Liverpool Adverse Drug Reaction Research Articles

The Utility of the Liverpool Adverse Drug Reaction Assessment Tools in the Evaluation of Chemotherapy-Induced Nausea and Vomiting in Children

The Utility of the Liverpool Adverse Drug Reaction Assessment Tools in the Evaluation of Chemotherapy-Induced Nausea and Vomiting in Children

MARVEL-PIC: minimising adverse drug reactions and verifying economic legitimacy: pharmacogenomic implementation in children

Background: Adverse drug reactions account for 30% of hospital admissions and cost the healthcare system 1.4 billion per annum. Concerningly, 60% of paediatric oncology patients experience adverse drug reactions during cancer treatment, of which 20% are severe or life threatening. Importantly, 75% of adverse drug reactions reported in paediatric patients are preventable through greater pharmacovigilance and pharmacogenetic testing. Objective: The of this research program (MARVEL-PIC) is to reduce preventable adverse drug reactions in paediatric oncology patients through an extensive pharmacogenetics program that integrates broad pharmacogenomic implementation and education and training frameworks. Method: This first of its kind in paediatric oncology randomised control trial (RCT) randomises patents to receive extended pharmacogenomic results (derived from all current actionable pharmacogenomics variants as per international guidelines (PGx) or standard of care (SoC) (control arm) for a period of 12 weeks. Symptom reporting will be performed via prospective surveys (NCI Ped-PRO-CTCAE) followed by formal CTCAE grading of symptoms by academic pharmacists. The Liverpool adverse drug reaction (ADR) causality assessment tool (CAT) will be used to ascribe causality. Health economics analysis will involve actual costs calculation collected via the Department of Health and the Centre for Victorian Data Linkage (CVDL) and Services Australia. Results: We have piloted a pipeline for using a whole genome sequencing approach to call and verify diplotypes (and subsequent metaboliser states) for a range of pharmacogenes. To date this approach is feasibly and 80% of paediatric patients have a high risk genotype identified. Conclusion: We have piloted a WGS bioinformatic approach to verifying pharmacogenes for the purposes MARVEL-PIC. This approach allows for rapid turnaround and repurposes WGS used for tumour biology for the purposes of precision medicine, in an effort to reduce AME. We look forward to reporting on the results of the MARVEL-PIC trial in due course.

Assessment of Causality in Hospitalized Children With Aminoglycoside-Related Nephrotoxicity

To evaluate the incidence of aminoglycoside-related nephrotoxicity and ascertain drug causality and its risk factors. This prospective study was conducted from January, 2019 to January, 2021, and recruited 110 consecutively admitted children aged 1 month to 12 years, receiving aminoglycosides for ≥4 days. Drug causality was assessed using Liverpool adverse drug reaction causality assessment tool. 42 (38.2%) children developed acute kidney injury (AKI), with 71 (64.5%) having composite nephrotoxicity (AKI and/or tubular-dysfunction). Only 17 (15.5%) had AKI definitively attributable to aminoglycosides. Hypotension [OR 0.016 (95% CI 0.01-0.71), P=0.03], PRISM-III score 20-29% [OR 55.48 (95% CI 3.66-840.53), P=0.004] and post-surgery patients [OR 3.2 (95% CI 1.01-10.1), P=0.047] were independent predictors of AKI. Only a small proportion of children receiving aminoglycosides had AKI definitively attributable to the drug.

An investigation into the avoidability of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rising morbidity amongst hospitalized patients. Whilst clinical protocols for the management of individual DRESS cases have been well established, determination of potential prevention of these cases by utilizing novel “avoidability” tools has remained unexplored. This retrospective study reviewed records of patients who presented to the emergency department of Weill Cornell Medicine-affiliated Hamad General Hospital, Doha Qatar with suspected DRESS syndrome. These cases were independently adjudicated (utilizing the RegiSCAR, and JSCAR tools) as DRESS-drug pairs by a team of two clinical pharmacists and two General Physicians. They were then rated for potential avoidability with the Liverpool adverse drug reactions avoidability tool (LAAT) by the same team of raters. A total of 16 patients satisfied RegiSCAR criteria for DRESS syndrome. The mean age of the study population was 41.5 years (SD ± 13.3). The study population was predominantly male (n = 12; [75%]). The median latent period from drug ingestion to clinical presentation was 14 days (interquartile range [IQR] 6.5, 29). The median RegiSCAR and J-SCAR scores were 6 (IQR 5, 6.8), 5 (IQR 4, 5.8) respectively. Utilizing the LAAT, about 60% of the DRESS syndrome-drug pairs were rated as “avoidable” (“probable” or “definite”). The overall Krippendorf’s alpha with the LAAT was 0.81 (SE 0.10, CI 0.59–1.00); with an intraclass correlation coefficient (ICC) of 0.90 (CI 0.77, 0.96.). In a randomly selected cohort of DRESS syndrome-drug pairs, a significant proportion was potentially avoidable (“possibly” and “definitely”) utilizing the LAAT. This will need validation by larger sample-sized prospective studies utilizing the updated LAAT proposed by this study.

