Chloramphenicol toxicity in neonates: its incidence and prevention.

Mulhall, Anne; Louvois, J de; Hurley, Rosalinde

doi:10.1136/bmj.287.6403.1424

Cited by 92 publications

(43 citation statements)

References 17 publications

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“…The LCAT, 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 (κ) = 0.48] compared with Naranjo (0, 100,172,8) with 'moderate' IRR (κ = 0.45). In a further 40 cases, the LCAT (0, 66,81,133) showed 'good' IRR (κ = 0.6), whereas Naranjo (1, 90, 185, 4) remained 'moderate'.…”

Section: Resultsmentioning

confidence: 99%

“…As with any population, distinguishing between an ADR and non-drug-induced pathology is difficult but is further compounded in this age group. Important examples of ADRs in children include deaths associated with propofol used for paediatric intensive care unit (PICU) sedation, 6 acute adrenal crisis associated with inhaled corticosteroids, 7 grey baby syndrome in neonates associated with chloramphenicol, 8 the threefold increase in Stevens-Johnson syndrome with lamotrigine 9 and colonic strictures in cystic fibrosis owing to high-strength pancreatic enzymes. 10 The last of these examples was first reported at Alder Hey Children's NHS Foundation Trust (Alder Hey) in Liverpool; the primary author led the study confirming the association with pancreatic enzyme therapy and because of this, and subsequent regulatory measures, this problem is no longer reported in the UK.…”

Section: Fundingmentioning

confidence: 99%

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ADRIC: Adverse Drug Reactions In Children – a programme of research using mixed methods

Smyth

Peak

Turner

et al. 2014

Programme Grants for Applied Research

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AimsTo comprehensively investigate the incidence, nature and risk factors of adverse drug reactions (ADRs) in a hospital-based population of children, with rigorous assessment of causality, severity and avoidability, and to assess the consequent impact on children and families. We aimed to improve the assessment of ADRs by development of new tools to assess causality and avoidability, and to minimise the impact on families by developing better strategies for communication.Review methodsTwo prospective observational studies, each over 1 year, were conducted to assess ADRs in children associated with admission to hospital, and those occurring in children who were in hospital for longer than 48 hours. We conducted a comprehensive systematic review of ADRs in children. We used the findings from these studies to develop and validate tools to assess causality and avoidability of ADRs, and conducted interviews with parents and children who had experienced ADRs, using these findings to develop a leaflet for parents to inform a communication strategy about ADRs.ResultsThe estimated incidence of ADRs detected in children on admission to hospital was 2.9% [95% confidence interval (CI) 2.5% to 3.3%]. Of the reactions, 22.1% (95% CI 17% to 28%) were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44 out of 249 (17.7%) of ADRs, the remainder originating from hospital. A total of 120 out of 249 (48.2%) reactions resulted from treatment for malignancies. Off-label and/or unlicensed (OLUL) medicines were more likely to be implicated in an ADR than authorised medicines [relative risk (RR) 1.67, 95% CI 1.38 to 2.02;p < 0.001]. When medicines used for the treatment of oncology patients were excluded, OLUL medicines were not more likely to be implicated in an ADR than authorised medicines (RR 1.03, 95% CI 0.72 to 1.48;p = 0.830). For children who had been in hospital for > 48 hours, the overall incidence of definite and probable ADRs based on all admissions was 15.9% (95% CI 15.0 to 16.8). Opiate analgesic drugs and drugs used in general anaesthesia (GA) accounted for > 50% of all drugs implicated in ADRs. The odds ratio of an OLUL drug being implicated in an ADR compared with an authorised drug was 2.25 (95% CI 1.95 to 2.59;p < 0.001). Risk factors identified were exposure to a GA, age, oncology treatment and number of medicines. The systematic review estimated that the incidence rates for ADRs causing hospital admission ranged from 0.4% to 10.3% of all children [pooled estimate of 2.9% (95% CI 2.6% to 3.1%)] and from 0.6% to 16.8% of all children exposed to a drug during hospital stay. New tools to assess causality and avoidability of ADRs have been developed and validated. Many parents described being dissatisfied with clinician communication about ADRs, whereas parents of children with cancer emphasised confidence in clinician management of ADRs and the way clinicians communicated about medicines. The accounts of children and young people largely reflected parents’ accounts. Clinicians described using all of the features of communication that parents wanted to see, but made active decisions about when and what to communicate to families about suspected ADRs, which meant that communication may not always match families’ needs and expectations. We developed a leaflet to assist clinicians in communicating ADRs to parents.ConclusionThe Adverse Drug Reactions In Children (ADRIC) programme has provided the most comprehensive assessment, to date, of the size and nature of ADRs in children presenting to, and cared for in, hospital, and the outputs that have resulted will improve the management and understanding of ADRs in children and adults within the NHS. Recommendations for future research: assess the values that parents and children place on the use of different medicines and the risks that they will find acceptable within these contexts; focusing on high-risk drugs identified in ADRIC, determine the optimum drug dose for children through the development of a gold standard practice for the extrapolation of adult drug doses, alongside targeted pharmacokinetic/pharmacodynamic studies; assess the research and clinical applications of the Liverpool Causality Assessment Tool and the Liverpool Avoidability Assessment Tool; evaluate, in more detail, morbidities associated with anaesthesia and surgery in children, including follow-up in the community and in the home setting and an assessment of the most appropriate treatment regimens to prevent pain, vomiting and other postoperative complications; further evaluate strategies for communication with families, children and young people about ADRs; and quantify ADRs in other settings, for example critical care and neonatology.FundingThe National Institute for Health Research Programme Grants for Applied Research programme.

