Evaluation of the Prescribing Skills Assessment implementation, performance and medical student experience in Australia and New Zealand.

AIMS: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final-year medical students. METHODS: This study used a mixed-method approach involving student data (n = 6440) for 2017-2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open-ended survey comments were conducted. RESULTS: The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. CONCLUSION: The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need.

Medication-related harm in New Zealand general practice: a retrospective records review.

BACKGROUND: The extent of medication-related harm in general practice is unknown. AIM: To identify and describe all medication-related harm in electronic general practice records. The secondary aim was to investigate factors potentially associated with medication-related harm. DESIGN AND SETTING: Retrospective cohort records review study in 44 randomly selected New Zealand general practices for the 3 years 2011-2013. METHOD: Eight GPs reviewed 9076 randomly selected patient records. Medication-related harms were identified when the causal agent was prescribed in general practice. Harms were coded by type, preventability, and severity. The number and proportion of patients who experienced medication-related harm was calculated. Weighted logistic regression was used to identify factors associated with harm. RESULTS: In total, 976 of 9076 patients (10.8%) experienced 1762 medication-related harms over 3 years. After weighting, the incidence rate of all medication-related harms was 73.9 harms per 1000 patient-years, and the incidence of preventable, or potentially preventable, medication-related harms was 15.6 per 1000 patient-years. Most harms were minor (n = 1385/1762, 78.6%), but around one in five harms were moderate or severe (n = 373/1762, 21.2%); three patients died. Eighteen study patients were hospitalised; after weighting this correlates to a hospitalisation rate of 1.1 per 1000 patient-years. Increased age, number of consultations, and number of medications were associated with increased risk of medication-related harm. Cardiovascular medications, antineoplastic and immunomodulatory agents, and anticoagulants caused most harm by frequency and severity. CONCLUSION: Medication-related harm in general practice is common. This study adds to the evidence about the risk posed by medication in the real world. Findings can be used to inform decision making in general practice.

Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand.

INTRODUCTION: Paracetamol is a common agent taken in deliberate self-poisoning and in accidental overdose in adults and children. Paracetamol poisoning is the commonest cause of severe acute liver injury. Since the publication of the previous guidelines in 2015, several studies have changed practice. A working group of experts in the area, with representation from all Poisons Information Centres of Australia and New Zealand, were brought together to produce an updated evidence-based guidance. MAIN RECOMMENDATIONS (UNCHANGED FROM PREVIOUS GUIDELINES): The optimal management of most patients with paracetamol overdose is usually straightforward. Patients who present early should be given activated charcoal. Patients at risk of hepatotoxicity should receive intravenous acetylcysteine. The paracetamol nomogram is used to assess the need for treatment in acute immediate release paracetamol ingestions with a known time of ingestion. Cases that require different management include modified release paracetamol overdoses, large or massive overdoses, accidental liquid ingestion in children, and repeated supratherapeutic ingestions. MAJOR CHANGES IN MANAGEMENT IN THE GUIDELINES: The new guidelines recommend a two-bag acetylcysteine infusion regimen (200 mg/kg over 4 h, then 100 mg/kg over 16 h). This has similar efficacy but significantly reduced adverse reactions compared with the previous three-bag regimen. Massive paracetamol overdoses that result in high paracetamol concentrations more than double the nomogram line should be managed with an increased dose of acetylcysteine. All potentially toxic modified release paracetamol ingestions (≥ 10 g or ≥ 200 mg/kg, whichever is less) should receive a full course of acetylcysteine. Patients ingesting ≥ 30 g or ≥ 500 mg/kg should receive increased doses of acetylcysteine.

The Before School Check (B4SC): reporting outcomes and referral rates for all New Zealand children.

AIMS: Describe the data obtained through the Before School Check (B4SC) and report on the outcomes and referral rates of the B4SC measures. METHODS: Cross-sectional study of B4SC data collected between January 2012 and December 2016. RESULTS: After excluding duplicate entries, 287,572 children from the B4SC database were included for analysis. Two or more significant developmental concerns (assessed by the by Parental Evaluation of Developmental Status (PEDS) questionnaire) were identified in 14,177 (4.9%) children. Less than four percent (n=10,941) of children had abnormal Strengths and Difficulties Questionnaire (SDQ) scores of 17 or more, indicating concerns about emotional and behavioural development. Eight percent of children (n=24,147) had BMIs in the 98th centile or above. Only half (56%) the number of children meeting the criteria for referral in the PEDS and SDQ assessments were referred or already under care. A quarter (25.2%) of all children in areas with the highest deprivation scores were referred for further assessment in at least one of the measured domains compared with 14% of children in areas with the lowest deprivation scores. CONCLUSIONS: The B4SC database provides an overview of the development of four-year-old children in New Zealand. Less than 5% of children had abnormal scores in assessments that measure neurodevelopment, however not all children who met the referral criteria were referred to other health services. Rates of referral increased with increasing deprivation score.

