Jean-Claude Levron

A comparison of alfentanil pharmacokinetics in children and adults

The pharmacokinetics of alfentanil have been studied in eight children aged between 4 and 8 yr and five adults during general anesthesia. All patients were given 20 micrograms/kg alfentanil as an intravenous bolus injection. Plasma concentrations were measured at intervals up to 6 h by radioimmunoassay. Plasma protein binding was measured by equilibrium dialysis using tritiated alfentanil. The optimal pharmacokinetic model for alfentanil was an open two-compartment model. Total apparent volume of distribution (Vdss) was 457 +/- 160 ml/kg in adults and 163 +/- 110 ml/kg in children (P less than 0.01). When recalculated by surface area Vdss was still decreased in children (P less than 0.01). Plasma clearance (Cl) was similar in the two groups. Terminal elimination half-life was significantly shorter in children (40 +/- 9 min) than in adults (97 +/- 22 min; P less than 0.01). The shorter elimination half-life could be due to the smaller total apparent volume of distribution in children. Plasma protein binding was comparable between children and adults and could not explain the smaller volume of distribution in children. It is suggested that the smaller volume of distribution of alfentanil in children is a result of the decreased percentage of fat tissue in children.

Effects of Age on Plasma Protein Binding of Sufentanil

The plasma protein binding of sufentanil has been studied in newborns, infants (0.5 +/- 0.3 yr), children (6.8 +/- 3.0 yr), and adults (39.5 +/- 9.0 yr). Binding of sufentanil was determined in vitro by equilibrium dialysis, and radioactive tritiated sufentanil was used for the determination of drug concentrations in plasma and buffer. The free fraction of sufentanil was significantly higher in the newborn (19.5 +/- 2.7%; P less than 0.01) than in the other age groups. The free fraction was also significantly higher in infants (11.5 +/- 3.2%; P less than 0.01) than in children (8.1 +/- 1.4%) or in adults (7.8 +/- 1.5%) but did not differ significantly between children and adults. The free fraction of sufentanil was strongly correlated with the alpha 1-acid glycoprotein plasma concentration (r = -0.73; P less than 0.001) whereas it was weakly correlated with albumin plasma concentration (r = -0.35; P less than 0.05). These data suggest that the lower concentration of alpha 1-acid glycoprotein in newborns and infants probably accounts for the decrease in protein binding of sufentanil in these age groups when compared with that in older children or adults. The increased free fraction in the neonate might contribute to the enhanced effects of lipophilic opioids in the neonate.

Ventilatory response to carbon dioxide after intramuscular and epidural fentanyl

: The authors compared the effects of administration of fentanyl 200 micrograms on the ventilatory response to carbon dioxide in two groups of nine healthy unpremedicated subjects: one group received fentanyl as an intramuscular injection; in the other group, fentanyl was injected into the epidural space. In the intramuscular group, the slope of the ventilatory response to CO2 did not decrease significantly. In the epidural group, the slope of the ventilatory response to CO2 decreased significantly from 2.48 +/- 1.05 to 1.77 +/- 0.7, 1.74 +/- 0.7, and 2.07 +/- 0.74 L X min-1 X mm Hg-1 at 30, 60, and 120 min after injection (chi +/- SD, P less than or equal to 0.05), respectively. At each time of the study, plasma fentanyl levels were significantly lower in the epidural group than in the intramuscular group (P less than or equal to 0.05). These results suggest that epidural fentanyl induces a nonsystemic ventilatory depression that may be due to the rostral spread of the drug.

Effects of Fentanyl on Baroreceptor Reflex Control of Heart Rate in Newborn Infants

Baroreceptor reflex control of heart rate was studied in ten neonates and young infants before and after intravenous fentanyl (10 μg/kg). All infants were in stable condition while being mechanically ventilated. Mean (±SD) corrected gestalional age was 40.1 ± 3.7 weeks, mean weight 3120 ± 700 g. The pressor response was tested using phenylephrine and the depressor response using nitroglycerin. Changes in heart rate (R-R interval) were plotted against changes in systolic arterial pressure, and the slope of the linear portion of this relationship expresses the baroreflex sensitivity. No significant changes in systolic arterial pressure, heart rate, and blood gas values were observed after fentanyl injection when compared to control values. Mean (±SEM) control phenylephrine slope was 8.44 ± 2.05 msec/mmHg, and mean nitroglycerin slope was 2.54 ± 0.37 msec/mmHg. Both slopes decreased significantly by 48% and 42%, respectively, after fentanyl injection (P < 0.02). Mean plasma fentanyl concentrations measured at the end of cach lest were not statistically different (5.11 ± 0.65 ng/ml and 4.28 ± 0.58 ng/ml, respectively). This suggests that the baroreflex control of heart rate is present in term neonates and markedly depressed during fentinyl anesthesia. Changes in blood pressure occurring during fentanyl anesthesia have to be carefully considered, because cardiac output is principally rate-dependent in newborns.

Analgesia and ventilatory response to CO2 following epidural sufentanil in children.