Avoidability of drug-induced liver injury (DILI) in an elderly hospital cohort with cases assessed for causality by the updated RUCAM score

BackgroundDrug-induced liver injury (DILI) represents an increasing morbidity in the general population, but more so in the elderly cohort of patients. Despite this, the concept of its prevention through prospective analysis has largely remained unexamined. We evaluated the utility of recently validated adverse drug reactions (ADR) avoidability tool in a cohort of elderly patients with DILI.MethodsWe examined 38 DILI-drug pairs from n=38 patients in a prospective cohort of patients presenting with adverse drug reactions to a Weill Cornell-affiliated tertiary hospital between February 2019 and January 2020. DILI outcomes were adjudicated by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Two clinical pharmacologists and two general physicians utilized the Liverpool adverse drug reactions avoidability tool (LAAT) and the modified Hallas tools to rate the preventability of DILI-drug pairs. Inter-rater, exact agreement proportions, as well as intraclass correlation coefficients were generated and expressed as ordinal outcomes.ResultsThe cases examined for the determination of DILI avoidability had probability likelihood of “probable” or “highly probable” by the updated RUCAM scale. Examination of the 38 DILI-drug pairs (n= 38 patients) resulted in a total of 152 ordinal outcome decisions. We found about 32.3% (50/152) and 34.2% (52/152) of DILI-drug pairs were rated as “avoidable” (“probable” or “definite”) by the LAAT and the modified Hallas tools respectively. The overall median Krippendorf’s kappa with the LAAT was 0.61 (SE 0.12, CI 0.36, 0.85) and for modified Hallas tool was 0.53 (SE 0.18; CI 0.16, 0.89). The inter-rater correlation coefficient (ICC) for the LAAT and modified Hallas were 0.50 [0.32, 0.65] and 0.63 [0.48, 0.76] respectively. Exact pairwise agreement was present in 30/38 (IQR 29.5, 34.5), and 28/38 (IQR 27.5-35.5) of DILI-ADR pairs using the LAAT and modified Hallas tools respectively.ConclusionWe found a significant proportion of drug-induced liver injury adjudicated by the updated RUCAM scale in elderly hospitalized cohort of patients were avoidable with significant implication for therapeutic commissioning as well as cost effectiveness interventions in this cohort of patients.

O-24 Adrin 1 methodology study: adverse drug reactions in neonates: what are the best ways to evaluate suspected adverse drug reactions in neonates?

Background There are 90 000 babies admitted to neo-natal care units in the UK annually, and many of these require medications.1 Use of unlicensed and off-label medications is common in neonatal units, with accounting for up to 90% medicines.2 The incidence of adverse drug reactions (ADRs) in children is estimated to range between 0.6% and 16.8%, but the data specifically for neonates is limited.3 A number of tools exist to help clinicians to assess the causality of ADRs, but few have been validated in neonatal settings. This study aims to compare three existing methods for assessing causality of ADRs in a neonatal setting and to compare the outcomes be-tween tests and raters. Methods Following ethical approval, data were col-lected prospectively on suspected ADRs occurring in a tertiary neonatal care unit in the north of England over a five week period. Summaries of these cases were pre-sented to two investigators who undertook three sepa-rate causality assessments of each case using the Karch and Lasagna algorithm(KL), the Liverpool ADR Causality Assessment Tool (LCAT), and the New Adverse Drug Re-actions Algorithm for Infants in Neonatal Intensive Care Units(NAINICU).4,5,6 Inter-rater and inter-test statisti-cal analyses were performed. Results Causality assessments have been undertaken on 21 ADR cases reported from the unit to date. The KL algorithm rated 14.3% of cases as definite/likely, NAINICU 42.9% definite and LCAT 0% definite. Inter-rater reliability Kappa scores were 0.131, 0.136 and 0.294 for the 3 tools respectively. Inter-test reliability was greatest between the KL algorithm and the LCAT (Kappa 0.211) and least between NAINICU and LCAT (Kappa −0.149). Conclusion These three tools produced varied causali-ty assessment outcomes when used on neonatal ADRs. Marked inter-test and inter-rater variability was noted. The study is continuing to collect cases to help determine the optimal way to assess causaility in this popualtion.

