For intravenous theophylline (aminophylline), guidelines and formularies recommend a target therapeutic range between 10 and 20 mg/l, with the commonest regimen being a loading dose of 5 mg/kg followed by an infusion calculated by age and weight. Optimizing the Dosing of Intravenous Theophylline in Acute Severe Asthma in Children. The World Health Organization estimates that 235 million people have asthma worldwide [1]. Optimizing the Dosing of Intravenous Theophylline in Acute Severe Asthma in Children, http://www.asthma.org.uk/get-involved/campaigns/data-portal/, https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/255237/2901304_CMO_complete_low_res_accessible.pdf, http://atlas.chimat.org.uk/IAS/dataviews/report/fullpage?viewId=365&reportId=327&geoId=4&geoReportId=4204, https://doi.org/10.1007/s40272-017-0281-x. Part of Springer Nature. Rational intravenous doses of theophylline. The PBPK models already exist, so this would be relatively quick to undertake and put into practice. Optimizing the management of children presenting with acute severe asthma is of utmost importance to minimize hospital stays, morbidity, and mortality. The Cochrane Library. Br J Clin Pharmacol. The systematic review also failed to show any differences in the frequency of adverse effects in children within the therapeutic range compared with those with levels > 20 mg/l [11]. The PBPK work has shown considerable inter-individual variation in the concentrations achieved using the intravenous aminophylline dose common in routine clinical practice. Clearly, expert clinical trial design and statistical input would be required to tackle these confounders. Several interconnected research strategies framed around the understanding of the disease, the classification of illness severity, the medications used, and the inter-individual variation present are required (Fig. 1 Standard therapy for an acute asthma exacerbation includes inhaled β-agonists, which relieve bronchospasm, and corticosteroids, which decrease airway inflammation. Serum concentration time profile for theophylline in children aged 1 month–18 years modelled using physiologically based pharmacokinetic modelling (PBPK) software. Therapeutic drug monitoring is also commonly used, with the aim of getting concentrations within the accepted therapeutic range of 10–20 mg/l. National Child and Maternal Health Intelligence Network. Local authorities in the north-west of England include seven of the ten highest rates of emergency admissions for childhood asthma in the UK [20], but the mortality in this region is the same as the national average. 2016;11(8):e0159965. Mol Pharmacol. The lack of evidence for aminophylline, as well as for the intravenous salbutamol dose and expected effect sizes for all three intravenous treatment options means a definitive RCT in the UK is some way from reality [3, 26, 27]. The evidence to date on intravenous aminophylline may not support the dose and therapeutic range as being optimal. Higher loading doses have been used. PLoS One. However, these PK studies, whilst suggesting we under-dose for the therapeutic range we are targeting, do not provide clinical teams with any feel for the likelihood of any particular serum concentration, as the inter-individual variation was so large. Global Initiative for Asthma (GINA) 2017. http://ginasthma.org/. Hendeles L, Weinberger M, Bighley L. Disposition of theophylline after a single intravenous infusion of aminophylline 1–4. Am Rev Respir Dis. A child is admitted to hospital with acute asthma every 20 min, and 25 children died in 2015 [1]. Similarly, the serum concentrations targeted with the intravenous aminophylline infusion need to be examined. <> Asthma is a common, chronic inflammatory disorder of the airways associated with airway hyper-responsiveness. Asthma is the most prevalent chronic disease of childhood. Sinha IP, Gallagher R, Williamson PR, Smyth RL. 100 mg per dose) Children 5 years and over and … Are the admitted children in these areas more unwell? PubMed  The Global Initiative for Asthma (GINA) guidance, used in the USA, recommends adults and children aged > 5 years receive a single bolus of magnesium sulphate only if escalating treatment is necessitated [4]. 1998;79(5):405–10. For intravenous aminophylline, this has only been undertaken for the current loading dose of 5 mg/kg infused over 20 min. BACKGROUND: Although the need for corticosteroids in acute severe asthma is well established the appropriate dose is not known. How does the current variation in admissions for acute presentation affect the choice of sites and drugs used? Additional PK studies suggested 6 mg/kg would be a more appropriate dose to achieve 10 mg/l [14]. While the value of corticosteroids in acute severe asthma has been … An initial dose of 6 mg/kg IV followed by 8 to 10 mg/kg/day IV given in 4 divided doses for 1 to 2 days was used in 2 studies (age 2 months to 11 years) of pediatric patients with acute asthma. 2014;99(9):873–7. Arch Dis Childhood Educ Pract Ed. This under-dosing was initially predicted from the 1970s pharmacokinetic (PK) work, which suggested that—in children—a dose of 5.6 mg/kg is required to achieve the target concentration of 10 mg/l [13]. �����g��S�{�L,Ɩ��,�����2�b�E���Ϯ�ܗ�JE���/4�>�3]B��z]dQ�������'*N���=�$�,�Bß���~���g�.�忣wy�� G?� � ԫ�x��ô�����V�OAqٝB�'Û��2�s��Oc����1�s�fDRe�]�$��!�&��Hy�qK�Ӌ$K�LZ�O�"� D�X���eN @��. There is now significant evidence that the dose used for intravenous loading (5 mg/kg) does not achieve the therapeutic range expected by clinicians in most patients. <> What about clinicians who are not in equipoise? Accessed 18 Aug 2017. 1973;289(12):600–3. This review assesses the evidence underpinning these recommendations, highlighting the shortcomings in our understanding of the association between serum concentrations achieved, dose given, and clinical improvement experienced. Studies investigating this relationship are inconsistent, with some studies demonstrating an effect of the *1F/*1F polymorphism on expression and higher inducibility of CYP1A2 [23, 24]. Yung M, South M. Randomised controlled trial of aminophylline for severe acute asthma. However, this review specifically excluded children from the analysis [5]. 1993;25(6):495–505. Administration: Can be given undiluted over at least 1 minute, or diluted as necessary. IV intravenous. A 3 to 5-day course is usually sufficient. This therapeutic range originated in the 1950s, when efficacy was only noted at a concentration > 10 mg/l in a small cohort (n = 25) of adult patients with chronic wheeze [8]. Daniel B. Hawcutt. Black line is mean profile, grey lines are 5th and 95th percentiles, and open circles are clinical data. London: RCPCH Publications; 2016. Asthma exacerbations are the leading cause of hospitalization in children , and the lifetime prevalence of asthma in Canadian children has been estimated at 11% to 16% . Accessed 18 Aug 2017. %PDF-1.7 The outcomes for children are worse in the UK than for many other similar countries, with higher mortality rates. For patients capable of asthma self-management, self-treatment with a short course of OCS (about 1 mg/kg per day up to a maximum of 50 mg) is clearly effective at reducing relapse, need for additional care and required dose … Which intravenous bronchodilators are being administered to children presenting with acute severe wheeze in the UK and Ireland? Intravenous medications, including theophyllines, are used as second-line treatments for children experiencing a life-threatening exacerbation. Google Scholar. CAS  Ha HR, Chen J, Freiburghaus AU, Follath F. Metabolism of theophylline by cDNA-expressed human cytochromes P-450. Google Scholar. Hydrocortisone - 200 mg IV, 5 hours and I hour prior to the procedure. Population pharmacokinetics of intravenous albuterol in children with status asthmaticus. Hospital admissions for asthma Public Health England. Diphenhydramine - 50 mg PO (or IM or IV, if patient cannot take PO), one hour prior to the procedure. Do they have less access to preventive healthcare or more environmental triggers? 2015;100(4):215–22. While any grand RCT remains out of reach, other initiatives are being picked up to help answer the important questions about intravenous aminophylline.
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