Comparison between remifentanil and other opioids in adult critically ill patients: A systematic review and meta-analysis.

BACKGROUND AND AIMS: To identify the efficacy and safety of remifentanil when compared with other opioids in adult critically ill patients. METHODS: We searched for studies in the Cochrane Library, MEDLINE, and EMBASE that had been published up to May 31st, 2019. Randomized clinical trials using remifentanil comparing with other opioids for analgesia were included. Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. Duration of mechanical ventilation was the primary outcome, and secondary outcomes included weaning time, intensive care unit (ICU), length of stay (LOS), hospital LOS, mortality, side effects, and costs. RESULTS: Fifteen studies with 1233 patients were included. Remifentanil was associated with a significant reduction in the duration of mechanical ventilation in the adult ICU patients when compared with other opioids (P = .01). Remifentanil also reduced the weaning time (P = .02) and the ICU LOS when compared with other opioids (P = .01). There was no difference in the hospital LOS (P = .15), side effects (P = .39), and mortality (P = .79) between remifentanil and other opioids, what's more, remifentanil increased the costs of anesthesia (P < .001) but did not increase cost of hospitalization (P = .30) when comparing with other opioids. CONCLUSIONS: Remifentanil reduced the duration of mechanical ventilation, weaning time, and ICU LOS when compared with other opioids in adult critically ill patients. Higher quality RCTs are necessary to prove our findings. PROSPERO REGISTRATION NUMBER: CRD42016041438.

Target-controlled-infusion models for remifentanil dosing consistent with approved recommendations.

BACKGROUND: Target-controlled infusion (TCI) systems use pharmacokinetic (PK) models to predict the drug infusion rates necessary to achieve a desired target plasma or effect-site concentration. As new PK models are developed and implemented in TCI systems, there can be uncertainty as to which target concentrations are appropriate. Existing dose recommendations can serve as a point of reference to identify target concentrations suitable for clinical applications. METHODS: Simulations of remifentanil TCI were performed using three PK models (Minto, Eleveld, and Kim). We sought to identify models and target concentrations for remifentanil administration in children, adult, older people, and severely obese individuals, consistent with the remifentanil product label. In a typical adult this is an induction dose of 0.5-1 µg kg-1 and starting maintenance infusion rate of 0.25 µg kg-1 min-1. RESULTS: For the Minto, Eleveld, and Kim remifentanil models, a plasma target concentration of ∼ 4 ng ml-1 achieves drug administration consistent with product label recommended initial doses for all groups with minor exceptions. With effect-site targeting in older individuals, a target concentration of ∼2 ng ml-1 is required for induction and ∼4 ng ml-1 for starting maintenance to achieve drug dosages close to product label recommendations. CONCLUSIONS: We identified remifentanil TCI target concentrations that resulted in drug administration similar to product label dosing recommendations. This approach did not necessarily identify target concentrations that achieve desired clinical effect, only those that are consistent with the product label recommended doses. We estimate that plasma target concentrations of 3.1-5.3 ng ml-1 are suitable for initial dosing.

Comparison of predicted and real propofol and remifentanil concentrations in plasma and brain tissue during target-controlled infusion: a prospective observational study.

Target-controlled infusion systems are increasingly used to administer intravenous anaesthetic drugs to achieve a user-specified plasma or effect-site target concentration. While several studies have investigated the ability of the underlying pharmacokinetic-dynamic models to predict plasma concentrations, there are no data on their performance in predicting drug concentrations in the human brain. We assessed the predictive performance of the Marsh propofol model and Minto remifentanil model for plasma and brain tissue concentrations. Plasma samples were obtained during neurosurgery from 38 patients, and brain tissue samples from nine patients. Propofol and remifentanil concentrations were measured using gas chromatography mass spectrometry and liquid chromatography tandem mass spectrometry. Data were analysed from the nine patients in whom both plasma and brain samples were simultaneously obtained. For the Minto model (five patients), the median performance error was 72% for plasma and -14% for brain tissue concentration predictions. The model tended to underestimate plasma remifentanil concentrations, and to overestimate brain tissue remifentanil concentrations. For the Marsh model (five patients), the median prediction errors for plasma and brain tissue concentrations were 12% and 81%, respectively. However, when the data from all blood propofol assays (36 patients) were analysed, the median prediction error was 11%, with overprediction in 15 (42%) patients and underprediction in 21 (58%). These findings confirm earlier reports demonstrating inaccuracy for commonly used pharmacokinetic-dynamic models for plasma concentrations and extend these findings to the prediction of effect-site concentrations.

