Browsing by Author "Contreras, Victor"

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    Assessment of the antinociceptive effect of a single fentanyl bolus dose in children: A pharmacokinetic and pharmacodynamic analysis based on the nociception level index during sevoflurane general anesthesia
    (WILEY, 2024) Cruzat, Francisco; Ibacache, Mauricio; González, Alejandro; Pedemonte, Juan Cristobal; Contreras, Victor; Giordano, Ady; Cortínez, Ignacio
    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.AimsTo 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.MethodsNineteen 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 mu g/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 (R).ResultsAfter 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.ConclusionThe 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.
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    Characterization of the temporal profile of the antinociceptive effects of an intravenous bolus of ketamine using the analgesia nociception index in no-anesthetized adult patients
    (2024) Navarrete, Victor; Ibacache, Mauricio; Contreras, Victor; Cortinez, Ignacio
    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 mgkg- 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 (R) 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% 0.20-0.28) min-1 to the described PK parameters set. 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.
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    Intraoperative electroencephalographic marker of preoperative frailty: a prospective cohort study
    (2023) Boncompte, Gonzalo; Sun, Haoqi; Elgueta Le-Beuffe, María Francisca; Benavides, Javiera; Carrasco, Marcela; Morales, María I.; Calderón, Natalia; Contreras, Victor; Westover, M. Brandon; Cortínez, Luis I.; Akeju, Oluwaseun; Pedemonte Trewhela, Juan Cristóbal
    Frailty was common in elderly patients undergoing non cardiac surgery. Electroencephalogram alpha-band power does not predict preoperative frailty above patients' age. Frailty predictions by machine learning algorithms, were not improved by the addition of electroencephalogram features. Frailty might be different to the concept of brain vulnerability, accounting for a possible brain-body dissociation.
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    Oral infectivity through carnivorism in murine model of Trypanosoma cruzi infection
    (2024) Torres, Victor; Contreras, Victor; Gutierrez, Bessy; San Francisco, Juan; Catalan, Alejandro; Vega, Jose Luis; Moon, Kyung-Mee; Foster, Leonard J.; de Almeida, Rafael F.; Kalergis, Alexis M.; Gonzalez, Jorge
    Introduction Oral transmission of T. cruzi is probably the most frequent transmission mechanism in wild animals. This observation led to the hypothesis that consuming raw or undercooked meat from animals infected with T. cruzi may be responsible for transmitting the infection. Therefore, the general objective of this study was to investigate host-pathogen interactions between the parasite and gastric mucosa and the role of meat consumption from infected animals in the oral transmission of T. cruzi. Methods Cell infectivity assays were performed on AGS cells in the presence or absence of mucin, and the roles of pepsin and acidic pH were determined. Moreover, groups of five female Balb/c mice were fed with muscle tissue obtained from mice in the acute phase of infection by the clone H510 C8C3 hvir of T. cruzi, and the infection of the fed mice was monitored by a parasitemia curve. Similarly, we assessed the infective capacity of T. cruzi trypomastigotes and amastigotes by infecting groups of five mice Balb/c females, which were infected orally using a nasogastric probe, and the infection was monitored by a parasitemia curve. Finally, different trypomastigote and amastigote inoculums were used to determine their infective capacities. Adhesion assays of T. cruzi proteins to AGS stomach cells were performed, and the adhered proteins were detected by western blotting using monoclonal or polyclonal antibodies and by LC-MS/MS and bioinformatics analysis. Results Trypomastigote migration in the presence of mucin was reduced by approximately 30%, whereas in the presence of mucin and pepsin at pH 3.5, only a small proportion of parasites were able to migrate (similar to 6%). Similarly, the ability of TCTs to infect AGS cells in the presence of mucin is reduced by approximately 20%. In all cases, 60-100% of the animals were fed meat from mice infected in the acute phase or infected with trypomastigotes or amastigotes developed high parasitemia, and 80% died around day 40 post-infection. The adhesion assay showed that cruzipain is a molecule of trypomastigotes and amastigotes that binds to AGS cells. LC-MS/MS and bioinformatics analysis, also confirmed that transialidase, cysteine proteinases, and gp63 may be involved in TCTs attachment or invasion of human stomach cells because they can potentially interact with different proteins in the human stomach mucosa. In addition, several human gastric mucins have cysteine protease cleavage sites. Discussion Then, under our experimental conditions, consuming meat from infected animals in the acute phase allows the T. cruzi infection. Similarly, trypomastigotes and amastigotes could infect mice when administered orally, whereas cysteinyl proteinases and trans-sialidase appear to be relevant molecules in this infective process.