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.