The role of pharmacokinetics and pharmacodynamics in clinical anaesthesia practice.

PURPOSE OF REVIEW: Growing concerns about the environmental effects of volatile anaesthetics are likely to lead to increased use of intravenous anaesthetic drugs. Pharmacokinetic/pharmacodynamic (PKPD) models can increase the accuracy of intravenous drug titration, especially in populations that differ from the 'average.' However, with a growing number of PKPD models, and other technology available to date, it can be hard to see the wood for the trees. This review attempts to guide the reader through the PKPD jungle. RECENT FINDINGS: General purpose PKPD models for propofol and remifentanil designed to apply to a broader population, including children, the elderly and the obese, reduce the need for population-specific models. PKPD models for drugs such as dexmedetomidine and antimicrobial agents may be useful for procedural sedation or in the ICU. Technological advances such as Bayesian model adjustment based on point-of-care plasma concentration measurements, closed-loop drug delivery and artificial intelligence may improve the ease of use of the anaesthetic drugs and increase the accuracy of titration. SUMMARY: Newer and more complex modelling techniques and technological advancements can help to deliver anaesthetic drugs, sedatives and other drugs in a more stable and thereby safer way.

External Validation of a Pharmacokinetic Model of Propofol for Target-Controlled Infusion in Children under Two Years Old.

BACKGROUND: Previously, a linked pharmacokinetic-pharmacodynamic model (the Kim model) of propofol with concurrent infusion of remifentanil was developed for children aged 2-12 years. There are few options for pharmacokinetic-pharmacodynamic model of propofol for children under two years old. We performed an external validation of the Kim model for children under two years old to evaluate whether the model is applicable to this age group. METHODS: Twenty-four children were enrolled. After routine anesthetic induction, a continuous infusion of 2% propofol and remifentanil was commenced using the Kim model. The target effect-site concentration of propofol was set as 2, 3, 4, and 5 µg/mL, followed by arterial blood sampling after 10 min of each equilibrium. Population estimates of four parameters-pooled bias, inaccuracy, divergence, and wobble-were used to evaluate the performance of the Kim model. RESULTS: A total of 95 plasma concentrations were used for evaluation of the Kim model. The population estimate (95% confidence interval) of bias was -0.96% (-8.45%, 6.54%) and that of inaccuracy was 21.0% (15.0%-27.0%) for the plasma concentration of propofol. CONCLUSION: The pooled bias and inaccuracy of the pharmacokinetic predictions are clinically acceptable. Therefore, our external validation of the Kim model indicated that the model can be applicable to target-controlled infusion of propofol in children younger than 2 years, with the recommended use of actual bispectral index monitoring in clinical settings that remifentanil is present. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0001752.

Efficient Pharmacokinetic Modeling Workflow With the MonolixSuite: A Case Study of Remifentanil.

MonolixSuite is a software widely used for model-based drug development. It contains interconnected applications for data visualization, noncompartmental analysis, nonlinear mixed effect modeling, and clinical trial simulations. Its main assets are ease of use via an interactive graphical interface, computation speed, and efficient parameter estimation even for complex models. This tutorial presents a step-by-step pharmacokinetic (PK) modeling workflow using MonolixSuite, including how to visualize the data, set up a population PK model, estimate parameters, and diagnose and improve the model incrementally.

OPRM1 and COMT polymorphisms: implications on postoperative acute, chronic and experimental pain after cardiac surgery.

Aim: Investigate the potential role of OPRM1 (mu-opioid receptor) and COMT (catechol-O-methyltransferase enzyme) polymorphisms in postoperative acute, chronic and experimental thermal pain. Methods: A secondary analysis of 125 adult cardiac surgery patients that were randomized between fentanyl and remifentanil during surgery and genotyped. Results: Patients in the fentanyl group with the COMT high-pain sensitivity haplotype required less postoperative morphine compared with the average-pain sensitivity haplotype (19.4 [16.5; 23.0] vs 34.6 [26.2; 41.4]; p = 0.00768), but not to the low-pain sensitivity group (30.1 [19.1; 37.7]; p = 0.13). No association was found between COMT haplotype and other pain outcomes or OPRM1 polymorphisms and the different pain modalities. Conclusion:COMT haplotype appears to explain part of the variability in acute postoperative pain in adult cardiac surgery patients.