Adverse Drug Reactions in Children

Adverse drug reactions (ADRs) are a common clinical problem in both paediatric and adult medicine. ADRs are a frequent cause of hospitalization and one of the leading causes of morbidity and mortality. The aim of the study was to prospectively identify the ADRs causing hospital admission of children and identification of the risk factors and involved drugs. All patients aged 19 years or under admitted to hospital were included in the study, and all admissions for ADRs were prospectively screened for a period of 9 months. Suspected ADRs were subsequently evaluated, and causality assessment was undertaken to determine whether each suspected reaction was possible, probable or definite. The assessment of ADR causality was performed using the Naranjo algorithm, the Liverpool ADR Causality Assessment Tool and the Edwards and Aronson causality assessment method. During the study period, 2903 admissions were identified; of these, there were 143 admissions of patients with an oncological disease. Sixty-four admissions (2.2%) were caused by an ADR. Anticancer chemotherapy accounted for 35% of the cases, followed by antibiotics (18%). The use of different scoring systems does not lead to the differences in the numbers of ADR-diagnosed patient but may result in differences in the determination of the level of certainty. The majority of the ADR-diagnosed patient affected the hematopoietic and gastrointestinal systems; the drugs most frequently involved were cytotoxic agents and antibiotics. The most important risk factors identified were female sex and oncological disease. ADRs cause a small but substantial proportion of children’s hospital admissions. Preventing avoidable ADRs requires careful adherence to good prescribing practice.

Mobile App Design, Development, and Publication for Adverse Drug Reaction Assessments of Causality, Severity, and Preventability.

BackgroundAdverse drug reactions (ADRs) cause significant morbidity and mortality. Improved assessment of ADRs to identify the causal relationship, the severity, and the preventability will aid ADRs prevention or reduce patient burden.ObjectiveThe aim of this study was to develop mobile apps in assisting clinical decision in ADR assessments of causality, severity, and preventability using validated tools. The usability of the apps was assessed.MethodsWe designed mobile apps using validated assessment tools for ADRs. They are the Liverpool ADRs Causality Assessment Tool, Hartwig’s Severity Assessment Scale, and the Modified Schumock and Thronton Preventability Scale. The apps were named “Adverse Drug ReactionCausality,” “Adverse Drug ReactionSeverity,” and “Adverse Drug RxnPreventability.” A survey was conducted using the System Usability Scale (SUS) to assess the usability of the developed apps among health care professionals.ResultsThese apps are available for download through Google Play Store for free since January 2015. From the survey, the mean SUS score was 70.9 based on 26 responses from the pediatric ward of Hospital Ampang, Malaysia.ConclusionsThe developed apps received an overall acceptable usability among health care professionals. The usage of these apps will improve detection, assessment, and avoidance of future ADRs. They will also contribute to future research on ADRs, thus increasing drug safety.

Development of the Liverpool Adverse Drug Reaction Avoidability Assessment Tool.

AimTo develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings.MethodsThe study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the ‘gold standard’ (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist).Main Outcome MeasuresInter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories.ResultsPreliminary work—Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16.Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62).Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52–90%.Phase 3: Percentage exact agreement ranged from 35–70%. Overall, individuals had better agreement with the ‘gold standard’.ConclusionAvoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than previous methods and that can be used by individuals or groups.

A pilot randomised controlled trial to assess the utility of an e-learning package that trains users in adverse drug reaction causality.

