BACKGROUND:Interfacial blocks often require large volumes of local anaesthetic, raising concerns about systemic absorption and potential toxicity. This study examined the pharmacokinetics of levobupivacaine with and without epinephrine during thoracic erector spinae plane (ESP) or transversus abdominis plane (TAP) blocks, simulating reported 48-h dosing regimens to evaluate safety. METHODS:Data from three studies were analysed. Study 1 included 38 patients receiving an ESP block before video-assisted thoracoscopy, whereas Study 2 analysed published data on TAP blocks. Both studies used 20 ml of levobupivacaine 0.25% with or without epinephrine (5 μg ml-1), measuring arterial concentrations over 90 min. Study 3 involved intravenous bupivacaine administration in 10 healthy volunteers. Pharmacokinetic analysis used NONMEM software, with significance set at P<0.05. RESULTS:We analysed 258 ESP samples, 150 TAP samples, and 190 bupivacaine i.v. SAMPLES:A one-compartment model described the data, with a mean distribution volume of 41.9 L (coefficient of variation, 47%) and clearance rate of 0.288 L min-1 (coefficient of variation, 38%). Epinephrine reduced bioavailability (54.3% vs 32.8%) and prolonged absorption half-life (0.84 min vs 1.55 min; P<0.05). Simulated doses of 50 mg plus 300 mg per 24 h over 48 h remained below toxic thresholds. CONCLUSIONS:Similar dosing regimens for ESP and TAP blocks are supported by this pharmacokinetic analysis, with epinephrine effectively reducing systemic drug concentrations by prolonging absorption half-life and lowering bioavailability. The findings suggest that extended 300 mg per 24 h dosing for 48 h is likely to be safe. Further studies in broader patient populations are warranted to evaluate safety. CLINICAL TRIAL REGISTRATION:NCT04799184.

An effect-site target-controlled infusion (TCI) would allow a more precise titration of intravenous analgesics effect. The analgesia nociception index (ANI) continuously monitors the analgesia/nociception balance during general anesthesia. This study aims to derive a PKPD model of ketamine antinociceptive effect using the Domino PK parameter set and the ANI response data in awake patients without other drugs affecting the ANI response. Twenty awake adult patients were prospectively studied before general anesthesia. Patients received a single intravenous bolus of ketamine 0.1 mg·kg− 1, and the subsequent ANI values were recorded. An effect compartment model incorporating the Domino PK parameter set was used to characterize the time lag between ketamine plasma concentrations and the ANI response. The model was parameterized with a single parameter Ke0. An Emax pharmacodynamic model was used to fit the ANI response data. Model parameters were estimated with NONMEM® 7.5. The minimum objective function value guided the model construction. After the ketamine administration, basal ANI values increased from 38.5 ± 4.95 to a maximum of 53.5 ± 4.95 with an observed time-to-peak effect of 1.83 ± 0.74 min. Modeling analysis revealed hysteresis between predicted plasma concentrations from the Domino model and observed ANI data. Hysteresis was characterized, incorporating an estimated Keo of 0.238 (CI95

Purpose An effect-site target-controlled infusion (TCI) would allow a more precise titration of intravenous analgesics effect. The analgesia nociception index (ANI) continuously monitors the analgesia/nociception balance during general anesthesia. This study aims to derive a PKPD model of ketamine to allow an effect-site TCI administration using the ANI information and previously described pharmacokinetic parameters. Methods Twenty adult patients under general anesthesia were prospectively studied. Patients received a single intravenous bolus of ketamine 0.1 mg·kg-1, and the subsequent ANI values were recorded. An effect compartment model incorporating the Domino PK parameter set was used to characterize the time lag between ketamine plasma concentrations and the ANI response. The model was parameterized with a single parameter Ke0. An Emax pharmacodynamic model was used to fit the ANI response data. Model parameters were estimated with NONMEM® 7.5. The minimum objective function value guided the model construction. Results After the ketamine administration, basal ANI values increased from 38.5 ± 4.95 to a maximum of 53.5 ± 4.95 with an observed time-to-peak effect of 1.83 ± 0.74 min. Modeling analysis revealed hysteresis between predicted plasma concentrations from the Domino model and observed ANI data. Hysteresis was characterized, incorporating an estimated Keo of 0.238 (CI95% 0.20–0.28) min-1 to the described PK parameters set. Conclusions The developed PKPD model, using Domino’s PK parameters and the ANI response data, adequately characterized the temporal profile of ketamine's antinociceptive effect. The current estimated model parameters can be used to perform an effect-site TCI of ketamine for analgesic purposes.

