Fentanyl with ropivacaine infusion for postoperative pain relief in infants and children. Kinetics of epidural fentanyl.

OBJECTIVES: The aim of the study was to evaluate pharmacokinetics of fentanyl administered as continuous epidural infusion with 0.2% ropivacaine for postoperative pain relief in infants and toddlers, and older children undergoing major abdominal and urological procedures. METHODS: Thirteen infants and toddlers (median age 14 [range 3-36] months, 11 [5-17] kg, Group I) and 11 children (68 [45-131] months, 21 [16-52] kg, Group II) participated in the study. Epidural catheter was placed under general anesthesia in the L1-L2, L2-L3, or L3-L4 epidural space and threaded up to 4 cm into the epidural space. Bolus dose of 0.2% ropivacaine, 0.5 ml·kg(-1) and fentanyl, 2 µg·kg(-1) was given, then followed by continuous infusion of 0.2% ropivacaine, 0.15 ml·kg(-1) ·h(-1) with fentanyl 1.12 µg·kg(-1) ·h(-1) . In the postoperative period, fentanyl dose was reduced to 0.375 µg·kg(-1) ·h(-1) . RESULTS: With this dosing regimen, fentanyl concentration in plasma was within the range of analgesic concentrations, and did not exceed 1.0 ng·ml(-1) . After discontinuation of epidural infusion, pharmacokinetics of fentanyl was complicated by a slight increase in plasma concentration during the elimination phase. Both elimination half-life of fentanyl (t1/2, MRT ) and mean residence time (MRT) were much longer than those observed after single IV bolus dose, and longer in Group I than in Group II (t1/2 MRT 15.9 [3.6-31.5] h vs 8.0 [7.1-13.3] h, P < 0.05, MRTstop-last 22.9 [5.1-45.5] h vs 11.5 [10.2-19.1] h, P < 0.05). Therefore, monitoring of vital signs seems warranted for several hours after the termination of the epidural infusion because risk of respiratory depression may persist, especially in the younger age group.

Pharmacokinetics of sufentanil administered with 0.2% ropivacaine as a continuous epidural infusion for postoperative pain relief in infants.

BACKGROUND AND OBJECTIVES: Our objective was to assess plasma sufentanil concentrations and postinfusion pharmacokinetics in infants receiving 0.2% ropivacaine with sufentanil as a continuous epidural infusion for postoperative pain relief. METHODS: With consent of local ethics committee and informed parental consent, 20 infants 3-36 months old (m.o.) (median 9.3 m.o., 9.0 [3.5-15] kg, ASA PS I/II) were enrolled. Epidural catheter was placed under general anesthesia in L3-L4, L4-L5, or L2-L3 interspace and threaded not farther than 4 cm into epidural space. After initial bolus of 0.2% ropivacaine, 0.5 ml·kg(-1) and sufentanil 200 ng·kg(-1) , continuous infusion of 0.2% ropivacaine, 0.3 mg·kg(-1) ·h(-1) with sufentanil 112 ng·kg(-1) ·h(-1) was started. For the postoperative period, sufentanil dose was reduced to 37 ng·kg(-1) ·h(-1) . Blood samples were drawn at the end of surgery, 24 h later, by the end of 2nd day of infusion and after 3, 6, and 18 h from the end of infusion. Sufentanil was measured using liquid-liquid extraction (LLE) procedure and HPLC-MS/MS method with LOQ = 5 pg·ml(-1) . RESULTS AND CONCLUSIONS: Elimination of sufentanil following epidural administration was very slow, with MRT = 28.25 [18.36-44.75] h and t1/2 MRT  = 19.57 [12.72-31.01] h. In infants, during a long-term infusion of sufentanil with ropivacaine, the opioid concentration in plasma increases during the postoperative infusion itself, then increases even further after discontinuation of the infusion, in some cases reaching the values consistent with a potential risk of respiratory depression. Meticulous monitoring of the infants' vital signs is therefore mandatory not only during the infusion, but also for several hours after its discontinuation.

C (max) and t (max) verification using Fibonacci sequence and absorption rate.

The aim of this study was to verify the values of maximal observed concentration (C max,obs) and the time, at which maximum concentration is observed (t max,obs) using the analysis of the absorption rate constant (k ab). It focused on the changes in concentration over time (C-T) for drugs, for which several peaks of concentration occur. In addition, the attempt was made to use Fibonacci sequence to facilitate the visual analysis of the dynamics in changes of concentration on C-T graphs. The analyses were conducted with the use of three hypothetical data groups (groups I, II and III), which had distinct C-T profiles, and with the in vivo data form healthy subjects (n = 10) taking part in a bioequivalence study, who was given a single oral dose of topiramate (100 mg). The comparison of hypothetical and real in vivo data demonstrated that for the C-T curves, in which there are several peaks of concentration C max,obs and t max,obs values can easily be miscalculated when the increase in concentration is not properly related to the appropriate absorption phase (63.2, 87.50, 96.88 %). It was also demonstrated that the data transformation with the use of Fibonacci sequence exposes slight differences in the observed concentration values in a semi-logarithmic scale. The results of this study show that in case of C-T curves with several peaks of concentration, the verification of C max and t max data obtained taking into account different absorption phases enables more precise evaluation of these parameters.

Application of liquid chromatography method with electrochemical detection for bioequivalence study of trimetazidine in human plasma.

A method to estimate trimetazidine (CAS: 13171-25-0) levels in human plasma by means of HPLC with electrochemical detection was developed. Trimethoprim (CAS: 26807-65-8) was used as an internal standard. This method of analysis was fully validated according to the guidelines of the United States Food and Drug Administration, European Medicines Agency and Organization for Economic Co-operation and Development and Good Laboratory Practice rules. The accuracy and precision of the developed method were found to be satisfactory and stability studies showed acceptable variation (below 15%) of trimetazidine concentrations when samples were stored frozen at -75 degrees C for 54 days. The developed method was successfully used for a comparative 2 x 2 period, crossover bioequivalence study of two extended-release preparations of trimetazidine performed on 24 healthy volunteers at the steady state after multiple dosing of 35 mg twice daily for 4 days and a single 35 mg dose on the 5th day and after a single dose of 35 mg under fasting or postprandial conditions.

Chromatographic/mass spectrometric method for the estimation of itraconazole and its metabolite in human plasma. Application to a bioequivalence study.

A HPLC/mass spectrometry method for the estimation of itraconazole (CAS 84625-61-6, ITR) and its active metabolite hydroxyitraconazole (CAS 112559-91-8, HOX) in human plasma was developed. Terconazole (CAS 67915-31-5) was used as an internal standard. The analytical method was fully validated according to FDA and EMEA requirements. The accuracy and precision of the developed method was satisfactory and stability studies showed an acceptable variation (below 15%) of ITR and HOX concentrations when the samples were stored frozen at -75 degrees C for 95 days. The developed method was successfully used for a comparative 2 x 2 period, crossover bioequivalence study of two preparations of ITR (Itrakonazol Genexo 100 mg as the test drug) performed on 36 healthy volunteers.