Sufentanil Disposition and Pharmacokinetic Model-Based Dosage Regimen for Sufentanil in Ventilated Full-Term Neonates.

INTRODUCTION: Sufentanil is a potent synthetic opioid used for analgesia in neonates; however, data concerning drug disposition of sufentanil and dosage regimen are sparse in this population. Therefore, the aim of the study was to explore sufentanil disposition and to propose optimal loading and maintenance doses of sufentanil in ventilated full-term neonates. METHODS: Individual sufentanil pharmacokinetic parameters were calculated based on therapeutic drug monitoring data using a 2-compartmental model. Linear regression models were used to explore the covariates. RESULTS: The median (IQR) central volume of distribution (Vdc) and clearance (CL) for sufentanil were 4.7 (4.1-5.4) L/kg and 0.651 (0.433-0.751) L/h/kg, respectively. Linear regression models showed relationship between Vdc (L) and GA (r2 = 0.3436; p = 0.0452) as well as BW (r2 = 0.4019; p = 0.0268). Median optimal sufentanil LD and MD were 2.13 (95% CI: 1.78-2.48) µg/kg and 0.29 (95% CI: 0.22-0.37) µg/kg/h, respectively. Median daily COMFORT-B (IQR) scores ranged from 6 to 23 while no significant relationship between pharmacokinetic parameters and COMFORT-B scores was found. DISCUSSION/CONCLUSION: Body weight and gestational age were found as weak covariates for sufentanil distribution, and the dosage regimen was developed for a prospective trial.

Phenylpiperidine opioid effects on isoflurane minimum alveolar concentration in cats.

Different structurally related phenylpiperidine opioids exhibit different isoflurane-sparing effects in cats. Because minimum alveolar concentration (MAC) in cats is affected only by very high plasma concentrations of some phenylpiperidine opioids, we hypothesized these effects are caused by actions on nonopioid receptors. Using a prospective, randomized, crossover design, six cats were anesthetized with isoflurane, intubated, ventilated, and instrumented. Isoflurane MAC was measured in triplicate using a tail-clamp and bracketing technique. A computer-controlled intravenous infusion using prior pharmacokinetic models targeted plasma concentrations of 60 ng/ml fentanyl, 10 ng/ml sufentanil, or 500 ng/ml alfentanil, and isoflurane MAC was measured in duplicate. Next, naltrexone 0.6 mg/kg was administered to cats hourly during the opioid infusion, and isoflurane MAC was measured in duplicate. Blood was collected during MAC determinations to measure opioid concentrations. Responses were analyzed using repeated measures ANOVA with significance at p < .05. Alfentanil and sufentanil decreased isoflurane MAC by 16.4% and 6.4%, respectively, and these effects were completely reversed by naltrexone. Fentanyl had no significant effect on isoflurane MAC. Alfentanil and sufentanil modestly reduce isoflurane MAC via agonist effects on opioid receptors. However, these effects are too small to justify clinical use of phenylpiperidine opioids as single agents to reduce MAC in cats.

Population pharmacokinetics of intravenous sufentanil in critically ill patients supported with extracorporeal membrane oxygenation therapy.

