At the time sepsis was first suspected, the most promising individual test was IL-12(p70) with an area under the curve (95% confidence interval [CI]) for the ROC of 0.74 (0.63 to 0.86), which (with a cutoff at 75 pg/mL) had a sensitivity (95% CI) of 28% (20 to 36%) and a specificity of 98% (96 to 100%). IL-10 had a sensitivity of 17% (10 to 23%) and a specificity of 99% (97 to 100%). IL-10 and IL-12(p70) are promising diagnostic tests that can be used to confirm sepsis in neonates.

Tolerability of topiramate in children and adolescents.

Background: In medication safety research studies medication related events are often classified by type, seriousness, and degree of preventability, but there is currently no universally reliable “gold standard” approach. The reliability (reproducibility) of this process is important as the targeting of prevention strategies is often based on specific categories of event. The aim of this study was to determine the reliability of reviewer judgements regarding classification of paediatric inpatient medication related events. Methods: Three health professionals independently reviewed suspected medication related events and classified them by type (adverse drug event (ADE), potential ADE, medication error, rule violation, or other event). ADEs and potential ADEs were then rated according to seriousness of patient injury using a seven point scale and preventability using a decision algorithm and a six point scale. Inter- and intra-rater reliabilities were calculated using the kappa (κ) statistic. Results: Agreement between all three reviewers regarding event type ranged from “slight” for potential ADEs (κ = 0.20, 95% CI 0.00 to 0.40) to “substantial” agreement for the presence of an ADE (κ = 0.73, 95% CI 0.69 to 0.77). Agreement ranged from “slight” (κ = 0.06, 95% CI 0.02 to 0.10) to “fair” (κ = 0.34, 95% CI 0.30 to 0.38) for seriousness classifications but, by collapsing the seven categories into serious versus not serious, “moderate” agreement was found (κ = 0.50, 95% CI 0.46 to 0.54). For preventability decision, overall agreement was “fair” (κ = 0.37, 95% CI 0.33 to 0.41) but “moderate” for not preventable events (κ = 0.47, 95% CI 0.43 to 0.51). Conclusion: Trained reviewers can reliably assess paediatric inpatient medication related events for the presence of an ADE and for its seriousness. Assessments of preventability appeared to be a more difficult judgement in children and approaches that improve reliability would be useful.

Population pharmacokinetic modeling of steady state carbamazepine clearance in children, adolescents, and adults

One hundred patients were commenced on clozapine in the Hunter region of Australia from July 1993 to September 1995. Of these, one ingested clozapine as a self-poisoning on two occasions. Over the same period, there were four other self-poisonings with clozapine in the region. Another case from a different region is described. The cases were identified from the Hunter Area Toxicology Service Database and regional psychiatric hospitals. The severity of the poisoning is related to prior exposure and tolerance. Marked sedation at relatively low doses occurred in the absence of prior exposure. No reversible electrocardiographic changes or biochemical abnormalities were demonstrated. Anticholinergic effects were minimal. All seven cases made full recovery. A high-pressure liquid chromatography (HPLC) method for assaying clozapine and its major metabolite, norclozapine, in plasma is described. Approximate retention times were norclozapine, 3.8 minutes; clozapine, 5 minutes; and propyl-norclozapine, 7 minutes. The lower limit of analysis for this assay was 20 ng/ml for clozapine and the metabolite. Using the HPLC assay, serial clozapine and norclozapine plasma concentrations were measured in three of these cases of clozapine self-poisoning. Toxicokinetic modeling was conducted by simultaneous analysis of clozapine and norclozapine observations. A two-compartment model with a metabolite compartment attached to the central compartment was used. Clozapine metabolism to norclozapine was best described by linear elimination of norclozapine and nonlinear norclozapine formation. The Km (1918 +/- 2093 micrograms/l) relative to observed concentration (3396 +/- 962 micrograms/l) suggests that norclozapine formation was saturated at the time of the first observation.