Ignacio Cortinez | Pontificia Universidad Catolica de Chile (original) (raw)
Papers by Ignacio Cortinez
European Journal of Anaesthesiology, 2006
Anaesthesia, 2017
It is commonly assumed that loss of responsiveness and recovery of responsiveness occur at simila... more It is commonly assumed that loss of responsiveness and recovery of responsiveness occur at similar concentrations of propofol. However, the 'conscious' and 'anaesthetised' conditions produced by general anaesthetics may behave as two bistable states. We hypothesised that loss of responsiveness and recovery of responsiveness occur at different propofol concentrations. Propofol was administered to 19 healthy volunteers by effect-site target-controlled infusion using increasing and decreasing stable concentration steps of 7 min. Propofol serum concentrations were measured from venous blood samples at the end of each 7-min step. A long step of 14 min was performed at loss of responsiveness. At this step, propofol concentrations were measured at 7 and 14 min. Propofol concentrations measured at loss of responsiveness and recovery of responsiveness were 2.6 (1.2-4.7) lg.ml À1 and 1.6 (0.6-3.3) lg.ml À1 , respectively (p < 0.001). Propofol plasma concentration and the corresponding bispectral index values measured at minute 7 and minute 14 of the long step performed at loss of responsiveness were 2.6 (1.2-4.7) vs. 2.6 (1.3-4.3) at recovery of responsiveness, (p = 0.96) and 61.2 (49.0-77.0) vs. 58.4 (45.0-74.0), (p = 0.058), respectively. Loss of responsiveness and recovery of responsiveness appear to occur at different propofol concentrations. However, it is possible that, if equilibration was not achieved between plasma and effect-sites at the end of each 7-min step, the higher concentrations found at loss of responsiveness compared with those observed during recovery of responsiveness could be explained by a possible bias in estimations of the effect-site concentrations of propofol by the Schnider model, rather than neural inertia.
F1000 - Post-publication peer review of the biomedical literature, 2015
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2012
Children
Acetaminophen is a commonly used perioperative analgesic drug in children. The use of a preoperat... more Acetaminophen is a commonly used perioperative analgesic drug in children. The use of a preoperative loading dose achieves a target concentration of 10 mg/L associated with a target analgesic effect that is 2.6 pain units (visual analogue scale 1–10). Postoperative maintenance dosing is used to keep this effect at a steady-state concentration. The loading dose in children is commonly prescribed per kilogram. That dose is consistent with the linear relationship between the volume of distribution and total body weight. Total body weight is made up of both fat and fat-free mass. The fat mass has little influence on the volume of distribution of acetaminophen but fat mass should be considered for maintenance dosing that is determined by clearance. The relationship between the pharmacokinetic parameter, clearance, and size is not linear. A number of size metrics (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale clearance and all cons...
Journal of Clinical Medicine
The intravenous induction or loading dose in children is commonly prescribed per kilogram. That d... more The intravenous induction or loading dose in children is commonly prescribed per kilogram. That dose recognizes the linear relationship between volume of distribution and total body weight. Total body weight comprises both fat and fat-free mass. Fat mass influences the volume of distribution and the use of total body weight fails to recognize the impact of fat mass on pharmacokinetics in children. Size metrics alternative to total body mass (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale pharmacokinetic parameters (clearance, volume of distribution) for size. Clearance is the key parameter used to calculate infusion rates or maintenance dosing at steady state. Dosing schedules recognize the curvilinear relationship, described using allometric theory, between clearance and size. Fat mass also has an indirect influence on clearance through both metabolic and renal function that is independent of its effects due to increased body...
Journal of Clinical Medicine
The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children t... more The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children through a better understanding of dose-concentration-response relationships, developmental pharmacokinetic changes, quantification of drug interactions and insights into how covariates (e.g., age, size, organ dysfunction, pharmacogenomics) impact drug prescription. Simulation using information from these models has enabled the prediction and learning of beneficial and adverse effects and decision-making around clinical scenarios. Covariate information, including the use of allometric size scaling, age and consideration of fat mass, has reduced population parameter variability. The target concentration approach has rationalised dose calculation. Paediatric pharmacokinetic-pharmacodynamic insights have led to better drug delivery systems for total intravenous anaesthesia and an expectation about drug offset when delivery is stopped. Understanding concentration-dependent adverse effects have...
