Use of Continuous Physiological Monitor Data to Evaluate Doxapram Therapy in Preterm Infants

Abstract

<b><i>Introduction:</i></b> Evaluation of pharmacotherapy during intensive care treatment is commonly based on subjective, intermittent interpretations of physiological parameters. Real-time visualization and analysis may improve drug effect evaluation. We aimed to evaluate the effects of the respiratory stimulant doxapram objectively in preterm infants using continuous physiological parameters. <b><i>Methods:</i></b> In this longitudinal observational study, preterm infants who received doxapram therapy were eligible for inclusion. Physiological data (1 Hz) were used to assess respiration and to evaluate therapy effects. The oxygen saturation (SpO<sub>2</sub>)/fraction of inspired oxygen (FiO<sub>2</sub>) ratio and the area under the 89% SpO<sub>2</sub> curve (duration × saturation depth below target) were calculated as measures of hypoxemia. Regression analyses were performed in 1-h timeframes to discriminate therapy failure (intubation or death) from success (no intubation). <b><i>Results:</i></b> Monitor data of 61 patients with a median postmenstrual age (PMA) at doxapram initiation of 28.7 (IQR 27.6–30.0) weeks were available. The success rate of doxapram therapy was 56%. Doxapram pharmacodynamics were reflected in an increased SpO<sub>2</sub> and SpO<sub>2</sub>/FiO<sub>2</sub> ratio as well as a decrease in episodes with saturations below target (SpO<sub>2</sub> <89%). The SpO<sub>2</sub>/FiO<sub>2</sub> ratio, corrected for PMA and mechanical ventilation before therapy start, discriminated best between therapy failure and success (highest AUC ROC of 0.83). <b><i>Conclusion:</i></b> The use of continuous physiological monitor data enables objective and detailed interpretation of doxapram in preterm infants. The SpO<sub>2</sub>/FiO<sub>2</sub> ratio is the best predictive parameter for therapy failure or success. Further implementation of real-time data analysis and treatment algorithms would provide new opportunities to treat newborns.

The Pharmacokinetics of Caffeine in Preterm Newborns: No Influence of Doxapram but Important Maturation with Age

“…A synergistic PD interaction between caffeine and doxapram is not expected because they act via different mechanisms, but based on our study, this cannot be excluded. Recently, novel methods have been identified to quantify the amount of apnea using monitor data that might be useful for the investigation of a PD interaction between doxa-pram and caffeine [18,19]. Based on the present results, we can conclude that the previously reported effects of doxapram on apnea in preterm infants cannot be attributed to increased caffeine concentrations [5][6][7].…”

New Ways to Measure the Effect of Pharmacotherapy in Newborn Infants: Feasible or Not That Much?

“…In the article by Poppe et al [5] in this issue of the journal, the effects of a respiratory stimulant, doxapram, were evaluated objectively in preterm neonates using continuous physiological parameters. Physiological data were used to continuously assess both respiration as well as the effects of therapeutic intervention with doxapram.…”

“…How feasible will it be to implement the exciting algorithm of Poppe et al [5] in daily clinical practice outside the neonatal centers that will have a team dedicated to respiratory monitoring? What will be needed is an algorithm that will help with optimizing the safe and effective use of pharmacotherapy in neonates and young infants, but that algorithm also needs to be easy to implement by neonatologists across the globe and not only in centers that have a specialized team in respiratory monitoring.…”

Apnoea of Prematurity and Neurodevelopmental Outcomes: Current Understanding and Future Prospects for Research

“…Computational techniques, such as machine learning algorithms, have the potential to predict apnoeic and hypoxemic events in individual infants, leading to earlier interventions ( 101 ). Optimising caffeine dosing regimen and tailoring pharmacological interventions, including doxapram ( 102 ), for individual infants could be achieved through accurate measurement of respiratory dynamics and will shift the balance toward efficacy and away from harm. Pharmacokinetics and pharmacodynamics will likely change with postnatal age, for example due to changes in hepatic enzymes and renal function ( 103 ), and so continuous monitoring of respiratory dynamics and adaptive treatment will be important.…”