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Clinical Pharmacokinetics Feb 2018Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the... (Review)
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 = 0.71, B 876 mL/min, K 16.3 kg) and alfentanil (R = 0.70, B 420 mL/min, K 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 = 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 = 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.
Topics: Adolescent; Alfentanil; Analgesics, Opioid; Body Weight; Child; Child, Preschool; Fentanyl; Humans; Infant; Infant, Newborn; Linear Models; Models, Biological; Remifentanil; Sufentanil
PubMed: 28688027
DOI: 10.1007/s40262-017-0569-6 -
Anaesthesia May 2023Propfol-remifentanil-based total intravenous anaesthesia has dominated recent clinical practice due to its favourable pharmacokinetic profile. Interruption in... (Review)
Review
Propfol-remifentanil-based total intravenous anaesthesia has dominated recent clinical practice due to its favourable pharmacokinetic profile. Interruption in remifentanil supply has presented an opportunity to diversify or even avoid the use of opioids and consider adjuncts to propofol-based total intravenous anaesthesia. Propofol, while a potent hypnotic, is not an effective analgesic. The administration of opioids, along with other adjuncts such as α-2 adrenoceptor agonists, magnesium, lidocaine, ketamine and nitrous oxide provide surgical anaesthesia and avoids large doses of propofol being required. We provide an overview of both target-control and manual infusion regimes for the alternative opioids: alfentanil, sufentanil and fentanyl. The optimal combination of hypnotic-opioid dose, titration sequence and anticipated additional postoperative analgesia required depend on the chosen combination. In addition, we include a brief discussion on the role of non-opioid adjuncts in total intravenous anaesthesia, suggested doses and expected reduction in propofol dose.
Topics: Humans; Remifentanil; Propofol; Anesthesia, Intravenous; Piperidines; Analgesics, Opioid; Anesthesia, General; Hypnotics and Sedatives; Anesthetics, Intravenous
PubMed: 36562193
DOI: 10.1111/anae.15952 -
Current Clinical Pharmacology 2019Opioid analgesics are commonly used along with propofol during general anesthesia. Due to the dearth of data on the quality of anesthesia achieved with this combination,... (Comparative Study)
Comparative Study Meta-Analysis
Comparison of Fentanyl, Remifentanil, Sufentanil and Alfentanil in Combination with Propofol for General Anesthesia: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
BACKGROUND
Opioid analgesics are commonly used along with propofol during general anesthesia. Due to the dearth of data on the quality of anesthesia achieved with this combination, the present meta-analysis was carried out.
METHODS
Electronic databases were searched for appropriate studies using a suitable search strategy. Randomized clinical trials comparing the combination of remifentanil/sufentanil/alfentanil with propofol with fentanyl and propofol, were included. The outcome measures were as follows: total propofol dose to achieve the desired general anesthesia; time of onset and duration of general anesthesia; depth of general anesthesia; and recovery time (time for eye-opening and time taken for extubation). Risk of bias was assessed and Forest plots were generated for eligible outcomes. The weighted mean difference [95% confidence intervals] was used as the effect estimate.
RESULTS
Fourteen studies were included in the systematic review and 13 were included in the metaanalysis. Statistically significant differences were observed for remifentanil in comparison to fentanyl when combined with propofol: Propofol dose (in mg) -76.18 [-94.72, -57.64]; time of onset of anesthesia (min) -0.44 [-0.74, -0.15]; time taken for eye-opening (min) -3.95 [-4.8, -3.1]; and time for extubation (min) -3.53 [-4.37, -2.7]. No significant differences were observed for either sufentanil or alfentanil about the dose of propofol required and due to scanty data, pooling of the data could not be attempted for other outcome measures for either sufentanil or alfentanil.
CONCLUSION
To conclude, we found that remifentanil has a statistically significant anesthetic profile than fentanyl when combined with propofol. Scanty evidence for both alfentanil and sufentanil precludes any such confirmation.