Pediatric Anesthesia, 2021
Pharmacokinetic parameter estimates are used in mathematical equations (pharmacokinetic models) t... more Pharmacokinetic parameter estimates are used in mathematical equations (pharmacokinetic models) to describe concentration changes with time in a population and are specific to that population. Simulation using these models and their parameter estimates can enrich understanding of drug behavior and serve as a basis for study design. Pharmacokinetic concepts are presented pertaining to future designs of dexmedetomidine target‐controlled infusion pumps in children. This manuscript provides the pediatric anesthesiologist with an understanding of the nuances that should be considered when using target‐controlled infusion pumps; how the central volume may differ between populations, how clearance changes with age, and the impact of adverse effects on dose. In addition, the ideal loading dose and rate of delivery to achieve target concentration without adverse cardiovascular effects are reviewed, and finally, dose considerations for obese children, based on contact‐sensitive half‐time, are introduced. An understanding of context‐sensitive half‐time changes with age enables anesthetic practitioners to better estimate duration of effect after cessation of dexmedetomidine infusion. Use of these known pharmacokinetic parameters and covariate information for the pediatric patient could readily be incorporated into commercial target‐controlled infusion pumps to allow effective and safe open‐loop administration of dexmedetomidine in children.
Journal of Clinical Medicine, 2021
The parameters for a three-compartment model described by Morse and colleagues [...].
Pediatric Anesthesia, 2021
Pharmacokinetic simulation was used to characterize levobupivacaine disposition after regional an... more Pharmacokinetic simulation was used to characterize levobupivacaine disposition after regional anesthetic rescue for failed spinal anesthesia in neonates and infants.
Journal of the Endocrine Society, 2021
Purpose Latin American reports on pheochromocytomas and paragangliomas (PPGLs) are scarce. Recent... more 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)...
Journal of Clinical Medicine, 2020
A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postm... more A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1–152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universa...
Frontiers in Pharmacology, 2020
Dexmedetomidine (DEX) is a highly selective a2-adrenergic agonist with sedative and analgesic pro... more Dexmedetomidine (DEX) is a highly selective a2-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.
Pediatric Anesthesia, 2019
What is already known about this subject: Propofol infusion regimens for neonates and infants hav... more What is already known about this subject: Propofol infusion regimens for neonates and infants have been developed from clinical observations in children 0-3 years undergoing anesthesia. These regimens have not been reviewed using published neonatal and infant pharmacokinetic parameters. What this study adds: A pharmacokinetic parameter set using current propofol infusion regimens in neonates predicted propofol plasma concentrations 6-8 µg.mL-1 in the first 30 min that were not sustained during 100 min infusions. Re-evaluation of propofol plasma time-concentration profiles led to alternative dose regimens that achieve a target plasma concentration of 3 µg.mL-1. Neonates (38-44 weeks postmenstrual age) required a loading dose of 2 mg.kg-1 followed by an infusion rate of 9 mg.kg-1 .h-1 for the first 15 min, 7 mg.kg-1 .h-1 from 15 to 30 min, 6 mg.kg-1 .h-1 from 30 to 60 min, 5 mg.kg-1 .h-1 from 1 to 2 hours.
F1000 - Post-publication peer review of the biomedical literature, 2017
F1000 - Post-publication peer review of the biomedical literature, 2015
European Journal of Anaesthesiology, 2006
Anaesthesia, 2017
It is commonly assumed that loss of responsiveness and recovery of responsiveness occur at simila... more It is commonly assumed that loss of responsiveness and recovery of responsiveness occur at similar concentrations of propofol. However, the 'conscious' and 'anaesthetised' conditions produced by general anaesthetics may behave as two bistable states. We hypothesised that loss of responsiveness and recovery of responsiveness occur at different propofol concentrations. Propofol was administered to 19 healthy volunteers by effect-site target-controlled infusion using increasing and decreasing stable concentration steps of 7 min. Propofol serum concentrations were measured from venous blood samples at the end of each 7-min step. A long step of 14 min was performed at loss of responsiveness. At this step, propofol concentrations were measured at 7 and 14 min. Propofol concentrations measured at loss of responsiveness and recovery of responsiveness were 2.6 (1.2-4.7) lg.ml À1 and 1.6 (0.6-3.3) lg.ml À1 , respectively (p < 0.001). Propofol plasma concentration and the corresponding bispectral index values measured at minute 7 and minute 14 of the long step performed at loss of responsiveness were 2.6 (1.2-4.7) vs. 2.6 (1.3-4.3) at recovery of responsiveness, (p = 0.96) and 61.2 (49.0-77.0) vs. 58.4 (45.0-74.0), (p = 0.058), respectively. Loss of responsiveness and recovery of responsiveness appear to occur at different propofol concentrations. However, it is possible that, if equilibration was not achieved between plasma and effect-sites at the end of each 7-min step, the higher concentrations found at loss of responsiveness compared with those observed during recovery of responsiveness could be explained by a possible bias in estimations of the effect-site concentrations of propofol by the Schnider model, rather than neural inertia.
