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

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.

[Determinants of doxapram utilization: a survey of practice in the French Neonatal and Intensive Care Units]. / Enquête sur l'utilisation du doxapram dans les unités de néonatologie en France.

UNLABELLED: Methylxanthines and doxapram have been used to stimulate breathing and to prevent apnea in preterm infants. The use of doxapram is controversial because the therapeutic index seems to be narrow and short-term adverse effects have been described. OBJECTIVE: To determine the use of doxapram in the French neonatal and intensive care units. METHODS: A structured postal questionnaire was sent to all the 236 neonatology and neonatal intensive care units of level IIa, IIb and III in France. The questionnaires were analysed after four months. RESULTS: Answers were obtained from 159 chiefs of department (67.4%), 102 used doxapram (64.1%). Doxapram was mainly used as a second step, if methylxanthines failed to reduce the frequency of apneic spells (102/159 units, 64.1%). Doxapram was usually administered intravenously (91/102 units, 89.2%). Only 57 respondents (35.8%) did not use doxapram, because they were aware of the potential adverse effects or they did not know the drug. Monitoring of drug plasma concentrations was rarely performed (11/102 services, 10.8%). Nevertheless, there was a significant interest in this monitoring. CONCLUSION: Doxapram is frequently used in France to reduce apnea of prematurity if methylxanthine therapy fails. Further studies are needed to determine safety of doxapram at short and long-term. A multicenter, randomised, double-blinded clinical trial would be interesting to perform, similar to the ongoing caffeine for Apnoea of Prematurity trial (CAP) . The French setting seems appropriate for this kind of study.

QT interval lengthening in premature infants treated with doxapram.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Once-a-day individualized amikacin dosing for suspected infection at birth based on population pharmacokinetic models.

Amikacin is widely used in the treatment of suspected or confirmed neonatal infections. However, dosage regimens are not well defined in this group of patients because of a wide inter-individual pharmacokinetic variability. An individualized goal-oriented amikacin dosage design was applied using population pharmacokinetic data. A dosing chart was developed for neonates during the first 2 days of life, by using population pharmacokinetic parameter values and USCPACK software. This dosing chart based on gestational age (GA) and body weight gives a once-a-day amikacin dosage regimen involving an injection every 24 h. Validation was performed in 57 neonates less than 2 days old, divided into three GA groups and prospectively treated using the dosing chart. Target peak serum levels of amikacin were obtained in 62-80% of patients after the first dose and in 80-100% after the second dose, and trough concentrations were obtained in 100%. This study has confirmed the need for individualization of amikacin dosage regimens in neonates.

Risks and benefits of therapies for apnoea in premature infants.

Apnoea in infants can result from a wide range of causes, and requires thorough evaluation before deciding on appropriate treatment. Continuous monitoring of premature infants with apnoea is mandatory in order to define the pathophysiology and type of apnoea; selection of treatment involves careful assessment of aetiology, as well as efficacy and tolerability in each individual case. The objective of treatment is to prevent the deleterious consequences of apnoeas that last >20 seconds and/or are associated with bradycardia, cyanosis or pallor, and occur more often than once an hour over a 12-hour period. Apnoea management involves both pharmacological and nonpharmacological treatment. We suggest methylxanthines as first-line therapy for idiopathic apnoeas; evidence suggests that caffeine is better tolerated and as efficacious as theophylline (since it is particularly efficacious against the 'central' component of idiopathic apnoea of prematurity). If treatment fails, additional measures such as doxapram may be appropriate when hypoventilation is present, or nasal continuous positive airway pressure when upper airway instability or obstructive apnoeas are predominant. Apnoea prophylaxis is an additional reason to advocate prenatal maturation with betamethasone. Weaning from treatment is attempted 4 to 5 days after complete resolution of apnoea, beginning with the last treatment introduced. Monitoring should be maintained for 4 to 5 days to detect any relapse of recurrent and severe apnoeas, which would lead to the resumption of the most recently withdrawn treatment.

Severe side effects and drug plasma concentrations in preterm infants treated with doxapram.