The authors studied the effects of epidural sufentanil (0.75 μg·kg-1) after urologic surgery in 15 children ranging in age from 4 to 12 yr, and in weight from 14 to 47 kg. The onset and duration of analgesia were 3.0 ± 0.3 and 198 ± 19 min, respectively (mean ± SEM), Side effects included pruritus (3/15), nausea and vomiting (5/15), drowsiness (10/15), and urinary retention (1/11). No apnea was observed. Periosteal analgesia and ventilation were studied in eight of the children (mean age 8.6 ± 0.8 yr). There was significant periosteal analgesia of the tibia (30,60,90, and 120 min after injection) and of the radius (60,90, and 120 min after injection). Resting respiratory rate and tidal volume did not change during the study. Resting minute-ventilation decreased from 6.3 ± 0.5 1 · min-1 preoperatively to 5.6 ± 0.6 1 · min-1 (P < 0.05) postoperatively, before epidural sufentanil injection; it did not decrease further after epidural sufentanil. Similarly, end-tidal CO2 tension increased significantly from 37.2 ± 0.7 mmHg preoperatively to 39.9 ± 1.2 mmHg (P < 0.05) postoperatively, before epidural sufentanil; epidural sufentanil did not cause a further significant increase in end-tidal CO2 tension. The slope of the CO2 ventilatory response curve decreased significantly from 1.68 ± 0.12 1 · min-1 · mmHg-1 preoperatively to 1.10 ± 0.13 1 · min-1 · mmHg-1 (P < 0.01) postoperatively. There were further significant decreases to 0.68 ± 0.10 and 0.89 ± 0.16 1 · min-1 · mmHg-1 30 and 60 min after epidural sufentanil. By 240 min after sufentanil, the slope had increased to 1.42 ± 0.08 1 · min-1 · mmHg-1, which was significantly greater than the immediate postoperative value. The authors conclude that epidural sufentanil provides rapid and effective analgesia in children; however, the clinical usefulness may be limited because of the relatively short duration of analgesia. Additionally, the significant early respiratory depression following epidural sufentanil mandates close monitoring of these patients for more than 1 h.

Ventilatory Response to Carbon Dioxide after Intra muscular and Epidural Fentanyl

The authors compared the effects of administration of fentanyl 200 μg on the Ventilatory response to carbon dioxide in two groups of nine healthy unpremedicated subjects: one group received fentanyl as an intramuscular injection; in the other group, fentanyl was injected into the epidural space. In the intra muscular group, the slope of the venti-latory response to CO2 did not decrease significantly. In the epidural group, the slope of the Ventilatory response to CO2 decreased significantly from 2.48 ± 1.05 to 1.77 ± 0.7, 1.74 ± 0.7, and 2.07 ± 0.74 L·min-1·mm Hg−1 at 30, 60, and 120 min after injection (x ± SD, P ≤ 0.05), respectively. At each time of the study, plasma fentanyl levels were significantly lower in the epidural group than in the intramuscular group (P ≤ 0.05). These results suggest that epidural fentanyl induces a non systemic Ventilatory depression that may be due to the rostral spread of the drug.

Analgesia and Ventilatory Response to Carbon Dioxide after Intramuscular and Epidural Alfentanil

The analgesic and ventilatory depressant effects of epidural and intramuscular alfentanil (15 μg/kg) were compared in two groups of seven healthy unpremedicated subjects. Fifteen minutes after IM injection, the slope of the ventilatory response to CO2 decreased significantly (from 2.72 ± 0.34 to 1.8 ± 0.20 L·min−1·mm Hg−1) while assessment of periosteal analgesia showed no change. After epidural injection, the slope of the ventilatory response to CO2 decreased significantly (from 2.32 ± 0.42 to 1.61 ± 0.29, 1.51 ± 0.29, and 1.53 ± 0.21 L ·min−1 ·mm Hg−1) at 15,45, and 90 minutes (x ± SD, P < 0.05), and there was significant periosteal analgesia of the tibia (15 and 30 minutes after injection) and of the radius (30 to 90 minutes after injection). Throughout the study, plasma alfentanil levels were similar after intramuscular and epidural injection. These results suggest that epidural alfentanil induces ventilatory depressiondue to the rostral spread of the drug rather than to systemic absorption.

Ventilatory Response to Carbon Dioxide After Intramuscular and Epidural Fentanyl

The authors compared the effects of administration of fentanyl 200 μg on the Ventilatory response to carbon dioxide in two groups of nine healthy unpremedicated subjects: one group received fentanyl as an intramuscular injection; in the other group, fentanyl was injected into the epidural space. In the intra muscular group, the slope of the venti-latory response to CO2 did not decrease significantly. In the epidural group, the slope of the Ventilatory response to CO2 decreased significantly from 2.48 ± 1.05 to 1.77 ± 0.7, 1.74 ± 0.7, and 2.07 ± 0.74 L·min-1·mm Hg−1 at 30, 60, and 120 min after injection (x ± SD, P ≤ 0.05), respectively. At each time of the study, plasma fentanyl levels were significantly lower in the epidural group than in the intramuscular group (P ≤ 0.05). These results suggest that epidural fentanyl induces a non systemic Ventilatory depression that may be due to the rostral spread of the drug.