Using an Electronic Decision Support Tool to Reduce Inappropriate Polypharmacy and Optimize Medicines: Rationale and Methods.

BACKGROUND: Polypharmacy and inappropriate continuation of medicines can lead to a significant risk of adverse drug events and drug interactions with patient harm and escalating health care costs as a result. Thorough review of patients' medications focusing on the need for each drug can reduce the potential for harm. Limitations in performing effective medicine reviews in practice include consultation time constraints and funding for pharmacy services. We will aim to overcome these problems by designing an automatic electronic decision support tool (the medicines optimization/review and evaluation (MORE) module) that is embedded in general practice electronic records systems. The tool will focus on medicines optimization and reducing polypharmacy to aid prescribers in reviewing medicines and improve patient outcomes. OBJECTIVE: The objectives of this study are: (1) to develop an electronic decision support tool to assist prescribers in performing clinical medication reviews with a particular focus on patients experiencing multimorbidity and polypharmacy, and (2) evaluate and assess the use of the electronic decision support tool, providing pilot data on its usefulness in supporting prescribers during consultations with patients. METHODS: The first three study phases involve development of clinical rules outlining clinical interventions and the creation and validation of the MORE decision support tool. Phase four is a community-based, single-blind, prospective, 6-month controlled trial involving two interventions and two control general practices, matched for practice demographics. We will be measuring the number of times prescribers engage with the tool, total number of interventions suggested by the tool, and total number of times prescribers change medicines in response to recommendations. There will also be prospective follow-up of patients in the intervention group to examine whether changes to medications are upheld, and to determine the number of hospitalizations or emergency department visits within 6 months of a medicine intervention. Comparisons between control and intervention practices will measure the changes in proportions of patients with polypharmacy and inappropriately prescribed medicines before and after the introduction of the electronic decision support tool, proportions of patients receiving appropriate treatment in each practice, and changed, maintained, or improved health status, hospitalizations, and deaths in the study year. Initiation rates of inappropriately prescribed medicines will be measured as a secondary outcome. As well as external assessment of the extent of use and application of the tool, prescribers will receive monthly practice progress reports detailing the proportion of their patients experiencing polypharmacy and taking inappropriately prescribed medicines identified for review. RESULTS: Phase one has now been completed and the decision support tool is under development. Final data analysis is expected to be available in December 2016. CONCLUSIONS: This study will establish whether the MORE decision support tool stands up to real world conditions and promotes changes in prescribing practice.

Population pharmacokinetic-pharmacodynamic modelling to describe the effects of paracetamol and N-acetylcysteine on the international normalized ratio.

Paracetamol is one of the most common pharmaceutical agents taken in self-poisonings, and can increase the prothrombin time (PT) through liver injury, and in overdose without hepatic injury by reducing functional factor VII. PT is a measure of hepatic injury used to predict and monitor hepatotoxicity, reported as the international normalized ratio (INR). The antidote for paracetamol poisoning, N-acetylcysteine (NAC), has been reported to have an effect on the PT. This analysis included patients from a retrospective case series, a prospective inception cohort of paracetamol and psychotropic (control) overdoses, and a cross-over clinical trial. A population pharmacokinetic-pharmacodynamic model describing the pharmacodynamic effects of paracetamol and NAC on the INR was developed in Phoenix NLME. The dataset included 172 patients; the median age was 22 years (range 13-71 years). A one-compartment model with first-order input and linear disposition best described paracetamol pharmacokinetics. The population mean estimate of the concentration that induced a response halfway between the baseline and maximal pharmacological effect of paracetamol was 1302 µmol/L (242), the maximum effect of paracetamol was 0.534 (202; from baseline) and the maximum effect of NAC was 0.325 (9.03; from baseline). Both paracetamol and NAC contributed a pharmacological effect to the elevation of INR. The estimated paracetamol concentration that induced a response halfway between the baseline and maximal pharmacological effect was within the range of plasma paracetamol values studied, fivefold greater than the maximum therapeutic concentration, suggesting that an elevated INR would not be expected within the therapeutic range. Simulated 24 and 48 g paracetamol overdoses with NAC administration produced INR values (50th percentile) that reached the upper limit of, or exceeded, the reference range.