BACKGROUND: Sufentanil is commonly used for analgesia and sedation during extracorporeal membrane oxygenation (ECMO). Both ECMO and the pathophysiological changes derived from critical illness have significant effects on the pharmacokinetics (PK) of drugs, yet reports of ECMO and sufentanil PK are scarce. Here, we aimed to develop a population PK model of sufentanil in ECMO patients and to suggest dosing recommendations. METHODS: This prospective cohort PK study included 20 patients who received sufentanil during venoarterial ECMO (VA-ECMO). Blood samples were collected for 96 h during infusion and 72 h after cessation of sufentanil. A population PK model was developed using nonlinear mixed effects modelling. Monte Carlo simulations were performed using the final PK parameters with two typical doses. RESULTS: A two-compartment model best described the PK of sufentanil. In our final model, increased volume of distribution and decreased values for clearance were reported compared with previous PK data from non-ECMO patients. Covariate analysis showed that body temperature and total plasma protein level correlated positively with systemic clearance (CL) and peripheral volume of distribution (V2), respectively, and improved the model. The parameter estimates of the final model were as follows: CL = 37.8 × EXP (0.207 × (temperature - 36.9)) L h-1, central volume of distribution (V1) = 229 L, V2 = 1640 × (total plasma protein/4.5)2.46 L, and intercompartmental clearance (Q) = 41 L h-1. Based on Monte Carlo simulation results, an infusion of 17.5 µg h-1 seems to reach target sufentanil concentration (0.3-0.6 µg L-1) in most ECMO patients except hypothermic patients (33 °C). In hypothermic patients, over-sedation, which could induce respiratory depression, needs to be monitored especially when their total plasma protein level is low. CONCLUSIONS: This is the first report on a population PK model of sufentanil in ECMO patients. Our results suggest that close monitoring of the body temperature and total plasma protein level is crucial in ECMO patients who receive sufentanil to provide effective analgesia and sedation and promote recovery. TRIAL REGISTRATION: Clinicaltrials.gov NCT02581280 , December 1st, 2014.

Sufentanil pharmacokinetics in a full-term neonate treated with extracorporeal membrane oxygenation: a case report.

INTRODUCTION: Sufentanil is a potent analgesic drug used for pain management. A few studies describe the pharmacokinetics of sufentanil in neonates; however, no pharmacokinetic data about sufentanil during extracorporeal membrane oxygenation have been published yet. CASE REPORT: A 1-day-old neonate with moderate hypoxic-ischemic encephalopathy received veno-arterial extracorporeal membrane oxygenation support for refractory respiratory and circulatory failure. Sufentanil plasma concentrations were determined during both extracorporeal membrane oxygenation (n = 14) and non-extracorporeal membrane oxygenation (n = 17) period. Based on these measurements, individual sufentanil pharmacokinetic parameters were calculated. DISCUSSION: We observed increased sufentanil volume of distribution (11.6 vs 5.6 L/kg) and decreased sufentanil clearance (0.535 vs 0.746 L/h/kg) in extracorporeal membrane oxygenation period. The increment of volume of distribution was attributed to ECMO influence, while difference in clearance was probably due to drug interaction. CONCLUSIONS: This is the first description of sufentanil pharmacokinetics in neonate treated with extracorporeal membrane oxygenation. We observed considerably larger volume of distribution during extracorporeal membrane oxygenation period in comparison with non-extracorporeal membrane oxygenation period.

Influence of Cardiac Output on the Pharmacokinetics of Sufentanil in Anesthetized Pigs.

BACKGROUND: Sufentanil is used for general anesthesia and analgesia. The study aim was to determine the effect of pharmacologically induced changes in cardiac output on the pharmacokinetics of sufentanil in anesthetized pigs. METHODS: Twenty-four pigs were randomly assigned to low, high, and control cardiac output groups. Cardiac output was decreased or increased from baseline by at least 40%, or maintained within ± 10% of baseline, respectively. Sufentanil was administered as a bolus followed by a continuous infusion for 120 min. Timed arterial samples were drawn for sufentanil concentration measurements. RESULTS: Data from 20 animals were analyzed. The cardiac outputs (means ± SD) were 2.9 ± 0.7, 5.4 ± 0.7, and 9.6 ± 1.6 l/min in the low, control, and high cardiac output groups, respectively. The parameters of the two-compartment pharmacokinetic model for these cardiac outputs were: CL1: 0.9, 1.2, and 1.7 l/min; CL2: 0.9, 3.1, and 6.9 l/min; V1: 1.6, 2.9, and 5.2 l; and V2: 27.5, 47.0, and 79.8 l, respectively. Simulated sufentanil doses to maintain a target plasma concentration of 0.5 ng/ml for 3 h were 99.5, 128.6, and 157.6 µg for cardiac outputs of 3, 5, and 7 l/min, respectively. The context-sensitive half-times for these cardiac outputs increased from 3.1 to 19.9 and 25.9 min, respectively. CONCLUSIONS: Cardiac output influences the pharmacokinetics of sufentanil. Simulations suggest that in the case of increased cardiac output, the dose should be increased to avoid inadequate drug effect at the expense of prolonged recovery, whereas for low cardiac output the dose should be reduced, and a faster recovery may be expected.

Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain.

BACKGROUND: Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 µg of sufentanil are described. METHODS: Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used. RESULTS: Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-µg dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 ± 0.85 h) and 12 doses (2.5 ± 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment. CONCLUSIONS: The time course of a single 30-µg dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting.

Pharmacokinetics and pharmacodynamics of sublingual sufentanil for postoperative pain management.

Achieving successful treatment of postoperative pain remains a challenge. Recently, a sufentanil sublingual tablet system has been developed for treatment of moderate-to-severe postoperative pain. The phenylpiperidine sufentanil is a potent analgesic that rapidly crosses the blood-brain barrier and selectively activates central µ-opioid receptors. The system makes use of a hand-held dispenser system, which contains forty 15-µg sufentanil sublingual micro-tablets. The patient can release one tablet at 20-min intervals using a unique radiofrequency adhesive tag, which is wrapped around the patient's thumb. In this review, the authors discuss the pharmacology of sublingual sufentanil with reference to its suitability in the treatment of postoperative pain, the current evidence for the sublingual sufentanil system in postoperative pain treatment, and advantages and limitations of the sublingual system. We conclude that sufentanil is suited for the transmucosal route due to its pharmacokinetic profile, including rapid onset, absence of active metabolites and low tissue accumulation. The efficacy and safety of the sufentanil sublingual tablet system has been shown in over 600 patients in a limited set of studies; further independent studies are required to determine the position of the system among other forms of postoperative pain treatment. We conclude that the sublingual sufentanil tablet system allows effective pain relief, and allows patients to control their own pain relief and early postoperative mobility.

Opioid receptor A118G polymorphism does not affect the consumption of sufentanil and ropivacaine by patient-controlled epidural analgesia after cesarean section.

BACKGROUND: Previous reports have suggested that polymorphism of the opioid receptor A118G affects the efficacy of opioid analgesia. The aim of this study was to investigate whether such polymorphism contributed to variability in epidural mixture (sufentanil plus ropivacaine) requirements through patient-controlled epidural analgesia (PCEA) after cesarean section. METHODS: One hundred eighty consenting women undergoing elective cesarean delivery were enrolled in the study. Patients received sufentanil and ropivacaine for pain control after surgery. Sufentanil (50 mcg) diluted with 0.2% ropivacaine in a total volume of 100 mL was administered by PCEA with a background infusion rate of 2 mL/h and a pump program set to deliver 0.5-mL boluses with a lockout time of 15 minutes. The analgesic effect and adverse effects were measured with rating scales. The total consumption of the epidural mixture in the first 24 hours postoperatively was recorded. Blood samples were genotyped to classify patients into 3 groups according to A118G polymorphism. RESULTS: Of 161 patients included in the analysis, 63 were homozygous (AA), 81 were heterozygous (AG), and 17 were homozygous (GG) for the A118G polymorphism. No difference was observed among groups in the consumption of the epidural mixture within the first 24 hours postoperatively (P = 0.3). Satisfaction with analgesia, pain scores, and adverse effects were similar among the groups. CONCLUSIONS: The analgesic requirements of patients receiving sufentanil and ropivacaine through PCEA after caesarean section were not associated with A118G polymorphism.

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.

Intranasal sufentanil/ketamine analgesia in children.

