Using pharmacokinetic modelling to improve prescribing practices of intravenous aminophylline in childhood asthma exacerbations.

OBJECTIVE: To evaluate physiologically based pharmacokinetic modelling (PBPK) software in paediatric asthma patients using intravenous aminophylline. METHODS: Prospective clinical audit of children receiving iv aminophylline (July 2014 to June 2016), and in-silico modelling using Simcyp software. RESULTS: Thirty-eight admissions (25 children) were included. Children with aminophylline levels ≥10 mg/l had equivalent clinical outcomes compared to those <10 mg/L, and adverse effects occurred in 57%. Therapeutic drug monitoring (TDM) data correlated well with PBPK model. PBPK modelling of a 5 mg/kg iv loading dose (≤18yr) shows a mean Cmax of 8.99 mg/L (5th-95th centiles 5.5-13.7 mg/L), with 70.3% of subjects <10 mg/L, 29.4% achieving 10-20 mg/L, and 0.1% > 20 mg/L. For an aminophylline infusion (0-12 y) of 1.0  mg/kg/h, the mean steady state infusion concentration was 16.4 mg/L, (5th-95th centiles 5.3-32 mg/L), with 26.8% having a serum concentration >20 mg/L. For 12-18yr receiving 0.5  mg/kg/h infusion, the mean steady state infusion concentration was 9.37 mg/L (5th-95th centiles 3.4-18 mg/L), with 59.8% having a serum concentration <10 mg/L. CONCLUSION: PBPK software modelling correlates well with clinical data. Current aminophylline iv loading dosage recommendations achieve levels <10 mg/l in 70% of children. Routine TDM may need altering as low risk of toxicity (>20 mg/l).

CPAP and High-Flow Nasal Cannula Oxygen in Bronchiolitis.

Severe respiratory failure develops in some infants with bronchiolitis because of a complex pathophysiologic process involving increased airways resistance, alveolar atelectasis, muscle fatigue, and hypoxemia due to mismatch between ventilation and perfusion. Nasal CPAP and high-flow nasal cannula (HFNC) oxygen may improve the work of breathing and oxygenation. Although the mechanisms behind these noninvasive modalities of respiratory support are not well understood, they may help infants by way of distending pressure and delivery of high concentrations of warmed and humidified oxygen. Observational studies of varying quality have suggested that CPAP and HFNC may confer direct physiologic benefits to infants with bronchiolitis and that their use has reduced the need for intubation. No trials to our knowledge, however, have compared CPAP with HFNC in bronchiolitis. Two randomized trials compared CPAP with oxygen delivered by low-flow nasal cannula or face mask and found some improvements in blood gas results and some physiologic parameters, but these trials were unable to demonstrate a reduction in the need for intubation. Two trials evaluated HFNC in bronchiolitis (one comparing it with headbox oxygen, the other with nebulized hypertonic saline), with the results not seeming to suggest important clinical or physiologic benefits. In this article, we review the pathophysiology of respiratory failure in bronchiolitis, discuss these trials in detail, and consider how future research studies may be designed to best evaluate CPAP and HFNC in bronchiolitis.