AL-Turkait, Asma
(2021)
Drug utilisation research in neonates: A step towards rational prescribing.
PhD thesis, University of Nottingham.
Abstract
Background: Since the initiation of drug utilisation research in the 1960s, the research in this area has continued to grow over the years, and in 2015 this search term reached over 20,000 hits in Medline. Whilst this area of research is known to be used in assessing the rational use of drugs, including prescribing, less is known about it in the neonatal population. In the UK, a drug utilisation study across neonatal units was conducted in 2009, but several limitations were observed that hinders a true representation of drug use patterns on a national level. Also, this study highlighted future research needs in one of the most challenging areas in neonatal medicine, which is managing patent ductus arteriosus (PDA). Ibuprofen is one of the drugs used to manage PDA; however, the rising reports of its adverse effects from observational studies requires further evaluation on when to use this agent, especially with the emergence of paracetamol as a suggestive alternative. In light of these existing gaps in knowledge, this thesis has been formulated to address a general question of ‘Where are we at when it comes to rational prescribing of drugs in one of the most vulnerable populations towards adverse effects from drugs?’. The aim was designed to assess the rational use of drugs in neonates at the very first step of the drug use process, which is prescribing. As a result, several questions were answered, and others set for future research.
Methods: An updated literature review was undertaken to provide an overall picture of neonatal drug utilisation studies across different regions. Then, this was narrowed to the UK setting by a retrospective pharmaco-epidemiological study investigating drug use patterns in England and Wales from 2010 to 2017 using the National Neonatal Research Database (NNRD), a large database from participating neonatal units across the UK. Having identified the drug use patterns and changes on drug use over time from 2010 to 2017, a follow up analysis to investigate the changes in drugs used in PDA was undertaken to explore the current practice in this condition. This was followed by a systematic review and meta-analyses of adverse effects of ibuprofen when used in preterm neonates with PDA to illuminate the safety profile of this popular agent. As a final explorative step, investigating the drugs’ prescribing contents were looked at across neonatal drug formularies and/or clinical practice guidelines across UK neonatal units.
Results The findings of the drug utilisation literature review have shown that drug use patterns are similar globally, especially in Europe, with antibiotics remaining the most frequently prescribed drugs. In the retrospective pharmaco-epidemiological study, 638,843 neonates across 187 neonatal units in England and Wales (from 2010 to 2017) were included in the final analysis. The number of drugs prescribed per neonate (median (range, IQR)) was 2 (0-69, 0-3), with extremely preterm neonates received the highest number of drugs, 17 (0-69, 12-25). Across the entire cohort, the most frequently prescribed drug was benzylpenicillin, prescribed to 355,679 (56%) of neonates at least once during their hospital stay, closely followed by gentamicin which was prescribed to 347,713 (54%) of neonates. Drug changes over time have also been explored; those with an overall increase in their use over the eight-year period across the entire cohort were sodium, benzylpenicillin, gentamicin, and pulmonary surfactants, whereas those with overall decrease were cefotaxime, domperidone, ranitidine, and ocular chloramphenicol. Across England and Wales, 18,181 (30%) of very and extremely preterm neonates had a record of PDA from 2010 to 2017. The analysis of different PDA treatment modalities has shown that ibuprofen was prescribed at least once to 27% of neonates with PDA, indomethacin to eight percent, and surgery to six percent, whereas 65% of neonates with PDA have not been recorded with any treatment (indomethacin and/or ibuprofen and/or surgery). A total of 90 studies were included in the systematic review of adverse effects of ibuprofen, with the largest number of neonates (3,831) receiving ibuprofen were recruited within 26 retrospective studies and accounted for half of the extracted adverse effects (2,264/4,700). Ibuprofen was discontinued in 56 neonates because of GI bleeding and renal toxicity. Inconsistencies in the dosage regimen of drugs with harm potential (e.g., gentamicin, caffeine) were found in the collected drug formularies.
Conclusion: Understanding how drugs are prescribed and the pattern of their use over time in any neonatal care setting is important as a primary step towards rational prescribing. This thesis provides a benchmark for referral when prioritising research agendas in neonates, especially in the UK. However, the resources (such as NNRD) used to assess drug utilisation need to be improved to provide more in-depth understanding of drug use in neonates and to detect any inappropriate/irrational prescribing in this population.
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