BACKGROUND: The management of procedural pain in children ranges from physical restraint to pharmacological interventions. Pediatric formulations that permit accurate dosing, are accepted by children and a have a rapid onset of analgesia are lacking. OBJECTIVES: To investigate a pediatric formulation of intranasal sufentanil 0.5 mcg·kg(-1) and ketamine 0.5 mg·kg(-1) for procedural pain and to characterize the pharmacokinetic (PK) profile. METHODS: Fifty children (≥10 kg) scheduled for a painful procedure were included in this prospective nonrandomized open-label clinical trial. Thirteen of these children had central venous access for drug assay sampling; enabling a compartmental PK analysis using nonlinear mixed-effects models. Pain intensity before and during the procedure was measured using age-appropriate pain scales. Heart rate, oxygen saturation and sedation were recorded. RESULTS: Children had a mean age of 8.8 (sd 4.9) years and weight 35.2 (sd 20.1) kg. Sufentanil/ketamine nasal spray was effective (procedural pain intensity scores ≤5 (0-10)) in 78% of the painful procedures. The spray was well accepted by 94% of the children. Oxygen saturation and heart rate remained stable, and sedation was minimal. The bioavailability of sufentanil and ketamine was 24.6% and 35.8%, respectively. Maximum plasma concentration (Cmax) of sufentanil was 0.042 mcg·l(-1) (coefficient of variation (CV) 12.9%) at 13.8 min (CV 12.4%) (Tmax). Cmax for ketamine was 0.102 mg·l(-1) (CV 10.8%), and Tmax was 8.5 min (CV 17.3%). CONCLUSION: Sufentanil/ketamine nasal spray provided rapid onset of analgesia for a variety of painful procedures with few adverse effects and has promising features for use in pediatric procedural pain management.

Pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats.

The aim of this study was to compare the pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats. Six adult cats were used. Anesthesia was induced and maintained with isoflurane in oxygen. End-tidal isoflurane concentration was set at 2% and adjusted as required due to spontaneous movement. Fentanyl (10 µg/kg), alfentanil (100 µg/kg), or sufentanil (1 µg/kg) was administered intravenously as a bolus, on separate days. Blood samples were collected immediately before and for 8 h following drug administration. Plasma drug concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to concentration-time data. A 3-compartment model best fitted the concentration-time data for all drugs, except for 1 cat in the sufentanil group (excluded from analysis). The volume of the central compartment and the volume of distribution at steady-state (L/kg) [mean ± SEM (range)], the clearance (mL/min/kg) [harmonic mean ± pseudo-SD (range)], and the terminal half-life (min) [median (range)] were 0.25 ± 0.04 (0.09-0.34), 2.18 ± 0.16 (1.79-2.83), 18.6 ± 5.0 (15-29.8), and 151 (115-211) for fentanyl; 0.10 ± 0.01 (0.07-0.14), 0.89 ± 0.16 (0.68-1.83), 11.6 ± 2.6 (9.2-15.8), and 144 (118-501) for alfentanil; and 0.06 ± 0.01 (0.04-0.10), 0.77 ± 0.07 (0.63-0.99), 17.6 ± 4.3 (13.9-24.3), and 54 (46-76) for sufentanil. Differences in clearance and volume of distribution result in similar terminal half-lives for fentanyl and alfentanil, longer than for sufentanil.

Anti-Nociceptive Effect of Sufentanil Polymeric Dissolving Microneedle on Male Mice by Hot Plate Technique

Background: Despite the widespread use of opioids to manage severe pain, its systemic administration results in side effects. Among the subcutaneous and transdermal drug delivery systems developed to deal with adverse effects, microneedles have drawn attention due to their rapid action, high drug bioavailability, and improved permeability. Sufentanil (SUF) is an effective injectable opioid for treating severe pain. In this study, we investigated the analgesic effects of SUF using dissolvable microneedles. Methods: SUF polymeric dissolvable microneedles were constructed through the mold casting method and characterized by SEM and FTIR analysis. Its mechanical strength was also investigated using a texture analyzer. Fluorescence microscopy was applied in vitro to measure the penetration depth of microneedle arrays. Irritation and microchannel closure time, drug release profile, and hemocompatibility test were conducted for the validation of microneedle efficiency. Hot plate test was also used to investigate the analgesic effect of microneedle in an animal model. Results: Local administration of SUF via dissolving microneedles had an effective analgesic impact. One hour after administration, there was no significant difference between the subcutaneous and the microneedle groups, and the mechanical properties were within acceptable limits. Conclusion: Microneedling is an effective strategy in immediate pain relief compared to the traditional methods.