BACKGROUND:The Nociception Level Index has shown benefits in estimating the nociception/antinociception balance in adults, but there is limited evidence in the pediatric population. Evaluating the index performance in children might provide valuable insights to guide opioid administration. AIMS:To evaluate the Nociception Level Index ability to identify a standardized nociceptive stimulus and the analgesic effect of a fentanyl bolus. Additionally, to characterize the pharmacokinetic/pharmacodynamic relationship of fentanyl with the Nociception Level Index response during sevoflurane anesthesia. METHODS:Nineteen children, 5.3 (4.1-6.7) years, scheduled for lower abdominal or urological surgery, were studied. After sevoflurane anesthesia and caudal block, a tetanic stimulus (50 Hz, 60 mA, 5 s) was performed in the forearm. Following the administration of fentanyl 2 μg/kg intravenous bolus, three similar consecutive tetanic stimuli were performed at 5-, 15-, and 30-min post-fentanyl administration. Changes in the Nociception Level Index, heart rate, mean arterial pressure, and bispectral index were compared in response to the tetanic stimuli. Fentanyl plasma concentrations and the Nociception Level Index data were used to elaborate a pharmacokinetic/pharmacodynamic model using a sequential modeling approach in NONMEM®. RESULTS:After the first tetanic stimulus, both the Nociception Level Index and the heart rate increased compared to baseline (8 ± 7 vs. 19 ± 10; mean difference (CI95) -12(-18--6) and 100 ± 10 vs. 102 ± 10; -2(-4--0.1)) and decrease following fentanyl administration (19 ± 10 vs. 8 ± 8; 12 (5-18) and 102 ± 10 vs. 91 ± 11; 11 (7-16)). In subsequent tetanic stimuli, heart rate remained unchanged, while the Nociception Level Index progressively increased within 15 min to values similar to those before fentanyl. An allometric weight-scaled, 3-compartment model best characterized the pharmacokinetic profile of fentanyl. The pharmacokinetic/pharmacodynamic modeling analysis revealed hysteresis between fentanyl plasma concentrations and the Nociception Level Index response, characterized by plasma effect-site equilibration half-time of 1.69 (0.4-2.9) min. The estimated fentanyl C50 was 1.93 (0.73-4.2) ng/mL. CONCLUSION:The Nociception Level Index showed superior capability compared to traditional hemodynamic variables in discriminating different nociception-antinociception levels during varying fentanyl concentrations in children under sevoflurane anesthesia.

Cognitive decline is common among older individuals, and although the underlying brain mechanisms are not entirely understood, researchers have suggested using EEG frontal alpha activity during general anaesthesia as a potential biomarker for cognitive decline. This is because frontal alpha activity associated with GABAergic general anaesthetics has been linked to cognitive function. However, oscillatory-specific alpha power has also been linked with chronological age. We hypothesize that cognitive function mediates the association between chronological age and (oscillatory-specific) alpha power. We analysed data from 380 participants (aged over 60) with baseline screening assessments and intraoperative EEG. We utilized the telephonic Montreal Cognitive Assessment to assess cognitive function. We computed total band power, oscillatory-specific alpha power, and aperiodics to measure anaesthesia-induced alpha activity. To test our mediation hypotheses, we employed structural equation modelling. Pairwise correlations between age, cognitive function and alpha activity were significant. Cognitive function mediated the association between age and classical alpha power [age -> cognitive function -> classical alpha; beta = -0.0168 (95% confidence interval: -0.0313 to -0.00521); P = 0.0016] as well as the association between age and oscillatory-specific alpha power [age -> cognitive function -> oscillatory-specific alpha power; beta = -0.00711 (95% confidence interval: -0.0154 to -0.000842); P = 0.028]. However, cognitive function did not mediate the association between age and aperiodic activity (1/f slope, P = 0.43; offset, P = 0.0996). This study is expected to provide valuable insights for anaesthesiologists, enabling them to make informed inferences about a patient's age and cognitive function from an analysis of anaesthetic-induced EEG signals in the operating room. To ensure generalizability, further studies across different populations are needed. Interpreting low intraoperative EEG alpha activity can be challenging due to its associations with both age and cognitive function. However, Boncompte et al. have skilfully addressed this issue by showing that cognitive function plays a significant role in mediating the relationship between age and the oscillatory component of alpha activity. Graphical Abstract

Background Improving anesthesia administration for elderly population is of particular importance because they undergo considerably more surgical procedures and are at the most risk of suffering from anesthesia-related complications. Intraoperative brain monitors electroencephalogram (EEG) have proved useful in the general population, however, in elderly subjects this is contentious. Probably because these monitors do not account for the natural differences in EEG signals between young and older patients. In this study we attempted to systematically characterize the age-dependence of different EEG measures of anesthesia hypnosis. Methods We recorded EEG from 30 patients with a wide age range (19–99 years old) and analyzed four different proposed indexes of depth of hypnosis before, during and after loss of behavioral response due to slow propofol infusion during anesthetic induction. We analyzed Bispectral Index (BIS), Alpha Power and two entropy-related EEG measures, Lempel-Ziv complexity (LZc), and permutation entropy (PE) using mixed-effect analysis of variances (ANOVAs). We evaluated their possible age biases and their trajectories during propofol induction. Results All measures were dependent on anesthesia stages. BIS, LZc, and PE presented lower values at increasing anesthetic dosage. Inversely, Alpha Power increased with increasing propofol at low doses, however this relation was reversed at greater effect-site propofol concentrations. Significant group differences between elderly patients (>65 years) and young patients were observed for BIS, Alpha Power, and LZc, but not for PE. Conclusion BIS, Alpha Power, and LZc show important age-related biases during slow propofol induction. These should be considered when interpreting and designing EEG monitors for clinical settings. Interestingly, PE did not present significant age differences, which makes it a promising candidate as an age-independent measure of hypnotic depth to be used in future monitor development.