Topics: Alfentanil; Anesthesia, General; Anesthesia, Intravenous; Anesthetics, Intravenous; Fentanyl; Humans; Propofol; Randomized Controlled Trials as Topic; Remifentanil; Sufentanil
PubMed: 30868958
DOI: 10.2174/1567201816666190313160438 -
CPT: Pharmacometrics & Systems... Oct 2018According to current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents, physiologically based pharmacokinetic (PBPK) modeling...
According to current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents, physiologically based pharmacokinetic (PBPK) modeling is a powerful tool to explore and quantitatively predict drug-drug interactions (DDIs) and may offer an alternative to dedicated clinical trials. This study provides whole-body PBPK models of rifampicin, itraconazole, clarithromycin, midazolam, alfentanil, and digoxin within the Open Systems Pharmacology (OSP) Suite. All models were built independently, coupled using reported interaction parameters, and mutually evaluated to verify their predictive performance by simulating published clinical DDI studies. In total, 112 studies were used for model development and 57 studies for DDI prediction. 93% of the predicted area under the plasma concentration-time curve (AUC) ratios and 94% of the peak plasma concentration (C ) ratios are within twofold of the observed values. This study lays a cornerstone for the qualification of the OSP platform with regard to reliable PBPK predictions of enzyme-mediated and transporter-mediated DDIs during model-informed drug development. All presented models are provided open-source and transparently documented.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Alfentanil; Clarithromycin; Cytochrome P-450 CYP3A; Digoxin; Drug Interactions; Humans; Itraconazole; Midazolam; Models, Biological; Rifampin
PubMed: 30091221
DOI: 10.1002/psp4.12343 -
BMC Anesthesiology Jun 2022Remimazolam tosilate (HR7056, RT), a novel ultrashort-acting benzodiazepine, can be used for procedural sedation and general anaesthesia. However, few studies have... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Remimazolam tosilate (HR7056, RT), a novel ultrashort-acting benzodiazepine, can be used for procedural sedation and general anaesthesia. However, few studies have focused on the sedative effect of RT during gastrointestinal endoscopy in elderly patients. The purpose of this study is to compare the sedative effect of RT and propofol for gastrointestinal endoscopy in elderly patients.
METHODS
A total of 82 patients aged ≥65 years with an American Society of Anaesthesiologists (ASA) grade I-II and a body mass index (BMI) of 18.0 to 30.0 kg/m who were scheduled for gastrointestinal endoscopy from Jan 2021 to Aug 2021 were selected and randomly divided into a RT group and a propofol group. Alfentanil 5 μg/kg was used for analgesia in both groups. The RT group was given remimazolam tosilate 0.15 mg/kg with supplemental doses of 0.05 mg/kg as need, while the propofol group was given propofol 1.5 mg/kg with supplemental doses of 0.5 mg/kg. The supplemental doses were determined by the modified observational alertness/sedation assessment (MOAA/S) score and the patients' body movements. Sedative effects, such as the time to loss of consciousness (LOC) (MOAA/S score ≤ 1), successful sedation in one dose, number of supplemental doses after successful induction, and recovery time, were evaluated. Sedation-related side effects, such as injection pain, haemodynamic events and respiratory depression, were also noted. Postoperative nausea and vomiting (PONV), visual analogue scale (VAS) scores at rest, remedial analgesics, and dizziness or headache were recorded. In addition, patients' satisfaction and physician's satisfaction of the procedure were compared between the two groups.