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Section: Resultsmentioning

confidence: 99%

Section: Fundingmentioning

confidence: 99%

ADRIC: Adverse Drug Reactions In Children – a programme of research using mixed methods

Smyth

Peak

Turner

et al. 2014

Programme Grants for Applied Research

View full text Add to dashboard Cite

show abstract

“…Because of the relative deficiency of glucuronide and high bilirubin levels (an endogenous glucuronidation substrate), it is possible that there will be greater internal exposure early in life to xenobiotics (or their metabolites) that require glucuronide conjugation. This is the case with the antibacterial drug chloramphenicol, in which a relative lack of glucuronidation contributed to its accumulation and toxicity (anemia) in infants (Mulhall et al 1983;Vest 1965). In …”

Section: Phase Ii: Data Analysis and Development Of Risk Assessment Amentioning

confidence: 99%

Incorporating children's toxicokinetics into a risk framework.

Ginsberg

Slikker

Bruckner

et al. 2004

Environ Health Perspect

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Children's responses to environmental toxicants will be affected by the way in which their systems absorb, distribute, metabolize, and excrete chemicals. These toxicokinetic factors vary during development, from in utero where maternal and placental processes play a large role, to the neonate in which emerging metabolism and clearance pathways are key determinants. Toxicokinetic differences between neonates and adults lead to the potential for internal dosimetry differences and increased or decreased risk, depending on the mechanisms for toxicity and clearance of a given chemical. This article raises a number of questions that need to be addressed when conducting a toxicokinetic analysis of in utero or childhood exposures. These questions are organized into a proposed framework for conducting the assessment that involves problem formulation (identification of early life stage toxicokinetic factors and chemical-specific factors that may raise questions/concerns for children); data analysis (development of analytic approach, construction of child/adult or child/animal dosimetry comparisons); and risk characterization (evaluation of how children's toxicokinetic analysis can be used to decrease uncertainties in the risk assessment). The proposed approach provides a range of analytical options, from qualitative to quantitative, for assessing children's dosimetry. Further, it provides background information on a variety of toxicokinetic factors that can vary as a function of developmental stage. For example, the ontology of metabolizing systems is described via reference to pediatric studies involving therapeutic drugs and evidence from in vitro enzyme studies. This type of resource information is intended to help the assessor begin to address the issues raised in this paper.

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“…A lack of research in children has caused harm. Children are at increased risk of adverse effects when administered offlabel medicines that were prescribed according to extrapolations of adult data [5][6][7][8]. These observations are well supported by research demonstrating that children are not small adults [8][9][10].…”

Section: Introductionmentioning

confidence: 63%

Ethics Review of Pediatric Multi-Center Drug Trials

2014

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The assessment of safety and efficacy of therapeutics for children and adolescents requires the use of multi-centered designs. However, the need to obtain ethical approval from multiple independent research ethics boards (REBs) presents as a challenge to investigators and sponsors who must consider local requirements while ensuring that the protection of human subjects is consistent across sites. In pediatrics, this requirement is complicated by pediatric-specific ethical concerns such as the acquisition of assent and consent and the need for pediatric expertise to assess the scholarly merit of the proposed research. Efforts to tackle these challenges have focused on the process of ethics review, which will improve efficiency. In addition to improving process, we suggest further research to fill gaps in the evidence base for recommendations and decisions made by REBs, specifically their effectiveness to protect human subjects. Evidence gathered will contribute to the successful development, adoption and implementation of harmonized guidance to apply ethics principles in order to protect children through research rather than from research.

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Chloramphenicol toxicity in neonates: its incidence and prevention.

Cited by 92 publications

References 17 publications

ADRIC: Adverse Drug Reactions In Children – a programme of research using mixed methods

ADRIC: Adverse Drug Reactions In Children – a programme of research using mixed methods

Incorporating children's toxicokinetics into a risk framework.

Ethics Review of Pediatric Multi-Center Drug Trials

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