Pharmacodynamic modelling of the effect of remifentanil using the Pupillary Pain Index.

Using a targeted controlled infusion of remifentanil during total intravenous anesthesia, we investigated the effect-site concentrations of remifentanil that correlate with different values of the Pupillary Pain Index and which concentrations were necessary for achieving a Pupillary Pain Index ≤ 4 and its usefulness in titrating opioids. The Pupillary Pain Index was measured in 54 patients prior to surgery under different remifentanil effect-site concentrations and subsequently modeled. One hundred and twenty-eight measurements were taken at different remifentanil concentrations while titrating propofol for a similar depth of hypnosis using a BIS monitor. Our modeled Hill equation revealed a remifentanil of 2.96 ng/mL for a PPI of 4, and the probability model a Ce of 3.22 ng/mL for the probability of 50% of patients achieving a PPI score ≤ 4. For the probability of 80% of patients achieving a PPI score ≤ 4 the Ce of remifentanil was 4.39 ng/mL. We conclude that concentrations of remifentanil that have been shown to suppress movement in response to noxious stimulation correspond to a Pupillary Pain Index ≤ 4.

Non-traditional administration of remifentanil in an experimental setting.

Remifentanil is ultrashort-acting opioid with a unique pharmacokinetic profile. It is used exclusively intravenously. While considering its rapid onset of action and other pharmacokinetic properties, we decided to assess its effects following administration via non-traditional routes. Rabbits (n=10 per each group) were randomized into six groups: remifentanil 1 microg/kg and 3 microg/kg IM, 5.0 and 10.0 microg/kg conjunctivally, and 10 microg/kg and 25.0 microg/kg intranasally. Sedating effects were assessed via a loss of the righting reflex. Secondary, mean arterial blood pressure, arterial oxygen saturation of hemoglobin, and pulse rate was monitored in all rabbits. Non-traditional routes of administration were shown to provide a rapid onset of action as well as fast recovery. Importantly, the administration of remifentanil did not result in any deterioration of cardiovascular functions.

Enhanced recovery after surgery: Prediction for early extubation in video-assisted thoracic surgery using a response surface model in anesthesia.

BACKGROUND/PURPOSE: Enhanced recovery after surgery (ERAS) is a growing tendency in modern perioperative period management, but no protocol has been established for a strategy that optimally facilitates rapid recovery from anesthesia. We hypothesized that applying a total intravenous anesthesia (TIVA) method to the response surface model (RSM) would allow prediction of the emergence and endotracheal tube extubation in cases undergoing video-assisted thoracotomy surgery (VATS). METHODS: Thirty patients who were scheduled to undergo VATs under TIVA were enrolled. Pharmacokinetic profiles were calculated using a Tivatrainer. Emergence from anesthesia was observed and the exact time point of the regained response (RR) was recorded. The effect of concentration was analyzed and applied to a response surface model. RESULTS: The cumulative prediction curve of the RR was closer to the 50% probability as set by the OAA/S ≥ 4 than by the OAA/S ≥ 2 model. The median, averages, and standard deviations of the time differences were 14.5, 22.05 ± 19.23 min for the OAA/S ≥2 model and 10.4, 14.26 ± 10.40 min for the OAA/S ≥ 4 model. CONCLUSION: The OAA/S ≥ 4 model could identify the target concentration in propofol-remifentanil pairs that predicted the time of emergence from VATS in 10 min. Our results indicate that RSM can be used to derive an ERAS protocol for VATS under TIVA. Further studies should investigate application of RSM to predict ERAS for various types of procedures.

Acceptance of a propofol and remifentanil infusion dosing algorithm to optimize postoperative emergence and analgesia.

We implemented a pharmacokinetic/pharmacodynamic (PK/PD) based optimization algorithm recommending intraoperative Remifentanil and Propofol infusion rates to minimize time to emergence and maximize the duration of analgesia in a clinical setting. This feasibility study tested the clinical acceptance of the optimization algorithm's recommendations during scoliosis surgical repair for 14 patients. Anesthesiologist accepted 359/394 (91%) of the recommendations given on the basis of the optimization algorithm. While following the optimization's recommendations the anesthesiologist decreased Propofol infusions from an average of 164-135 mcg/kg/min [p = 0.002] and increased Remifentanil infusions from an average of 0.22-0.30 mcg/kg/min [p = 0.004]. The anesthesiologists appeared to accept and follow the recommendations from a PK/PD based optimization algorithm.

