Introduction
An adverse drug reaction (ADR) is defined as a noxious and unintended response to a drug administered at doses normally used for desired effect [1]. They are encountered in all disciplines of medicine. Unfortunately patients with disorders such as cancer or requiring intensive care have higher rates of ADRs, and this is often accepted as an undesired but necessary part of life-saving therapies[2, 3]. Of note, ADRs do not include adverse drug events such as errors in drug administration or dosing.
There are significant consequences for ADRs as they produce significant morbidity, mortality and economic burdens to healthcare worldwide. The overall incidence of serious ADRs in hospitals requiring prolonged hospitalization, permanent damage or death is more than 5%, and up to 6.5% of all hospital admissions are related to ADRs[4, 5]. ADRs rank between 4th and 6th most common causes of death in the United States, ranking only behind heart diseases, cancer, and stroke[4]. ADRs are a considerable burden to the healthcare system costing billions of dollars annually for screening and treatment [6]. These financial figures are comparable to system wide high-cost diseases such as diabetes and obesity[7]. Despite identifying ADRs as a socioeconomic concern they continues to be underreported and challenges are faced in establishing causality between a drug and ADR[8].
Adults and children alike are all at risk for ADRs. Children can be considered to be at higher risk due to limited clinical trial data on safety of drugs in children[9, 10] and also as drugs are often prescribed off-label. It is estimated up to one third of medications prescribed for children are off-label in the community and up to 60% on hospital wards[11]. It is reported that ADR incidence is approximately 1.5% for outpatient children and up to 10% for hospitalized children[12]. The majority of children only require one or less prescription per year but those that do require regular therapy often receive multiple prescriptions, placing them at higher risk for ADRs given increased complexity in their care[13]. With this increased complexity in clinical presentation and the lack of clinical trials specifically in children, it is more challenging for clinicians to establish causality of ADRs in children.
There are multiple scales and tools to establish causality between a drug and suspected ADR. The most commonly used assessment tool is the Naranjo Scale[14] but its poor consistency with confounders was recognized by Macedo et al . when comparing a large panel of existing ADR algorithms[15]. Other investigators also questioned its reliability in multiple clinical settings including the paediatric population[16, 17, 18]. Investigators at the University of Liverpool and Alder Hey Children’s Hospital pursued the question of causality analysis and developed the Liverpool Causality Assessment Tool after analyzing questions from the Naranjo Scale[19]. This tool is a flow chart rather than a scoring system as a more user-friendly appraohc. The investigators considered possible confounders in suspected ADRs such as sequela even after discontinuing the drug and objective evidence supporting ADR mechanism. This instrumenbt had improved inter-rater reliability when it was evaluated over 80 case reports and 37 published ADR cases[19]. This instrument was developed based on an in-patient population. We investigated the use of the Liverpool Causality Assessment Tool compared to the Naranjo scale in a larger number of suspected ADR cases which were assessed in an ambulatory setting.