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Doxapram Dosing for Apnea of Prematurity Based on Postmenstrual Age and Gender: A Randomized Controlled Trial

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Abstract

Introduction

Doxapram is used as a third-line treatment for apnea unresponsive to caffeine and continuous positive airway pressure (CPAP) in preterm infants.

Objectives

The objectives of this study were to compare the effects of dosing adjusted for gender and postmenstrual age (PMA) (GrA) versus infants’ weight alone (GrW) on doxapram plasma levels, clinical efficacy, and side effects.

Methods

This was a randomized, double-blind study, including premature infants for whom optimized caffeine and CPAP therapy for apnea of prematurity had failed. Failure was defined as the persistence of more than one significant apnea per hour over an 8-h period. Plasma levels of doxapram and ketodoxapram were measured with high-performance liquid chromatography (HPLC) 48 h after the onset of treatment. Dosing aimed to maintain the combined doxapram and ketodoxapram plasma level in the therapeutic range of 1.5–4 mg/l. Infants were followed-up for 4 days after the onset of treatment.

Results

A total of 85 infants were included: 46 in GrW (27.7 ± 1.9 weeks’ gestational age [GA]), 39 in GrA (27.9 ± 1.4 weeks’ GA); available plasma levels showed that 25 of 40 in the GrW group and 27 of 37 in the GrA group had levels within the therapeutic range (p = 0.344). Of note, plasma level variance was significantly higher in GrW for doxapram + ketodoxapram (1.87 vs. 0.89; p = 0.028). Clinical efficacy was better in the GrA group, with a reduction from 32 to 3 of 38 (76 %) infants with significant apnea versus 30 to 5 of 45 (56 %) in the GrW group (p < 0.001). No adverse effects were observed during the study.

Conclusions

Taking gender and PMA into account for doxapram dosing did not significantly increase the number of infants with a plasma level in the therapeutic range. However, it improved plasma level stability and clinical efficacy without adverse effects.

ClinicalTrials.gov number: NCT00389909.

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Acknowledgments

The authors thank Marie-Christine Buchweiller, Sabine Guignon (Research Nurses), and Anne-Fleur André (Research Technician) for data monitoring and management.

Author contributions

Greze E. acquired and interpreted the data, wrote the first draft of the manuscript, critically revised the manuscript, and approved the final submitted version. Hamon I. conceptualized the study, interpreted the data, critically revised the manuscript, and approved the final submitted version. Benard M. acquired the data, critically revised the manuscript, and approved the final submitted version. Casper C. conceptualized the study, acquired the data, critically revised the manuscript, and approved the final submitted version. Haddad F.E. acquired the data, monitored the data collected, critically revised the manuscript, and approved the final submitted version. Boutroy M-J conceptualized and designed the study, critically revised the manuscript, and approved the final submitted version. Hascoët J-M conceptualized the study, analyzed and interpreted the data, critically reviewed and revised the manuscript, and approved the final submitted manuscript.

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Authors and Affiliations

  1. Neonatology, Maternite Regionale, EA3450 Université de Lorraine, 10 Rue du Docteur Heydenreich, 54035, Nancy, France

    E. Greze, I. Hamon, F. E. Haddad, M.-J. Boutroy & J.-M. Hascoët

  2. Neonatology, Children’s Hospital, 330 Avenue de Grande-Bretagne, TSA 70034, 31059, Toulouse Cedex 9, France

    M. Benard & C. Casper

Authors
  1. E. Greze
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  2. M. Benard
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  3. I. Hamon
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  4. C. Casper
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  5. F. E. Haddad
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  6. M.-J. Boutroy
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  7. J.-M. Hascoët
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Corresponding author

Correspondence to J.-M. Hascoët.

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Conflict of interest

Greze E, Benard M, Hamon I, Casper C, Haddad F.E, Boutroy M-J, Hascoët J-M have no conflicts of interest that are directly related to the content of this study.

Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Ethical approval/informed consent

The study was approved by the Ethical Committee (Number: CPPESTIII-06.03.09). Infants were included in the study after parental consent was obtained.

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Greze, E., Benard, M., Hamon, I. et al. Doxapram Dosing for Apnea of Prematurity Based on Postmenstrual Age and Gender: A Randomized Controlled Trial. Pediatr Drugs 18, 443–449 (2016). https://doi.org/10.1007/s40272-016-0192-2

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  • DOI: https://doi.org/10.1007/s40272-016-0192-2

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