Changes in total and unbound concentrations of sufentanil during target controlled infusion for cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Target controlled infusion (TCI) with sufentanil is usually performed using the Gepts model, which was derived from patients undergoing general surgery. It is, however, known that pharmacokinetics of sufentanil can be changed during cardiopulmonary bypass (CPB). We tested whether TCI during coronary artery bypass surgery with CPB produces constant total, unbound sufentanil concentration-time course or both. METHODS: After IRB approval, written informed consent was obtained from 38 male patients (48-74 yr) undergoing coronary artery bypass surgery. Anaesthesia was managed with propofol and TCI of sufentanil, using the Gepts model, targeting plasma concentrations of 0.4 (n=18) or 0.8 ng ml(-1) (n=20). Arterial blood samples were taken before, during, and after CPB. Total and unbound sufentanil concentrations were measured by HPLC with tandem mass spectrometry. The accuracy of the TCI model was assessed by the prediction error, and a pharmacokinetic model was determined by population analysis. RESULTS: The median prediction error of the TCI with the Gepts model before, during, and after CPB was 59.6, 3.9, and -10.4%, respectively. The unbound sufentanil concentrations increased significantly during CPB. Pharmacokinetic modelling showed an increase in elimination and intercompartmental clearance after initiation of CPB. CONCLUSIONS: Neither total nor unbound sufentanil concentrations remained constant when performing a TCI with the Gepts model in coronary artery bypass surgery with CPB. A pharmacokinetic model derived from patients undergoing cardiac surgery with CPB might improve the performance of TCI in this population.

Aspects of pharmacokinetics and pharmacodynamics of sufentanil in pediatric practice.

Sufentanil is a potent synthetic opioid. Like other opioids, sufentanil creates a stable hemodynamic environment in cardiovascularly compromised pediatric patients. Clearance, expressed as per kilogram, is increased in children compared to adults. The P450 CYP3A4 enzyme is responsible for the major metabolic N-dealkylation pathway. Enzyme activity is reduced in neonates but the maturation of sufentanil clearance is not described. The free active fraction is affected by age because of the reduced α(1) -acid glycoprotein plasma concentrations in neonates. Intranasal administration of sufentanil is a possible option for premedication, procedural sedation and analgesia in children, as this option has been found to be safe and effective. Studies concerning the pharmacokinetics and dynamics of sufentanil administered as a bolus or continuous infusion in children are few.

Comparison of sufentanil versus fentanyl in ventilated term neonates.

BACKGROUND: Increasingly frequent applications of opioid analgesics in neonatal intensive care require the evaluation of efficacy and side effects. PATIENTS: Mechanically ventilated term neonates were consecutively enrolled. METHODS: In a double-blind randomized trial 20 newborns received a continuous intravenous infusion of fentanyl (n=10) or sufentanil (n=10) in an assumed equipotent dose of 7:1. The analgesic dose was individually adjusted according to sedation scores. The period between cessation of analgesic medication and successful extubation (weaning time), adverse drug effects and urinary cortisol concentrations were evaluated. RESULTS: No significant difference of weaning time was seen between fentanyl and sufentanil group (mean weaning time (+/-SD) of fentanyl group 520+/-381 min, median 380 min; sufentanil group 585+/-531 min, median 405 min, p=0.78, 2-tailed U-Test, Mann and Whitney). The mean opioid dose resulted in a 10:1 ratio (fentanyl 4.11 microg/(kg x h) vs sufentanil 0.41 microg/(kg x h)). We found no marked differences in sedation levels, blood pressure, heart rate, oxygenation index, co-medication or urinary cortisol levels. In both groups similar adverse effects were assessed including respiratory depression, mild withdrawal symptoms or decrease of gastrointestinal motility. CONCLUSION: In our study sufentanil did not reduce the weaning period in ventilated term neonates when compared to fentanyl. The equipotent dose ratio for fentanyl/sufentanil was 10:1. According to sedation scores both substances provided effective pain and stress protection.

Malfunctioning sufentanil intrathecal pain pump: a case report.