A high-performance liquid chromatography method has been developed for simultaneous determination of doxapram and its metabolites including ketodoxapram, the main and only active metabolite. The aim of the study was to evaluate this microtechnique and to report the cases involving severe adverse effects to determine toxic plasma levels in neonates. The method was found to be selective, and showed a good baseline separation of doxapram and metabolites. Recovery, linearity, intraday/interday precision, and limit of detection determined in aqueous solutions and in spiked plasma were satisfactory. The assay is simple, rapid, and plasma-sparing, which represents a true advantage in managing neonates. Case analysis was performed in two consecutive periods: 124 preterm infants in the first period and 173 in the second period. Severe toxic effects were observed in 4 cases in the first period, with doxapram plus keto-doxapram levels 9 mg/L. In the second period, only one case was observed. High-range plasma concentrations were significantly less frequent in the second period than in the first one. The authors conclude that measuring doxapram plus keto-doxapram in plasma may be of interest to avoid severe toxic effects in preterm neonates treated with doxapram.

Neonatal catecholamine content of adrenal and extra-adrenal chromaffin tissue after prenatal exposure to dexamethasone.

We investigated the effects of prenatal exposure to dexamethasone on paraganglia and adrenal catecholamine stores in rabbit neonates. We compared pregnant rabbits injected with 0.01 mg x kg(-1) of dexamethasone (Dex) from day 24 to day 27 of gestation to an untreated group of unmanipulated rabbits. A group injected with 0.9% saline solution was added to evaluate the effect of injection and handling. Catecholamines were assessed by HPLC in offspring paraganglia and adrenal glands on days 0, 1, and 7 after birth. Data were analyzed by a two-factor ANOVA and Bonferroni-Dunn and t tests. Statistical significance was accepted at p < 0.05. Paraganglia catecholamine levels were significantly higher in the Dex animals than in the untreated ones at every maturational stage studied. For saline animals, the levels were lower than in the Dex group and higher than in the untreated one. In adrenal glands, the same pattern was observed for noradrenaline only. These findings suggest that such a treatment has a positive long-term effect on catecholamine levels of both structures with a more marked effect on paraganglia, an extra-adrenal structure exerting a main function during the perinatal period in providing the child with catecholamine stores.

[Treatment of apnea in prematurity]. / Traitement des apnées du prématuré.

Continuous monitoring of premature infants with apnea is mandatory in order to define the pathophysiology and the type of apnea, and to assess the efficacy and tolerance of the treatment. Etiological treatment must be first considered before deciding on a symptomatic treatment adapted to the type of apnea. In our practice, methylxanthines are the first line treatment considering their efficiency on the 'central' component of apnea of prematurity. In case of treatment failure, doxapram or continuous positive pressure can be associated to methylxanthines, especially when obstructive apnea or hypoventilation are predominant. The first attempt to stop the treatment is undertaken 4 to 5 days after complete resolution of apnea, starting with the last treatment used, the monitoring being maintained 4 to 5 days in order to detect eventual new apnea.

Immunocytochemical localization of NCAM and catecholamine-synthesizing enzymes in rabbit intra- and extra-adrenal chromaffin tissue.

The expression of the neural cell adhesion molecule, chromogranin A, and catecholamine-synthesizing enzymes (tyrosine hydroxylase and phenylethanolamine N-methyl transferase) in adrenal medulla and para-aortic bodies (paraganglia) of the adult rabbit, was studied by immunofluorescence. The specificity of the neural cell adhesion molecule antibody employed was demonstrated on rabbit tissue by immunoblotting. Neural cell adhesion molecule was found to be expressed not only by adrenal medullary cells but also by extra-adrenal chromaffin cells present in para-aortic bodies. These paraganglionic cells were as intensely immunolabelled for chromogranin A as adrenal medullary chromaffin cells. They were also labelled for the catecholamine-synthesizing enzymes tested here. However, their levels of the adrenalin-synthesizing enzyme phenylethanolamine N-methyl transferase were lower than those of medullary chromaffin cells.

Circulating chromogranin A and catecholamines in human fetuses at uneventful birth.