RESULTS
Data from 77 patients were analysed. The success rate of sedation in both groups was 100%. The time to LOC (MOAA/S score ≤ 1) in the RT group was longer than that in the propofol group (20.7 ± 6.1s vs. 13.2 ± 5.2s, P < 0.001). There were fewer patients in the RT group reporting injection pain than that in the propofol group (0/39 vs. 5/38, P = 0.025). Haemodynamic events and respiratory depression in the RT group were less frequent than those in the propofol group ((6/39 vs. 17/38, P = 0.005), (2/39 vs. 9/38, P = 0.026), respectively). The number of supplemental doses after successful induction in the RT group was greater than that in the propofol group (4/9/11/13/1/1 vs. 8/4/18/6/2/0 requiring 0, 1, 2, 3, 4 or 5 supplemental doses, P = 0.014). The characteristics of the patients enrolled, postoperative parameters of the patients, and patients' and physician's satisfaction of the procedure were comparable in the two groups.
CONCLUSIONS
Compared with propofol, RT can be safely and effectively used for gastrointestinal endoscopy sedation in elderly patients, and the incidence of sedation-related adverse reactions, especially haemodynamic events and respiratory depression, is lower. When RT is used, the number of supplemental doses after successful induction may increase slightly.
TRIAL REGISTRATION
Chictr.org.cn ChiCTR2000040498. Retrospectively registered (date of registration: December 1, 2020).
Topics: Aged; Benzodiazepines; Endoscopy, Gastrointestinal; Humans; Hypnotics and Sedatives; Pain; Propofol; Prospective Studies; Respiratory Insufficiency
PubMed: 35689208
DOI: 10.1186/s12871-022-01713-6 -
Journal of Clinical Anesthesia Jun 2023In many countries, the combination of propofol and opioid is used as the preferred sedative regime during ERCP. However, the most serious risks of propofol sedation are... (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVE
In many countries, the combination of propofol and opioid is used as the preferred sedative regime during ERCP. However, the most serious risks of propofol sedation are oxygen deficiency and hypotension. Compared to midazolam, remimazolam has a faster onset and offset of hypnotic effect, as well as cardiorespiratory stability, and to achieve widespread acceptance for procedural sedation, remimazolam must replace propofol which is the most commonly used for procedural sedation. The objective of this study was to compare the safety and efficacy profiles of the remimazolam and propofol when combined with alfentanil for sedation during ERCP procedures.
DESIGN
A randomized, controlled, single-center trial.
SETTING
The Endoscopic Centre of Tianjin Nankai Hospital, China.
PATIENTS
518 patients undergoing elective ERCP under deep sedation.
INTERVENTIONS
Patients scheduled for ERCP were randomly assigned to be sedated with either a combination of remimazolam-alfentanil or propofol-alfentanil.
MEASUREMENTS
The primary outcome was the prevalence of hypoxia, which was defined as SpO < 90% for >10 s. Other outcomes were the need for airway maneuver, procedure, and sedation-related outcomes and side effects (e.g., nausea, vomiting, and cardiovascular adverse events).
MAIN RESULTS
A total of 518 patients underwent randomization. Of these, 250 were assigned to the remimazolam group and 255 to the propofol group. During ERCP, 9.6% of patients in the remimazolam group showed hypoxia, while in the propofol group, 15.7% showed hypoxia (p = 0.04). The need for airway maneuvering due to hypoxia was significantly greater in the propofol group (p = 0.04). Furthermore, patients sedated with remimazolam had a lower percentage of hypotension than patients sedated with propofol (p < 0.001). Patients receiving remimazolam sedation expressed higher satisfaction scores and were recommended the same sedation for the next ERCP. The procedure time in the remimazolam group was much longer than in the propofol group due to the complexity of the patient's disease, which resulted in a longer sedation time.
CONCLUSION
During elective ERCP, patients administered with remimazolam showed fewer respiratory depression events under deep sedation with hemodynamic advantages over propofol when administered in combination with alfentanil.
Topics: Humans; Propofol; Alfentanil; Cholangiopancreatography, Endoscopic Retrograde; Hypnotics and Sedatives; Hypoxia; Hypotension; Conscious Sedation
PubMed: 36764022
DOI: 10.1016/j.jclinane.2023.111077