BACKGROUND: Sufentanil is a potent opioid uncommonly used to manage pain and is rarely administered via an intrathecal pain pump system. CASE PRESENTATION: This case illustrates the use of intrathecal sufentanil in a 50-year-old Caucasian man for the management of chronic pain; however, the intrathecal drug delivery system experienced a malfunction which led to 1/100th output of the correct dosage. Interesting aspects of this case report include the uncommon choice of sufentanil use for an intrathecal drug delivery system, as well as the unusual pharmacokinetics of this drug. Specifically, this patient did not experience the major withdrawal that would be expected given significant under dosing of opioid, and this may be explained by the lipophilicity and context-sensitive half-times of sufentanil. CONCLUSIONS: Because of the absence of a clinically significant withdrawal in this case report, clinicians must be aware of relevant pharmacokinetic properties and unusual intrathecal drug delivery system technologies that influence a patient's response when device malfunction occurs.

The optimal bolus dose of sufentanil for satisfactory laryngeal mask airway (LMA) insertion conditions in chinese pediatric patients: A prospective double-blind randomized controlled trial (CONSORT).

BACKGROUND: This study aimed to estimate the optimal dose of sufentanil, coadministered with 2.5 mg/kg propofol, for satisfactory laryngeal mask airway (LMA) insertion conditions in Chinese children and to determine the optimal bolus dose. METHODS: Seventy-five Chinese children aged 2 to 6 years with the American Society of Anesthesiologists physical status I or II, undergoing elective minor surgery were recruited. They were randomly divided into 5 different dosage groups (0, 0.05, 0.1, 0.15, 0.2 µg/kg). A predetermined sufentanil diluted with 5 mL saline was injected 30 s, 200 s later, followed by 2.5 mg/kg propofol over 10 s. After that the insertion conditions were assessed, using a 6-category score. The duration of apnea was recorded. A Probit analysis was performed to determine the ED50 and ED95 with 95% confidence interval for optimal conditions. RESULTS: There were less hemodynamic changes in all sufentanil groups than propofol-only group, with 0.2 µg/kg patients showing the most stable cardiovascular responses and best insertion conditions. However, the duration of apnea increased with the increasing dosage of sufentanil. From Probit analysis, the ED50 and ED95 of sufentanil for optimum score were 0.064 µg/kg and 0.177 µg/kg, respectively. CONCLUSION: In combination with propofol for anesthesia induction in Chinese children, sufentanil 0.2 µg/kg could prevent patients from dramatic hemodynamic change, providing satisfactory LMA insertion conditions.

Effects of OPRM1 and ABCB1 gene polymorphisms on the analgesic effect and dose of sufentanil after thoracoscopic-assisted radical resection of lung cancer.

OBJECTIVE: To study the effects of single-nucleotide polymorphisms of the OPRM1 and ABCB1 genes on the analgesic effect and consumption of sufentanil after thoracoscopic-assisted radical resection of lung cancer. METHODS: A total of 225 Chinese Han nationality patients undergoing thoracoscopic-assisted radical resection of lung cancer were enrolled in the present study. Among them, 132 were males (58.67%) and 93 (41.33%) were females having American Society of Anesthesiologists statuses classified as grades I or II. The rs1799971, rs563649 and rs1323040 genotypes of the OPRM1 gene and rs2032582, rs1045642 and rs1128503 genotypes of the ABCB1 gene were detected by Sanger sequencing. The state anxiety index and pressure pain threshold were assessed preoperatively. Sufentanil was administered intravenously to maintain anesthesia. The doses and side effects of sufentanil consumed 6 h (T1), 24 h (T2) and 48 h (T3) after surgery were recorded. RESULTS: The sufentanil doses at T1, T2 and T3 were significantly higher in radical-operation lung cancer patients with mutant homozygous rs1799971 and rs1323040 loci in the OPRM1 gene and rs2032582 and rs1128503 loci in the ABCB1 gene. The doses of sufentanil consumed by mutant heterozygous lung cancer patients at T1, T2 and T3 were significantly higher than those consumed by patients without mutations, and the differences were statistically significant (P<0.05). There was no significant difference in sufentanil doses consumed by lung cancer patients with mutant homozygous, mutant heterozygous and wild-type rs563649 locus of the OPRM1 gene and rs1045642 locus of the ABCB1 gene at T1, T2 and T3 (P>0.05). There was no significant difference in the visual analog scale scores at T1, T2 and T3 for different genotypes of OPRM1 and ABCB1 genes in lung cancer patients (P>0.05). No significant difference was found between the adverse reactions of OPRM1 and ABCB1 genotypes in patients undergoing radical resection of lung cancer (P>0.05). CONCLUSION: The rs1799971 and rs1323040 polymorphisms of the OPRM1 gene and rs2032582 and rs1128503 polymorphisms of the ABCB1 gene are related to the analgesic effect and consumed dose of sufentanil in Chinese Han patients undergoing radical operation of lung cancer.