Optimizing intraoperative administration of propofol, remifentanil, and fentanyl through pharmacokinetic and pharmacodynamic simulations to increase the postoperative duration of analgesia.

Titrating an intraoperative anesthetic to achieve the postoperative goals of rapid emergence and prolonged analgesia can be difficult because of inter-patient variability and the need to provide intraoperative sedation and analgesia. Modeling pharmacokinetics and pharmacodynamics of anesthetic administrations estimates drug concentrations and predicted responses to stimuli during anesthesia. With utility of these PK/PD models we created an algorithm to optimize the intraoperative dosing regimen. We hypothesized the optimization algorithm would find a dosing regimen that would increase the postoperative duration of analgesia, not increase the time to emergence, and meet the intraoperative requirements of sedation and analgesia. To evaluate these hypotheses we performed a simulation study on previously collected anesthesia data. We developed an algorithm to recommend different intraoperative dosing regimens for improved post-operative results. To test the post-operative results of the algorithm we tested it on previously collected anesthesia data. An anesthetic dataset of 21 patients was obtained from a previous study from an anesthetic database at the University of Utah. Using the anesthetic records from these surgeries we modeled 21 patients using the same patient demographics and anesthetic requirements as the dataset. The anesthetic was simulated for each of the 21 patients with three different dosing regimens. The three dosing regimens are: from the anesthesiologist as recorded in the dataset (control group), from the algorithm in the clinical scenario one (test group), and from the algorithm in the clinical scenario two (test group). We created two clinical scenarios for the optimization algorithm to perform; one with normal general anesthesia constraints and goals, and a second condition where a delayed time to emergence is allowed to further maximize the duration of analgesia. The algorithm was evaluated by comparing the post-operative results of the control group to each of the test groups. Comparing results between the clinical scenario 1 dosing to the actual dosing showed a median increase in the duration of analgesia by 6 min and the time to emergence by 0.3 min. This was achieved by decreasing the intraoperative remifentanil infusion rate, increased the fentanyl dosing regimen, and not changing the propofol infusion rate. Comparing results between the clinical scenario 2 dosing to the actual dosing showed a median increase in the duration of analgesia by 26 min and emergence by 1.5 min. To dosing regimen from clinical scenario 2 greatly increased the fentanyl dosing regimen and greatly decreased the remifentanil infusion rate with no change to the propofol infusion rate. The results from this preliminary analysis of the optimization algorithm appear to imply that it can operate as intended. However a clinical study is warranted to determine to what extent the optimization algorithm determined optimal dosing regimens can maximize the postoperative duration of analgesia without delaying the time to emergence in a clinical setting.

Population Pharmacokinetic Modeling of Remifentanil in Infants with Unrepaired Tetralogy of Fallot.

BACKGROUND: Although there is literature suggesting that pathophysiologic changes in children with congenital heart disease alter the pharmacokinetics of anesthetics and may result in dosage adjustment, limited information exists regarding the pharmacokinetics of remifentanil in infants with unrepaired tetralogy of Fallot (TOF). The objectives of the current analysis were to characterize the population pharmacokinetics of remifentanil in infants, and to evaluate the effects of TOF on remifentanil's pharmacokinetics. METHODS: Twenty-seven infants (16 with TOF and 11 with normal cardiac anatomy; aged 114-360 days) scheduled to undergo elective surgery under general anesthesia were recruited in the study. All children received remifentanil 1 µg/kg/min intravenously for anesthesia induction and early maintenance [until ~ 20 min before cardiopulmonary bypass (CPB) for patients with TOF]. Serial arterial blood samples were drawn and analyzed. Population pharmacokinetics of remifentanil was characterized using NONMEM software. The estimates were standardized to a 70-kg adult using a per-kilogram model. RESULTS: A two-compartment disposition model adequately described the pharmacokinetics of remifentanil. Besides body weight, the introduction of any other covariates, including TOF status, did not improve the model significantly (P > 0.05). The population parameter estimates for systemic clearance (Cl1) and inter-compartment clearances (Cl2) were 6.03 × (WT/70 kg) and 1.23 × (WT/70 kg) L/min, respectively, and central volume of distribution (V1) and peripheral volumes of distribution (V2) were 19.6 × (WT/70 kg) and 21.7 × (WT/70 kg) L, respectively. CONCLUSIONS: Unrepaired TOF does not change the pharmacokinetics of remifentanil, suggesting a similar dosage for infants with TOF compared to normal cardiac anatomy infants. CLINICAL TRIAL REGISTRATION: The patient enrollment in this study started at 2012, so we do not have clinic trial number, but we still think this is a valuable research and hope it could be considered for publication.

