Table 1

Studies in the past 5 years concerning use of aminophylline in children with acute severe asthma

First authors [ref.], yearTypeMethodsFindings of the studyConclusion and comments
Indinnimeo et al. [5], 2018GuidelineThe Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was agreed. Used Cochrane library and Medline/PubMed databases for literature search, and including children over 2 years of age.Aminophylline use should be avoided in mild to moderate attacks.Moreover, weak clinical evidence supports its use in life-threatening attacks.This guideline emphasises that few studies are available regarding the use of a low dose of aminophylline, but then again, further data is needed regarding this issue.
Morris et al. [7], 2015Audit, research and guideline updateA prospective observational multicentre study in the UK and Ireland.3238 children aged 1–16 years presented with acute wheeze over a 10-week period.
In those receiving i.v. bronchodilators, i.v. magnesium sulphate (MgSO4) was used in 67 (60.9%), salbutamol in 61 (55.5%) and aminophylline in 52 (47.3%) of cases.
The most common aminophylline regimen was a load followed by an infusion.
Authors point at the inadequate evidence in significant areas of childhood wheeze and emphasise the need for further robust multicentre research studies.
Lyttle et al. [8], 2015Cross sectional observational study examining current practice across the UK and IrelandSurvey study involving physicians in the UK and Ireland.Variation exists in the treatment of acute severe childhood wheeze, especially in inhaled and i.v. bronchodilator selection, dosage and frequency.
Aminophylline is the third most commonly used medication, Salbutamol is first, and MgSO4 is second.
Authors identified strategic areas of variation, which require further exploration to determine their impact on the patient interface.
Despite the presence of national guidance, there is a significant discrepancy in managing childhood asthma from physicians.
Cooney et al. [10], 2016A systematic reviewSystematic review compared dosage regimens of i.v. aminophylline in children suffering an exacerbation of asthma.In this review, 14 RCTs were included and it concluded that there is a weak relationship between the dosage administered to children and symptom resolution, length of stay or need for mechanical ventilation.The currently recommended dosage regimens may not symbolise the optimum safety and efficacy of i.v. aminophylline.There is a need to improve the evidence base correlating dosage with patient-centred clinical outcomes, to improve prescribing practices.
Saint et al. [13], 2018Current opinionReview of the literature.Review assessing the evidence underpinning use of aminophylline in acute asthma, its recommendations, highlighting the shortcomings in the understanding of the association between serum concentrations achieved, the dose is given, and clinical improvement experienced.The dosing regimen with aminophylline in the management of acute severe asthma is minimally evidenced.
Cluster and standardised prospective studies are required.
Mahemuti et al. [18], 2018A systematic review and meta-analysisIn this review, 52 study arms were included that compared theophylline with other drugs, like adrenaline, β2- agonists or leukotriene receptor antagonists, or placebo.Theophylline significantly reduced heart rate when compared with active control (p=0.01) and overall duration of stay (p=0.002), but β2-agonists were superior to theophylline at improving FEV1 (p=0.002). Theophylline was not significantly different from other drugs in its effects on respiratory rate, forced vital capacity (FVC), peak expiratory flow rate, admission rate, use of rescue medication, oxygen saturation, or symptom score. When other intravenous bronchodilators are given in addition to theophylline, this significantly improves the effectiveness of theophylline (subgroup difference: p<0.00001).
Most notable side-effects were nausea and vomiting.
This evidence shows that i.v. theophylline is superior to other treatments with regard to  heart rate and duration of hospital stay. 
Authors feel that given the small cost and similar safety profile, theophylline should be considered as a cost-effective treatment for acute asthma exacerbations. Considering this evidence, it is useful, especially for developing countries with restricted health budgets.
Cooney et al. [19], 2017A prospective study, single centredProspective clinical audit of children receiving i.v. aminophylline, and in-silico modelling using Simcyp software.Aminophylline was used with a loading dose of 5 mg·kg−1 over 20 min and found that resulted in a serum concentration of <10 mg·L−1 in 70.3% of cases, 10–20 mg·L−1 in 29.4%, and >20 mg·L−1 in only 0.1% of cases who receive it.
Nevertheless, almost all cases achieved a serum concentration of 5–15 mg·L−1 using this loading dose.
Used only one loading dose and need to have more information about efficacy when used other loading doses like 10 mg·kg−1 loading dose?
There is still doubt that serum level is sub-optimal, the dose incorrect, or both?
Eid et al. [20], 2016Retrospective studyAuthors used low-dose theophylline (5–7 mg·kg−1·day−1) in addition to the current standard of treatment for children with acute asthma.57 children are included in the low-dose theophylline group and 109 in the control group.
Theophylline significantly reduces LOS, time to discontinue oxygen, time to spirometric improvement and time to space salbutamol, as well as reduced costs.
Moreover, there is no significant difference in adverse effects between patients who receive low-dose theophylline and those who did not.
Authors’ opinion is low-dose and oral theophylline may have a positive effect on acute status asthmaticus.
Neame et al. [21], 2015Review- pharmacy updateReview of RCTs and Cochrane reviews comparing salbutamol and aminophylline.Both drugs have proven use in treating acute asthma.
Both drugs have shown similar results.
The variance of practice at individual clinician and departmental level is likely to continue with regards which of these agents should be used first.
The choice of the first drug is based on the risk management considerations such as easiness of prescription, preparation and administration factors and availability of resources like high-dependency beds.
This qualitative analysis failed to draw any conclusions due to “minimal and inconsistent” evidence.
Singhi et al. [22], 2014RCT, prospective studyThis study compared the effectiveness of i.v. MgSO4, terbutaline and aminophylline for children as the second line of treatment in acute severe asthma.The MgSO4 group had significant treatment success (97%) compared with the terbutaline and aminophylline groups (70%) and quicker resolution of retractions, wheeze and dyspnoea.Recommends using MgSO4 as the second line of medication but needs a multicentre study.
The sample size was small (100), and the age range of the participants includes very young children.
Castro-Rodriguez et al. [23] 2015Systematic reviews of RCTs with or without meta-analysis in children (1–18 years)A limited review of the use of aminophylline in children with acute asthma and included a Cochrane review which included both children and adults.There is no consistent evidence favouring either i.v. β2-agonists or i.v. aminophylline for patients with acute asthma.The opportunity to draw definite conclusions is limited by the heterogeneity of outcomes evaluated and the small sample sizes in the included studies.
Tiwari et al. [24] 2016RCTSingle centre study involving children from 1–12-years age group. It randomised 24 patients each in ketamine and aminophylline groups.
The primary outcome was the PRAM score.
Both ketamine and aminophylline were equally effective for children with acute asthma who responded poorly to standard therapy.Authors have used objective scoring to assess the outcome but limited in numbers of patients.
May not be applicable in all settings as a need for intensive care support.
Albertson et al. [25] 2015The clinical review includes adults and childrenA comprehensive summary is provided concerning the currently available drugs approved for asthma.The use of theophylline in the treatment of acute asthma is limited because of both the lack of supportive data and significant adverse effects associated with its use.Authors conclude that there is no clear consensus in using theophylline dosage, administration, or preference.

RCT: randomised controlled trial; LOS: length of stay; PRAM: Pediatric Respiratory Assessment Measure.