Multistep Unified Models Using Prior Knowledge for the Prediction of Drug Clearance in Neonates and Infants.

Allometric approaches are widely used for interspecies scaling for the prediction of pharmacokinetic (PK) parameters during drug development. The concept of allometry can also be extended to predict PK parameters from adults to children. Three methods for extrapolating pediatric clearance were developed and evaluated using the clearance values of 4 drugs. The first method was established using a simple allometric (SA) model with estimated coefficient and exponent based on data ranging from children older than 2 years to adult. Then we developed a unified multistep single-exponent (MSE) and multistep body-weight-dependent exponent (MBDE) models. The major steps in these 2 new methods include generating pseudopredicted clearance for unobserved new populations such as preterm neonates, term neonates, and infants. Subsequent steps involve incorporating the pseudopredicted clearance with the actual PK data from older children and adults. All 3 models were then used to predict drug clearance in children ≤2 years old (N = 278). Drug clearance was predicted with mean absolute error of 29.6, 14.2, and 12.9 using SA, MSE, MBDE, respectively. The root mean square error was 65.9, 29.8, 24.7 for SA, MSE, MBDE, respectively. Approximately 41%, 72%, and 74% of the children's clearance data were within 0.5 to 1.5-fold of the observed values when drug clearance was extrapolated using SA, MSE, and MBDE models, respectively. The present multistep unified extrapolation approaches improved the prediction of clearance from preterm neonates to 2 years of age and may have practical use for first-in-pediatric dose selection.

Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review.

Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the pediatric population was performed using the National Library of Medicine PubMed. Studies were included if they contained original pharmacokinetic parameters or models using established routes of administration in patients younger than 18 years of age. Of 372 retrieved articles, 44 eligible pharmacokinetic studies contained data of 821 patients younger than 18 years of age, including more than 46 preterm infants, 64 full-term neonates, 115 infants/toddlers, 188 children, and 28 adolescents. Underlying diagnoses included congenital heart and pulmonary disease and abdominal disorders. Routes of drug administration were intravenous, epidural, oral-transmucosal, intranasal, and transdermal. Despite extensive use in daily clinical practice, few studies have been performed. Preterm and term infants have lower clearance and protein binding. Pharmacokinetics was not altered by chronic renal or hepatic disease. Analyses of the pooled individual patients' data revealed that clearance maturation relating to body weight could be best described by the Hill function for sufentanil (R 2 = 0.71, B max 876 mL/min, K 50 16.3 kg) and alfentanil (R 2 = 0.70, B max (fixed) 420 mL/min, K 50 28 kg). The allometric exponent for estimation of clearance of sufentanil was 0.99 and 0.75 for alfentanil clearance. Maturation of remifentanil clearance was described by linear regression to bodyweight (R 2 = 0.69). The allometric exponent for estimation of remifentanil clearance was 0.76. For fentanyl, linear regression showed only a weak correlation between clearance and bodyweight in preterm and term neonates (R 2 = 0.22) owing to a lack of data in older age groups. A large heterogeneity regarding study design, clinical setting, drug administration, laboratory assays, and pharmacokinetic estimation was observed between studies introducing bias into the analyses performed in this review. A limitation of this review is that pharmacokinetic data, based on different modes of administration, dosing schemes, and parameter estimation methods, were combined.