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Optimising intravenous salbutamol in children: a phase 2 study
  1. Sandra Walsh1,
  2. Shan Pan2,
  3. Yucheng Sheng2,
  4. Frank Kloprogge3,
  5. Joe F Standing4,
  6. Brian J Anderson5,
  7. Padmanabhan Ramnarayan6,7
  8. OSTRICH Study Group
    1. 1Paediatric and Neonatal Intensive Care Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
    2. 2Infection, Immunity and Inflammation Section, UCL Great Ormond Street Institute of Child Health Library, London, UK
    3. 3Institute for Global Health, University College London, London, UK
    4. 4Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
    5. 5Department of Anaesthesiology, University of Auckland, Auckland, New Zealand
    6. 6Children's Acute Transport Service, Great Ormond Street Hospital, London, UK
    7. 7Department of Surgery and Cancer, Imperial College London, London, UK
    1. Correspondence to Dr Sandra Walsh, Paediatric and Neonatal Intensive Care Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK; swalshieis{at}hotmail.com

    Abstract

    Objective The β2-agonists such as salbutamol are the mainstay of asthma management. Pharmacokinetic–pharmacodynamic (PKPD) models to guide paediatric dosing are lacking. We explored the relationship between salbutamol dose, serum concentration, effectiveness and adverse effects in children by developing a PKPD model.

    Design A prospective cohort study of children admitted to hospital with acute asthma, who received intravenous salbutamol.

    Setting Children were recruited in two cohorts: the emergency departments of two London hospitals or those retrieved by the Children’s Acute Transport Service to three London paediatric intensive care units.

    Patients Patients were eligible if aged 1–15 years, admitted for acute asthma and about to receive or receiving intravenous salbutamol.

    Interventions Treatment was according to local policy. Serial salbutamol plasma levels were taken. Effectiveness measurements were recorded using the Paediatric Asthma Severity Score (PASS). Toxicity measurements included lactate, pH, glucose, heart rate, blood pressure and arrhythmias. PKPD modelling was performed with non-linear mixed-effect models.

    Main outcomes Fifty-eight children were recruited with 221 salbutamol concentration measurements from 54 children. Median (range) age was 2.9 (1.1–15.2) years, and weight was 13.6 (8–57.3) kg. Ninety-five PASS measurements and 2078 toxicity measurements were obtained.

    Results A two-compartment PK model adequately described the time course of salbutamol–plasma concentrations. An EMAX (maximum drug effect) concentration–effect relationship described PASS and toxicity measures. PKPD simulations showed an infusion of 0.5 µg/kg/min (maximum 20 µg/min) for 4 hours after bolus achieves >90% maximal bronchodilation for 12 hours.

    Conclusions A paediatric PKPD model for salbutamol is described. An infusion of 0.5 µg/kg/min after bolus achieves effective bronchodilation. Higher rates are associated with greater tachycardia and hyperglycaemia.

    • intensive care units, paediatric
    • pharmacology
    • child health
    • paediatric emergency medicine
    • respiratory medicine

    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Collaborators OSTRICH Study Group: Mark Peters, David Inwald, Ami Parikh, Ian Maconochie and Mario Cortina-Borja.

    • Contributors SW and PR created the study concept and design, sourced funding and MHRA approval. They formed a collaborative study group and assisted with patient recruitment and data collection. They provided clinical interpretation for the outcomes and wrote and approved the research paper. JFS, BJA, FK, YS and SP assisted with the study design. They performed the data analysis, PKPD modelling and simulation analysis and interpretation. They assisted with writing the research paper.The OSTRICH Study Group comprised the clinical leads for each research centre. They assisted with study design, patient recruitment and data collection. They edited and approved the final research paper. SW accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish, and will act as guarantor.

    • Funding This study was funded by Great Ormond Street Children’s Charity Starter Grant (protocol no 13CC34 and EudraCT no 2014-002996-27). There was no involvement in the collection, analysis and interpretation of data or in the writing of the report by the funding body.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.