Chromogranin A (CGA), a large acidic 48-kD protein, costored and coreleased by exocytosis with catecholamines, has been shown to be a precursor of peptides that exert feedback regulatory control on catecholamine secretion. In plasma, CGA levels increase in response to a large-amplitude physical stimulation in adult subjects and may be related to catecholamine levels. Any skin information is not yet available when the sympathoadrenal system is highly active during birth. This activation is strongly related to parturition circumstances such as the mode of delivery. The aim of our study was to determine CGA plasma levels in infants delivered vaginally or by elective cesarean section and to investigate the possible correlation between CGA and catecholamine concentrations. Plasma levels of catecholamines (norepinephrine and epinephrine) and CGA were assessed by HPLC with electrochemical detection and immunoenzymology, respectively. CGA and norepinephrine concentrations were significantly higher (p < 0.0002 and p < 0.02) in infants vaginally born than in the group delivered by elective cesarean section. A significant relationship (p < 0.04) was found between CGA and norepinephrine levels. However, for epinephrine, no significant difference was found between both groups. These results demonstrate the fetus' ability to corelease CGA and norepinephrine massively in response to stress of birth.

Drug-induced apnea.

Drugs have been in the past and will in the future still be liable to induce apnea in neonates, infants and older children. At these different stages of development, the child may be abnormally vulnerable to respiratory disorders and apnea, and doses of drugs, without any abnormal side effects in adult patients, can be harmful in younger subjects. Drugs responsible for apnea during development are numerous, but more than half of the problems are induced by sedatives and hypnotics, among which phenothiazines, barbiturates, benzodiazepines (included transplacentally acquired) and general anesthetics are a few. Other pharmacological families are apnea inducers in the neonatal period and childhood: analgesics and opioid narcotics, agents acting at the levels of neuromuscular function and autonomic ganglia, and cardiovascular agents. The pathogenesis of these apneas depends on the disturbance of any mechanism responsible for the respiratory activity: medullary centers and brain stem structures, afferent influx to CNS, sleep stages, upper airways, lungs and respiratory muscles. At key stages such as birth and infancy, drugs may emphasize the particular sensitivity of the mechanisms responsible for inducing apnea. This might explain unexpected respiratory disorders during development.

[T.O.M. ointment, breast feeding and serum estradiol in newborn infants. A double-blind, randomized controlled study]. / Pommade T.O.M., allaitement et estradiolémie des nouveau-nés, Etude contrôlée, randomisée, à double insu.

OBJECTIVE: To study whether there is an iatrogenic transfer of oestradiol through the use of T.O.M. ointment administered to prevent or to cure trophic changes in the breast while breastfeeding and what the dangers of plasma levels of oestradiol in the newborn will be. TYPE OF STUDY: Controlled, randomised, double blind. SUBJECTS AND METHODS: 80 mother/infant couples were included in the study: 40 received the ointment containing oestradiol (the treated group), and 40 received an ointment without oestradiol (the non-treated group); the ointment was applied before each breastfeeding from the 2nd to the 6th or 7th day of life. Mothers' milk and blood from the newborn babies were taken for estimating the levels of oestradiol using a radio-immunological technique. The total quantity of ointment was measured for each subject. RESULTS: The mean level of oestradiol in the treated mothers' milk was significantly higher (p. 0.0014) than in the milk of the mothers who had not been treated. The concentration of oestradiol in the plasma of the newborn dropped from the first to the last day of the trial without any difference in the treated or non-treated groups no matter what the sex of the child was, nor the quantity of ointment used.

Rat neonates renal function after beta-receptors and adrenoceptors blockade during pregnancy.

Pregnant Wistar rats were given by subcutaneous route 1 of 3 different adrenoreceptor blockers, 2 of them mainly beta-blockers. P5 and P7 group received propranolol (5 and 7 mg/kg respectively), L10 and L20 groups received labetalol (10 and 20 mg/kg) and B5 group received betaxolol (5 mg/kg). Drugs were given daily from the 7th to the 16th day of gestation. A control group received saline injections. 16 out 24 treated mothers delivered prematurely on the 21st day of gestation. Functional renal parameters were studied in neonates on the first day of life. Renal function of the full term rats prenatally exposed were compared with controls. Average body weight was higher in P5 but lower in L10-L20-B5 groups. Diuresis increased in L20. Creatinine clearance, urinary/plasmatic creatinine ratio and urea clearance decreased in L10-L20 groups and fractional excretion of H2O increased in L20. Thus these adreno- and beta-blockers given to pregnant rats induced a shorter gestation. Moderate functional renal effects were observed in all neonates.

