QT interval lengthening in premature infants treated with doxapram

Doxapram, routinely used in premature infants treated for apnea of prematurity unresponsive to methylxanthines, has been related to cardiac conduction disorders. This study was designed to evaluate doxapram cardiac and general tolerance and its relationship to drug plasma concentrations in very premature infants.

Forty infants (mean +/- SEM, 28.9 +/- 0.3 weeks of gestation) who were given intravenous doxapram, 0.5 to 1 mg/kg per hour, at 15.9 +/- 2.4 days of life were evaluated prospectively. Electrocardiograms were monitored before and during the first 3 days of treatment. QT interval corrected for heart rate (QTc) longer than 440 ms was regarded as clinically pertinent, given that it is considered a significant risk of conduction disorder leading to torsades de pointes and sudden death. Other side effects were recorded. Toxic plasma concentration of doxapram and ketodoxapram was set at >4 mg/L.

A statistically significant but moderate lengthening of QTc interval has been observed from 394 +/- 4 ms before doxapram to 409 +/- 4 ms at 48 and 72 hours of treatment (P =.0065). For 6 patients, QTc interval became longer than 440 ms without any other rhythm or conduction disorder. Digestive disorders were observed in 20 infants but 9 presented with concomitant septicemia. No relationship was found between presence or absence of adverse effects and drug plasma concentrations.

Our study enlightened the lengthening effect of doxapram on QTc interval in premature infants with a risk of exceeding the 440 ms threshold that is considered life-threatening. This finding emphasizes the need for electrocardiogram follow-up when using doxapram in neonates.