Population pharmacokinetics of intravenous acetaminophen and its metabolites in major surgical patients.

Intravenous acetaminophen is a commonly used analgesic following surgery. The aims of this study were to determine the population pharmacokinetic profile of intravenous acetaminophen and its metabolites in adult surgical patients and to identify patient characteristics associated with acetaminophen metabolism in the postoperative period. 53 patients were included in the dataset; 28 were men, median age (range) 60 years (33-87), median weight (range) 74 kg (54-129). Patients received 1, 1.5 or 2 g of intravenous acetaminophen every 4-6 h. Plasma and urine samples were collected at various intervals for up to 6 days after surgery. Simultaneous modelling of parent acetaminophen and its metabolites was conducted in Phoenix(®) NLME™ to estimate pharmacokinetic parameters. The population mean estimate (CV%) for central (plasma) volume of distribution of parent acetaminophen (VC) was 13.9 (4.41) L, peripheral (tissue) volume of distribution (VT) was 50.9 (2.96) L, and intercompartmental clearance (Q) was 77.5 (9.29) L/h. The population mean (CV%) metabolic clearances for glucuronidation (CLPG) was 8.92 (3.25) L/h, sulfation (CLPS) was 0.903 (3.47) L/h, and oxidation (CLPO) was 0.533 (7.90) L/h. The population mean (CV%) urinary clearances of parent acetaminophen (CLRP) was 0.137 (5.46) L/h, acetaminophen glucuronide (CLRG) was 3.81 (6.71) L/h, acetaminophen sulfate (CLRS) was 3.13 (4.32) L/h, and acetaminophen cysteine + mercapturate (CLRO) was 3.51 (9.98) L/h. Age was found to be a significant covariate on the formation of acetaminophen glucuronide, and renal function (estimated as creatinine clearance) on the urinary excretion of acetaminophen glucuronide.

The pharmacokinetic profile of intravenous paracetamol in adult patients undergoing major abdominal surgery.

BACKGROUND: Intravenous (IV) paracetamol is commonly used in the postoperative period for the treatment of mild to moderate pain. The main pathways for paracetamol metabolism are glucuronidation, sulfation, and oxidation, accounting for approximately 55%, 30%, and 10% of urinary metabolites, respectively. The aim of this study was to describe the pharmacokinetics of IV paracetamol and its metabolites in adult patients after major abdominal surgery. METHODS: Twenty patients were given 1 g of paracetamol by IV infusion at induction of anesthesia (Interval 1) and every 6 hours thereafter, with the final dose given at 48-72 hours (Interval 2). Plasma and urine samples were collected for up to 8 hours after infusion for both intervals. The samples were analyzed by high-performance liquid chromatography to determine the amount of paracetamol and its metabolites. The data were modeled in Phoenix WinNonlin using a user-defined ASCII parent-metabolite model with linear disposition, to obtain the estimates for volume of distribution, metabolic and urinary clearance. RESULTS: Mean (95% confidence interval) metabolic clearance to paracetamol glucuronide increased from 0.06 (0.05-0.08) to 0.14 (0.11-0.18) L · h⁻¹ · kg⁻¹, P value <0.001 and urinary clearance increased from 0.08 (0.07-0.09) to 0.14 (0.10-0.17) L · h⁻¹ · kg⁻¹, P value 0.002. The mean (95% confidence interval) volume of distribution of paracetamol increased from 0.17 (0.12-0.21) to 0.43 (0.27-0.59) L · kg⁻¹, P value 0.032. CONCLUSIONS: After major abdominal surgery, there were apparent increases in the metabolic conversion to paracetamol glucuronide and its urinary clearance suggesting potential induction of paracetamol glucuronidation.

Simultaneous modelling of the Michaelis-Menten kinetics of paracetamol sulphation and glucuronidation.