ObjectivesCausality assessment of adverse drug reactions (ADRs) by healthcare professionals is often informal which can lead to inconsistencies in practice. The Liverpool Causality Assessment Tool (LCAT) offers a systematic approach. An interactive, web‐based, e‐learning package, the Liverpool ADR Causality Assessment e‐learning Package (LACAeP), was designed to improve causality assessment using the LCAT. This study aimed to (1) get feedback on usability and usefulness on the LACAeP, identify areas for improvement and development, and generate data on effect size to inform a larger scale study; and (2) test the usability and usefulness of the LCAT.MethodsA pilot, single‐blind, parallel‐group, randomised controlled trial hosted by the University of Liverpool was undertaken. Participants were paediatric medical trainees at specialty training level 1+ within the Mersey and North‐West England Deaneries. Participants were randomised (1 : 1) access to the LACAeP or no training. The primary efficacy outcome was score by correct classification, predefined by a multidisciplinary panel of experts. Following participation, feedback on both the LCAT and the LACAeP was obtained, via a built in survey, from participants.Key findingsOf 57 randomised, 35 completed the study. Feedback was mainly positive although areas for improvement were identified. Seventy‐four per cent of participants found the LCAT easy to use and 78% found the LACAeP training useful. Sixty‐one per cent would be unlikely to recommend the training. Scores ranged from 4 to 13 out of 20. The LACAeP increased scores by 1.3, but this was not significant.ConclusionsImproving the LACAeP before testing it in an appropriately powered trial, informed by the differences observed, is required. Rigorous evaluation will enable a quality resource that will be of value in healthcare professional training.

PO-0926 Are Group Assessments Superior To Individual Avoidability Assessments? A Test Of The Liverpool Adverse Drug Reaction Avoidability Assessment Tool

Background There is currently no standardised method for determining avoidability of adverse drug reactions (ADRs) and many of the established tools are not suitable for use in paediatrics. We have developed a new tool; the Liverpool ADR avoidability assessment tool (LAAT). Initial testing showed mixed inter-rater reliability. Aim To test the hypothesis that group assessments are superior to individual avoidability assessments. Methods Participants were assigned either to a consensus group or to individually assess avoidability for a purposive sample of 20 ADR cases. Individual participants (nurses, pharmacists and doctors) independently assessed the cases. Groups took part in multidisciplinary meetings to assess the cases and reach consensus. The results were compared to the ‘gold standard’ (the avoidability outcome set by a panel of senior investigators). An ethnographic approach was taken; the consensus meetings were overseen by a facilitator and non-participant observations of the meetings were recorded. Post consensus meeting semi-structured interviews were conducted with the group members. Qualitative and quantitative analyses were carried out. We examined the extent to which individuals and groups agreed with the ‘gold standard’ using percentage exact agreement (%EA) (Figure 1). Results Agreement ranged from 35–70%. The mean agreement for individuals was 54% and 47% for the consensus groups. Conclusion In assessing avoidability of ADRs individual assessments had better agreement with the ‘gold standard’ evaluation than group assessments. Qualitative analysis of meeting observations and participant interviews may help identify reasons for this and inform the optimisation of the LAAT for assessment of ADR avoidability.

Adverse drug reactions causing hospital admissions in childhood: a prospective, observational, single-centre study.

Adverse drug reactions (ADRs) are common problems in both paediatric and adult medicine. The aim of this study was to prospectively identify the ADRs causing hospital admission of children and identification of the risk factors and involved drugs. The study was performed at the University Hospital in Olomouc, Czech Republic. All patients aged 19years or under admitted to hospital were included in the study, and all admissions for ADRs were prospectively screened for a period of 9months. Suspected ADRs were subsequently evaluated in detail, and causality assessment was undertaken to determine whether each suspected reaction was possible, probable or definite. The assessment of ADR causality was performed using the Naranjo algorithm, the Liverpool ADR Causality Assessment Tool and the Edwards and Aronson causality assessment method. During the study period, 2903 admissions were identified; of these, there were 143 admissions of patients with an oncological disease. Sixty-four admissions (2.2%) were caused by an ADR. Anticancer chemotherapy accounted for 35% of the cases, followed by antibiotics (18%), immunosuppressants and vaccines (9% each). The use of different scoring systems does not lead to the differences in the numbers of ADR-diagnosed patient but may result in differences in the determination of the level of certainty. ADRs cause a substantial proportion of children's hospital admissions. The majority of the ADR-diagnosed patient affected the hematopoietic and gastrointestinal systems; the drugs most frequently involved were cytotoxic agents and antibiotics. The most important risk factors identified were female sex and oncological disease.

QT Interval Prolongation Associated with Intramuscular Ziprasidone in Chinese Patients: A Case Report and a Comprehensive Literature Review with Meta-Analysis.

