Continuous infusion of clonidine in ventilated newborns and infants: a randomized controlled trial.

OBJECTIVES: To assess the influence of an infusion of clonidine 1 µg/kg/hr on fentanyl and midazolam requirement in ventilated newborns and infants. DESIGN: Prospective, double-blind, randomized controlled multicenter trial. Controlled trials.com/ISRCTN77772144. SETTING: Twenty-eight level 3 German PICUs/neonatal ICUs. PATIENTS: Ventilated newborns and infants: stratum I (1-28 d), stratum II, (29-120 d), and stratum III (121 d to 2 yr). INTERVENTIONS: Patients received clonidine 1 µg/kg/hr or placebo on day 4 after intubation. Fentanyl and midazolam were adjusted to achieve a defined level of analgesia and sedation according to Hartwig score. MEASUREMENTS AND MAIN RESULTS: Two hundred nineteen infants were randomized; 212 received study medication, 69.7% were ventilated in the postoperative care and 30.3% for other reasons. Primary endpoint: consumption of fentanyl and midazolam in the 72 hours following the onset of study medication (main observation period) in the overall study population. The confirmatory analysis of the overall population showed no difference in the consumption of fentanyl and midazolam. Explorative age-stratified analysis demonstrated that in stratum I (n = 112) the clonidine group had a significantly lower consumption of fentanyl (clonidine: 2.1 ± 1.8 µg/kg/hr, placebo: 3.2 ± 3.1 µg/kg/hr; p = 0.032) and midazolam (clonidine: 113.0 ± 100.1 µg/kg/hr, placebo: 180.2 ± 204.0 µg/kg/hr; p = 0.030). Strata II (n = 43) and III (n = 46) showed no statistical difference. Sedation and withdrawal-scores were significantly lower in the clonidine group of stratum I (p < 0.001). Frequency of severe adverse events did not differ between groups. CONCLUSIONS: Clonidine 1 µg/kg/hr in ventilated newborns reduced fentanyl and midazolam demand with deeper levels of analgesia and sedation without substantial side effects. This was not demonstrated in older infants, possibly due to lower clonidine serum levels.

Prospective evaluation of the pharmacodynamics of piritramide in neonates and infants.

Piritramide is a synthetic opioid commonly used in Germany and Austria for the analgesia of pediatric patients. Little pharmacokinetic and pharmacodynamic data for the pediatric population is available. The aim of this investigation was to gain pharmacodynamic data on postsurgical analgesia and the side effects of piritramide. The study was approved by the Ethics Committee of the Medical Faculty. Data were collected in an open, prospective clinical trial. After obtaining the parents' informed written consent, patients received a bolus of piritramide 50 mug/kg for postsurgical analgesia or to prevent pain resulting from invasive procedures. Titration doses of 15 microg/kg were allowed. Vital signs and pain intensity were closely monitored. Data from 39 patients could be included in the analysis. Of the patients, 95% were in the immediate postsurgical course, 5% had piritramide for invasive procedures, and 46% of the patients were ventilated. The mean piritramide dosage was 64 +/- 24 microg/kg. Pharmacodynamic analysis showed adequate analgesia for at least 50% of the spontaneously breathing patients for 120 min after piritramide bolus. More than 50% of the ventilated patients showed inadequate analgesia at any point in time after piritramide bolus. Fifty-nine percent (59%) of the ventilated patients received additive analgesia versus 31% of spontaneously breathing patients. No relevant changes of vital signs could be observed. One patient received naloxone for apnea. We conclude that dosages of more than 50-70 microg/kg are needed for sufficient analgesia in ventilated postsurgical infants. In spontaneously breathing patients, 50-70 microg/kg provides a 120-min period of analgesia for more than 50% of patients. Cardiovascular stability of the patients was good and, with one exception, there was no respiratory depression.

Pharmacokinetics of piritramide in newborns, infants and young children in intensive care units.

Piritramide is indicated for treatment of postoperative pain and analgosedation in the intensive care unit (ICU) setting. In an open prospective study the pharmacokinetics of piritramide were investigated in four groups: newborns (NB, age: 1-28 days) (n=8), infants 1 (IF1, age: 2-4 months) (n=7), infants 2 (IF2, age: 5-12 months) (n=14) and young children (YC, age: 2-4 years) (n=10). The recommended paediatric dose range for therapy of postoperative pain is 50-200 microg/kg. Piritramide was administered intravenously as a single dose by bolus injection of 50 microg/kg. Blood samples were collected at 0, 15, 45, 90 min and 3, 6, 9, 12 h after application, and urine samples were collected before application and during the following intervals: 1-2, 2-6, 6-12 h. Piritramide was measured in blood and urine by HPLC-ESI-MS. The following pharmacokinetic parameters: maximum plasma concentration (C(max)), distribution half-life (t 1/2 alpha), elimination half-life (t 1/2 beta), total clearance (Cl(t)) and median volume of distribution at equilibrium (Vd(ss)) were calculated using a non-compartment and a two-compartment model for the disposition of piritramide (TOPFIT and NONMEM-pharmacokinetic analysis). Newborns (NB) showed the highest maximum plasma concentrations (median+/-SD) C(max) (79+/-240 microg/l) compared to the other three groups (IF1 36+/-367, IF2 12+/-81 and YC 16+/-9 microg/l) without statistical significance. The median elimination half-lives (t 1/2 beta) were 702+/-720 min in NB, 157+/-102 min in IF1, 160+/-68 min in IF2 and 166+/-143 min in YC. For t 1/2 beta the difference between NB and the other three groups (IF1, IF2 and YC) was statistically significant (Mann-Whitney-U, P<0.05). Cl(t) was 15.9+/-16.7, 46.6+/-76.9, 235.5+/-454.1 and 338+/-168.1 ml/min in NB, IF1, IF2 and YC respectively. The total clearance increased exponentially with an elimination half-life of 702 min from 15.9 ml/min in NB to 46.6 ml/min in IF2. Differences between the NB/IF1 groups and IF2/YC groups were significantly significant (NB vs. IF2, NB vs. YC, IF1 vs. IF2 and IF1 vs. YC). Vd(ss) was 2.0+/-4.93, 1.7+/-2.5, 7.0+/-5.2 and 6.7+/-2.2 l/kg in NB, IF1, IF2 and YC respectively. In comparison to group IF1 the Vd(ss) was significantly larger in groups IF2 and YC (Mann-Whitney U, P<0.05). Newborns showed a high initial concentration and a distinct prolongation of the elimination half-life of piritramide compared to infants, young children and adults. Therefore, dosage needed to treat postoperative pain should be reduced, and the repetitive doses should be geared to the analgesic effects. In infants and young children the elimination of piritramide is increased compared to adults; therefore the duration of the effects of piritramide will be shortened, and dose intervals ought to be reduced. Subsequent clinical trials for detailed dose adjustment of piritramide in paediatric patients comparing pharmacokinetics and effectiveness are needed.