Altered Pharmacokinetics in Prolonged Infusions of Sedatives and Analgesics Among Adult Critically Ill Patients: A Systematic Review.

PURPOSE: The pharmacokinetic (PK) parameters of many drugs are altered as a consequence of the pathophysiological changes associated with critical illness. The critically ill population presents challenges when titrating infusions of sedatives and analgesics to maintain optimal sedation and pain levels. This systematic review examined the PK data in critically ill adult patients with prolonged infusions (>24 hours) of commonly used sedatives and analgesics to highlight possible altered PK parameters compared with noncritically ill patients. METHODS: A literature search of PK studies was performed by using MEDLINE (1946-December 2017) and EMBASE (1910-December 2017); we identified further studies by citation tracking (Web of Science) and checked references of retrieved studies and review articles. All studies were included that were published in English, Chinese, or German; conducted in critically ill adult patients receiving lorazepam, midazolam, propofol, dexmedetomidine, sufentanil, alfentanil, remifentanil, morphine, or fentanyl infusion for ≥24 hours; and reported PK parameters. When appropriate, we conducted a meta-analysis on volume of distribution at steady state (Vdss) (liters), clearance (Cl) (liters per hour), and elimination t1/2 (hours) by using a DerSimonian-Laird random effects model to estimate the summary mean and 95% CIs. Results were compared with commonly reported PK ranges in 70-kg noncritically ill patients. FINDINGS: Thirty-three randomized controlled trials and prospective cohort studies were identified involving 1803 adult critically ill patients with 35 drug treatment arms: fifteen midazolam (n = 906) studies, three dexmedetomidine (n = 561), nine propofol (n = 165), four lorazepam (n = 86), one morphine (n = 20), two remifentanil (n = 55), and one sufentanil (n = 10). Each study showed large variations in Vdss, Cl, and elimination t1/2 within and between individual participants. High clinical and methodical heterogeneity between the dexmedetomidine studies prevented the direct comparison of PK parameters between critically ill and noncritically ill patients. Use of midazolam, propofol, and lorazepam in critically ill patients was associated with at least a 2- to 4-fold increase in Vdss compared with noncritically ill patients; Cl decreased ∼2-fold for midazolam and 10-fold for morphine. Critically ill patients receiving prolonged infusions of midazolam, propofol, remifentanil, and sufentanil had at least 2-fold longer elimination or terminal t1/2 than noncritically ill patients. IMPLICATIONS: These findings show a marked difference in many PK parameters from those reported for noncritically ill patients. Initiatives to improve the delivery of prolonged sedatives and analgesic infusions should be informed by PK parameters (Vdss, context-sensitive t1/2, and elimination t1/2) and data derived from critically ill patients.

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.

Population pharmacokinetics of remifentanil in critically ill patients receiving extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is associated with pharmacokinetic (PK) changes of drugs. It presents considerable challenges to providing optimal dosing regimens for patients receiving ECMO. We aimed to describe the population PK of remifentanil in critically ill adult patients receiving venoartrial extracorporeal membrane oxygenation (VA-ECMO) and to identify determinants associated with altered remifentanil concentrations. The population PK model of remifentanil was developed using nonlinear mixed effects modelling (NONMEM). Fifteen adult patients who received a continuous infusion of remifentanil during VA-ECMO participated in the study. The PK of remifentanil was best described by a one-compartment model with additive and proportional residual errors. Remifentanil concentrations were affected by sex and ECMO pump speed. The final PK model included the effect of sex and ECMO pump speed on clearance is developed as followed: clearance (L/h) = 366 × 0.502sex × (ECMO pump speed/2350)2.04 and volume (L) = 41. Remifentanil volume and clearance were increased in adult patients on VA-ECMO compared with previously reported patients not on ECMO. We suggest that clinicians should consider an increased remifentanil dosing to achieve the desired level of sedation and provide a dosing regimen according to sex and ECMO pump speed.