P80 Objective pharmacodynamic evaluation of doxapram in preterm infants

Abstract

BackgroundPharmacodynamic evaluation is challenging in neonatal clinical care, and often based on subjective human interpretation of clinical signs and the available ‘snapshot’ of physiological parameters. High frequency data (≥ 1Hz) of bedside patient monitors provide the opportunity of continuous and objective drug evaluation.1 This study investigates the predictive value of continuously available vital and ventilatory parameters to evaluate doxapram therapy. Doxapram is a respiratory stimulant to avoid mechanical ventilation and adverse outcomes of hypoxemia in preterm infants.2 MethodsPreterm infants admitted to a level III NICU centre who received doxapram therapy were eligible for inclusion. Stored vital and ventilatory parameters were retrospectively analysed. Multivariate analysis was performed to identify variables that influenced therapy failure (intubation or death) or success. Variables with a p value < 0.1 in univariate analysis were included in the multivariate analysis. Additionally, the ΔSpO2/FiO2-ratio was calculated by subtracting the median SpO2/FiO2-ratio 1 day after therapy from the median SpO2/FiO2-ratio 1 day before therapy.ResultsThe first episode of doxapram treatment was analysed in a total of 61 preterm infants with a median postnatal age at therapy start (PNA) of 3.0 weeks (IQR; 2.0–3.6). The success rate of doxapram therapy was 57%. Out of all parameters, the SpO2/FiO2-ratio showed to be the most indicative for therapy outcome. The predictive model included the ΔSpO2/FiO2-ratio, the PNA, the administration of a loading dose at start, and intubation within 24 hours before the start of doxapram (area under the curve of 0.828). The ΔSpO2/FiO2-ratio was inversely associated with therapy outcome (OR 0.26, CI 95% 0.07–0.83; p = 0.03).ConclusionThe ΔSpO2/FiO2-ratio between 1 day before and 1 day after start of the therapy is predictive of failure or success of doxapram therapy. The use of physiological data shows potential in the pharmacodynamic evaluation of doxapram therapy.ReferencesFlint R, Weteringen WV, Voller S, Poppe JA, Koch BC, Groot R, et al. Big data analyses for continuous evaluation of pharmacotherapy: A proof of principle with doxapram in preterm infants. Curr Pharm Des. 2017.Poets CF, Roberts RS, Schmidt B, Whyte RK, Asztalos EV, Bader D, et al. Association Between Intermittent Hypoxemia or Bradycardia and Late Death or Disability in Extremely Preterm Infants. JAMA. 2015;314(6):595–603.Disclosure(s)Nothing to disclose

Precision Dosing of Doxapram in Preterm Infants Using Continuous Pharmacodynamic Data and Model-Based Pharmacokinetics: An Illustrative Case Series

“…Two retrospective studies concluded that doxapram therapy may avoid mechanical ventilation (Prins et al, 2013;Flint et al, 2017a). In our earlier studies, doxapram therapy had a positive effect on the SpO 2 , the applied FiO 2 (Flint et al, 2017b), the oxygen need (SpO 2 /FiO 2 ratio), and hypoxia (cumulative oxygen shortage under the 89% limit) (Poppe et al, 2019). The present study is the first in which doxapram therapy effects were continuously evaluated in individual patients.…”

“…The first response to doxapram therapy can already inform the clinician on therapy outcome. Previously we have found that the SpO 2 /FiO 2 ratio in the 48 h around start of doxapram, corrected for postnatal age and mechanical ventilation before therapy start, was a predictor for therapy failure or success (Poppe et al, 2019). Clearance, and the related exposure and effect, may differ from the general preterm population in, for instance, those small for gestational age with different severity of illness and co-medication (Allegaert et al, 2017).…”

“…A subset of patients from a cohort of 61 preterm infants, described in an earlier study (Poppe et al, 2019), was selected for this study. These patients provide various illustrative patient profiles with respect to the indication, the first response to doxapram start, the dosing regimen and the dose-response relationship of doxapram therapy.…”

“…This type of alarm interpretation by clinicians has been found inconsistent when compared to objectively analyzed monitor data (Brockmann et al, 2013). Continuous data on arterial oxygen saturation (SpO 2 ) and administered fraction of inspired oxygen (FiO 2 ) recently showed potential in assessing the PD of doxapram (Flint et al, 2017b;Poppe et al, 2019). Especially composite parameters that reflect oxygen need (SpO 2 /FiO 2 ratio) and hypoxia (oxygen shortage under the 89% limit) were found strong indicators of therapy effect (Poppe et al, 2019).…”