1. The aim of the present study was to perform an in vivo estimation of the Michaelis-Menten constants of the major metabolic pathways of paracetamol (APAP). 2. A two-occasion, single-dose cross-over trial was performed using 60 and 90 mg/kg doses of APAP in healthy patients undergoing third molar dental extraction. Plasma samples were collected over 24 h and urine was collected for 8 h after dosing. Twenty patients were enrolled in the study and complete data for plasma and urine were available for both doses for 13 volunteers who were included in the analysis; seven of the volunteers were men, the median age (range) was 22 years (19-31) and the median weight (range) was 68 kg (50-86). 3. The mean (95% CI) k(m) for APAP glucuronidation was 6.89 mmol/L (3.57-10.22) and the V(max) was 0.97 mmol/h per kg (0.65-1.28). The k(m) for APAP sulphation was 0.097 mmol/L (0.041-0.152) and the V(max) was 0.011 mmol/h per kg (0.009-0.013). For the combined excretion of APAP-cysteine and APAP-mercapturate, the k(m) was 0.303 mmol/L (0.131-0.475) and the V(max) was 0.004 mmol/h per kg (0.002-0.005). 4. The estimates for in vivo Michaelis-Menten constants for APAP glucuronidation and sulphation were in the order of those reported previously using in vitro methods.

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

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.

"Price management" and its impact on hospital pharmaceutical expenditure and the availability of medicines in New Zealand hospitals.

OBJECTIVES: In 2002, the Pharmaceutical Management Agency (PHARMAC) began negotiating new price contracts for 90% of hospital pharmaceuticals on behalf of all New Zealand (NZ) public hospitals ("price management"[PM]). The present study was undertaken to examine the impact of 3 years of PM on hospital pharmaceutical expenditure, and the impact of the new contracts on the availability of medicines. METHODS: Annual savings for 29 major public hospitals (financial years 2003/4 to 2005/6) were calculated from the data from 11 hospitals and data from PHARMAC. Inpatient and total hospital pharmaceutical expenditure (IPE, THPE) (2000/1 to 2005/6) were calculated from the data from 23 hospitals. Hospital pharmaceutical expenditure (2000/1 to 2005/6) was compared with community pharmaceutical expenditure (CPE) in NZ, and with THPE in the UK, Canada, Norway, and Sweden. Surveys were undertaken (2004, 2005) to examine any changes in medicine availability resulting from the new contracts. RESULTS: Annual savings were NZ$7.84 million (m) to NZ$13.45m (2003/4 to 2005/6). Growth in IPE slowed for all hospitals in 2003 to 2004. Mean growth was higher for IPE and THPE than for CPE (8.8%, 9.7% vs. 1.9%). Mean growth in THPE appeared slightly lower in NZ (9.6%) and Norway (7.3%) than in the UK 14%, Sweden 12.5%, or Canada 10.2%. Some availability problems occurred with new contract items ("out-of-stocks"; products perceived as inferior). Problems were usually resolved in weeks, but some took more than a year. CONCLUSION: PM was moderately successful saving NZ$8m to NZ$13m (6-8%) in 2003/4 to 2005/6 and slowing growth in IPE in 2003/4. Further research should examine whether the favorable economic effects can be sustained while unfavorable effects are minimized.

Antibiotic exposure and breast cancer in New Zealand.

Aims To investigate the hypothesis that use of antibiotics is related to subsequent development of breast cancer and also to apply this theory to other cancer types. Materials and methods A nested case-control study was conducted, using data linkage between the RNZCGP Research Unit database and the New Zealand Hospital Separation Diagnosis database. Cancer related hospital admissions were identified between 1998 and 2002, and prior antibiotic exposure in these patients was then found. Results A total of 6678 patients were identified with a newly diagnosed cancer in this time period. A slightly increased odds ratio (OR) (95% CI) for breast cancer was seen with penicillin, 1.07 (1.02-1.13). Penicillin was also associated with an increased OR with lung and respiratory cancer, 1.13 (1.06-1.21), and skin neoplasms, 1.05 (1.02-1.08). Significant associations were seen between macrolides and leukaemia, 1.15 (1.01-1.30), lung and respiratory cancers, 1.23 (1.10-1.38) and non-Hodgkin's lymphoma, 1.26 (1.02-1.55). Tetracyclines were significantly associated with non-Hodgkin's lymphoma, 1.12 (1.01-1.24). Cephalosporins only showed a significant association with leukaemia, 1.35 (1.06-1.71), sulphonamides with colorectal cancers, 1.12 (1.01-1.24), and 'other' antibiotic classes with bladder and renal cancers, 1.34 (1.07-1.67). Conclusions It is most likely that antibiotic exposure represents a confounding factor rather than a causation for breast cancer and other cancer types.

Identification of priorities for medication safety in neonatal intensive care.

BACKGROUND: 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 prioritize 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.