Intramuscular (IM) ziprasidone has been associated with QTc interval prolongations in patients with preexisting risk factors. A 23-year-old male Chinese schizophrenia patient experienced an increase of QTc interval of 83 milliseconds (ms) after receiving 20 mg IM ziprasidone (baseline and increased QT/QTc were, respectively, 384/418 and 450/501). This was rated as a probable adverse drug reaction (ADR) by the Liverpool ADR causality assessment tool. A systematic review including all types of trials reporting the effect of IM ziprasidone on the QTc interval prolongation identified 19 trials with a total of 1428 patients. Mean QTc change from baseline to end of each study was −3.7 to 12.8 ms after IM ziprasidone. Four randomized trials (3 of 4 published in Chinese) were used to calculate a meta-analysis of QTc interval prolongation which showed no significant differences between IM ziprasidone and IM haloperidol groups (risk ratio 0.49 to 4.31, 95% confidence interval 0.09 to 19.68, P = 0.06 to 0.41). However, our review included two cases of patients who experienced symptoms probably related to QTc prolongation after IM ziprasidone. Thus, careful screening and close monitoring, including baseline ECG, should be considered in patients receiving IM ziprasidone for the first time.

638 5-Aminosalicylate (5-ASA) Induced Nephrotoxicity in Inflammatory Bowel Disease

Introduction Nephrotoxicity is a rare idiosyncratic reaction to 5-ASA therapy. The precise pathogenic mechanisms are unknown. This study aims to a) describe the clinical features of this rare complication b) explore underlying mechanisms and c) identify clinically useful predictive genetic markers so these drugs can be avoided, or monitoring intensified, in high-risk patients. Here we report the clinical features. Methods Patients were identified and recruited from 185 sites (130 UK). Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine after starting 5-ASA and medical opinion implicating 5-ASA justified drug withdrawal. An adjudication panel assessed causality from case report forms using the validated Liverpool Adverse Drug Reaction Causality Assessment Tool. Results 154 patients were recruited. 19 patients were excluded following adjudication. The cohort included patients with Crohn’s disease, ulcerative colitis and indeterminate colitis (42%, 55%, 4% respectively). 74% of cases were male. Nephrotoxicity was seen with all aminosalicylates including 1 patient treated with topical therapy only. Nephrotoxicity occurred at a median age of 36.5 yrs (range 15.4–88.4 yrs). Two patients had a confirmed family history of 5-ASA-induced nephrotoxicity. 78% were detected by routine blood monitoring. Only 45% of cases recovered completely after drug withdrawal, with 18 requiring renal replacement therapy (14 transplantation). The median time for peak creatinine after commencing 5-ASA was 3.5 yrs (range 0.16–43.4 yrs). There was no evidence that time on 5-ASA treatment was associated with a higher peak creatinine or the likelihood of full recovery (p = 0.87). Women were more likely to reach full recovery than men (p = 0.00148; OR 8.26; CI 2.46–34.94). There was no evidence that early withdrawal of 5-ASA led to a higher likelihood of complete recovery. There was no difference in recovery between the three disease groups on logistic regression analysis. Conclusion This is the largest and most detailed study of 5-ASA induced nephrotoxicity to date. Whilst the incidence is low, the morbidity is high with 13% of patients requiring renal replacement therapy and 55% of patients failing to return to a normal creatinine after 5-ASA withdrawal. The next step is to carry forward these patients to a genome-wide association analysis, to be performed in February 2013. Disclosure of Interest None Declared

Development and Inter-Rater Reliability of the Liverpool Adverse Drug Reaction Causality Assessment Tool

AimTo develop and test a new adverse drug reaction (ADR) causality assessment tool (CAT).MethodsA comparison between seven assessors of a new CAT, formulated by an expert focus group, compared with the Naranjo CAT in 80 cases from a prospective observational study and 37 published ADR case reports (819 causality assessments in total).Main Outcome Measures Utilisation of causality categories, measure of disagreements, inter-rater reliability (IRR).ResultsThe Liverpool ADR CAT, using 40 cases from an observational study, showed causality categories of 1 unlikely, 62 possible, 92 probable and 125 definite (1, 62, 92, 125) and ‘moderate’ IRR (kappa 0.48), compared to Naranjo (0, 100, 172, 8) with ‘moderate’ IRR (kappa 0.45). In a further 40 cases, the Liverpool tool (0, 66, 81, 133) showed ‘good’ IRR (kappa 0.6) while Naranjo (1, 90, 185, 4) remained ‘moderate’.ConclusionThe Liverpool tool assigns the full range of causality categories and shows good IRR. Further assessment by different investigators in different settings is needed to fully assess the utility of this tool.