en fentanilo, administrado de forma estándar o guiada por NoL, en pacientes sometidos a cirugía electiva con anestesia general

PURPOSE:Latin American reports on pheochromocytomas and paragangliomas (PPGLs) are scarce. Recent studies demonstrate changes in clinical presentation and management of these patients. Herein, we assessed the main characteristics of PPGL patients in our academic center over the past 4 decades.METHODS:Demographic, clinical, biochemical, and perioperative data from 105 PPGL patients were retrospectively and prospectively collected over the 1980-2019 period. Data were organized into 4 periods by decade.RESULTS:Age at diagnosis, gender, tumor size and percentage of bilaterality, percentage of paragangliomas, and metastases remained stable across the 4 decades. The proportion of genetic testing and incidentalomas increased in recent decades (all P < 0.001). Therefore, we compared PPGLs diagnosed as incidentalomas (36%) with those clinically suspected (64%). Incidentalomas had fewer adrenergic symptoms (38 vs. 62%; P < 0.001) and lower rates of hypertension (64% vs. 80%; P = 0.01) and hypertensive crisis (28% vs. 44%; P = 0.02); also, they had lower functionality (79% vs. 100%; P = 0.01) and lower catecholamines levels (8.4-fold vs. 12.5-fold above upper cutoffs; P = 0.04). Regarding management of all PPGLs over the decades, we observed significant increases in both perioperative doxazosin dose (P = 0.003) and laparoscopic approach rates (P < 0.001), along with a decrease in the length of hospital stays (P = 0.007).CONCLUSIONS:We observed a change in the clinical presentation of PPGL in recent decades, with a marked increase in incidental cases and milder symptoms. The implementation of a multidisciplinary program for adrenal disorders in our institution has translated into more timely diagnoses, more genetic testing, and improvements in perioperative management.

Dexmedetomidine (DEX) is a highly selective alpha 2-adrenergic agonist with sedative and analgesic properties, with minimal respiratory effects. It is used as a sedative in the intensive care unit and the operating room. The opioid-sparing effect and the absence of respiratory effects make dexmedetomidine an attractive adjuvant drug for anesthesia in obese patients who are at an increased risk for postoperative respiratory complications. The pharmacodynamic effects on the cardiovascular system are known; however the mechanisms that induce cardioprotection are still under study. Regarding the pharmacokinetics properties, this drug is extensively metabolized in the liver by the uridine diphosphate glucuronosyltransferases. It has a relatively high hepatic extraction ratio, and therefore, its metabolism is dependent on liver blood flow. This review shows, from a basic clinical approach, the evidence supporting the use of dexmedetomidine in different settings, from its use in animal models of ischemia-reperfusion, and cardioprotective signaling pathways. In addition, pharmacokinetics and pharmacodynamics studies in obese subjects and the management of patients subjected to mechanical ventilation are described. Moreover, the clinical efficacy of delirium incidence in patients with indication of non-invasive ventilation is shown. Finally, the available evidence from DEX is described by a group of Chilean pharmacologists and clinicians who have worked for more than 10 years on DEX.

Dexmedetomidine (DEX) is a highly selective α2-adrenergic agonist with sedative and analgesic properties, with minimal respiratory effects. It is used as a sedative in the intensive care unit and the operating room. The opioid-sparing effect and the absence of respiratory effects make dexmedetomidine an attractive adjuvant drug for anesthesia in obese patients who are at an increased risk for postoperative respiratory complications. The pharmacodynamic effects on the cardiovascular system are known; however the mechanisms that induce cardioprotection are still under study. Regarding the pharmacokinetics properties, this drug is extensively metabolized in the liver by the uridine diphosphate glucuronosyltransferases. It has a relatively high hepatic extraction ratio, and therefore, its metabolism is dependent on liver blood flow. This review shows, from a basic clinical approach, the evidence supporting the use of dexmedetomidine in different settings, from its use in animal models of ischemia-reperfusion, and cardioprotective signaling pathways. In addition, pharmacokinetics and pharmacodynamics studies in obese subjects and the management of patients subjected to mechanical ventilation are described. Moreover, the clinical efficacy of delirium incidence in patients with indication of non-invasive ventilation is shown. Finally, the available evidence from DEX is described by a group of Chilean pharmacologists and clinicians who have worked for more than 10 years on DEX.

This report provides a brief description of the 2018 Red Iberoamericana de Farmacometria (RedIF) Congress that took place in Guadalajara (Mexico) on November 7-9, 2018. The meeting aimed to foster modeling and simulation (M&S) approaches for drug development, regulatory sciences, and clinical application in Latin America. The organizations that cosponsored the meeting were the following: University of Guadalajara, International Society of Pharmacometrics (ISoP), International Pharmaceutical Federation (FIP), Clinic of Chronic Diseases and Special Procedures (CECyPE), Zurich Pharma, Pharmet (Pharmometrica), Lixoft, and ICON.