Effects of pentylenetetrazol-induced seizures on dopamine and norepinephrine levels and on glucose utilization in various brain regions of the developing rat.

Levels of dopamine and norepinephrine were measured in seven brain areas after 60 min of sustained seizure activity induced by intraperitoneal repetitive timed administrations of pentylenetetrazol in rats at 10, 14, 17 and 21 days of postnatal life. The tissue levels of norepinephrine were markedly reduced in the majority of brain structures, except for striatum at 10 and 14 days. Conversely, dopamine concentrations increased in many areas and at various ages, except in cerebral cortex at 10 and 14 days and in midbrain between 14 and 21 days. PTZ seizures induced marked increases over control levels in the rates of glucose utilization, measured by the quantitative autoradiographic [14C]2-deoxyglucose method, in all dopamine- and norepinephrine-innervated areas studied at 10 and 14 days, except in cerebellar cortex at both ages and in frontal cortex and anteroventral thalamus at 14 days. At 17 and 21 days, glucose utilization remained increased over control levels in some areas, mainly in catecholaminergic cell groupings such as substantia nigra, ventral tegmental area and locus coeruleus, but was significantly reduced in cortex, caudate nucleus and thalamus, and similar to control rates in other regions. The present results suggest that pentylenetetrazol-induced seizures lead to a simultaneous increase in functional activity of norepinephrine neurons and an inhibition of dopaminergic-mediated neurons. They also confirm the maturation of connections, of metabolic activity and of neurotransmitter interaction within the brain, occurring mainly during the third week of postnatal life, paralleled by an increased selective vulnerability of some regions to this kind of insult.

[Hemodynamic and renal adaptation of newborn infants of hypertensive mothers treated with acebutolol]. / Adaptation hémodynamique et rénale du nouveau-né de mère hypertendue traitée par acébutolol.

A prospective study of the hemodynamic and renal changes was undertaken in 11 neonates whose mothers were treated with acebutolol for hypertension during pregnancy, compared with a control group of 11 infants born to normotensive mothers. Monitoring of the cardio-respiratory system was performed for a period of 4 days. Renal function was studied during 2 periods (12-36, 60-84 hours of life). Hemodynamic failure was observed in 5 of 11 children from treated mothers. The data concerning the renal function of treated group showed: 1) a diuresis significantly lower during the first period (p less than 0.05); 2) the absence of significant rise in the glomerular filtration rates during the second period; 3) a lower sodium balance during the 1st and 2nd periods (p less than 0.02 and p less than 0.05), a lower calcium balance during the 1st period (p less than 0.01). No relationship was found between the renal changes and the hemodynamic disturbances. The direct effect of the drug on the glomerular and tubular functions and/or the renal arteriolar vasomotricity could explain these changes in the renal function in the newborns prenatally exposed to acebutolol.

Clonazepam in neonatal seizures: dose regimens and therapeutic efficacy.

The attempt has been made to define the optimal dose regimen of clonazepam in newborns suffering from neonatal convulsions. Results obtained from 22 patients (GA 28-41 weeks; PNA 4 h to 23 days) indicated that a dose of 0.1 mg/kg every 24 h was satisfactory in the majority of the patients. It is recommended as a starting regimen.

[The choice between theophylline and caffeine in the treatment of apnea in premature infants]. / Le choix entre théophylline et caféine dans le traitement des apnées du prématuré.

In a double blind study, two comparable groups (each n = 10) of premature infants less than 34 weeks of gestational age, with idiopathic apnea were given an IV treatment of either theophylline or caffeine. The loading doses were respectively 6 and 10 mg/kg and the maintenance doses were 2 and 1.25 mg/kg every 12 hours. In both groups, apneas greater than or equal to 15 s. with or without bradycardia were similarly reduced (p less than 0.01). Both drugs increased significantly the respiratory rate. Compared to caffeine, theophylline induced a significant acceleration of heart rates, an increase in urinary sodium excretion, more frequent gastrointestinal intolerance and behavioral changes. Plasma concentrations of theophylline were less stable than those of caffeine. These data suggest that a single daily dose of caffeine should be preferentially used in the treatment of idiopathic apneas of prematurity.