F1000 - Post-publication peer review of the biomedical literature, 2015
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2012
F1000 - Post-publication peer review of the biomedical literature, 2012
Children
Acetaminophen is a commonly used perioperative analgesic drug in children. The use of a preoperat... more Acetaminophen is a commonly used perioperative analgesic drug in children. The use of a preoperative loading dose achieves a target concentration of 10 mg/L associated with a target analgesic effect that is 2.6 pain units (visual analogue scale 1–10). Postoperative maintenance dosing is used to keep this effect at a steady-state concentration. The loading dose in children is commonly prescribed per kilogram. That dose is consistent with the linear relationship between the volume of distribution and total body weight. Total body weight is made up of both fat and fat-free mass. The fat mass has little influence on the volume of distribution of acetaminophen but fat mass should be considered for maintenance dosing that is determined by clearance. The relationship between the pharmacokinetic parameter, clearance, and size is not linear. A number of size metrics (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale clearance and all cons...
Journal of Clinical Medicine
The intravenous induction or loading dose in children is commonly prescribed per kilogram. That d... more The intravenous induction or loading dose in children is commonly prescribed per kilogram. That dose recognizes the linear relationship between volume of distribution and total body weight. Total body weight comprises both fat and fat-free mass. Fat mass influences the volume of distribution and the use of total body weight fails to recognize the impact of fat mass on pharmacokinetics in children. Size metrics alternative to total body mass (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale pharmacokinetic parameters (clearance, volume of distribution) for size. Clearance is the key parameter used to calculate infusion rates or maintenance dosing at steady state. Dosing schedules recognize the curvilinear relationship, described using allometric theory, between clearance and size. Fat mass also has an indirect influence on clearance through both metabolic and renal function that is independent of its effects due to increased body...
Journal of Clinical Medicine
The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children t... more The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children through a better understanding of dose-concentration-response relationships, developmental pharmacokinetic changes, quantification of drug interactions and insights into how covariates (e.g., age, size, organ dysfunction, pharmacogenomics) impact drug prescription. Simulation using information from these models has enabled the prediction and learning of beneficial and adverse effects and decision-making around clinical scenarios. Covariate information, including the use of allometric size scaling, age and consideration of fat mass, has reduced population parameter variability. The target concentration approach has rationalised dose calculation. Paediatric pharmacokinetic-pharmacodynamic insights have led to better drug delivery systems for total intravenous anaesthesia and an expectation about drug offset when delivery is stopped. Understanding concentration-dependent adverse effects have...
Pediatric Anesthesia, 2021
Pharmacokinetic parameter estimates are used in mathematical equations (pharmacokinetic models) t... more Pharmacokinetic parameter estimates are used in mathematical equations (pharmacokinetic models) to describe concentration changes with time in a population and are specific to that population. Simulation using these models and their parameter estimates can enrich understanding of drug behavior and serve as a basis for study design. Pharmacokinetic concepts are presented pertaining to future designs of dexmedetomidine target‐controlled infusion pumps in children. This manuscript provides the pediatric anesthesiologist with an understanding of the nuances that should be considered when using target‐controlled infusion pumps; how the central volume may differ between populations, how clearance changes with age, and the impact of adverse effects on dose. In addition, the ideal loading dose and rate of delivery to achieve target concentration without adverse cardiovascular effects are reviewed, and finally, dose considerations for obese children, based on contact‐sensitive half‐time, are introduced. An understanding of context‐sensitive half‐time changes with age enables anesthetic practitioners to better estimate duration of effect after cessation of dexmedetomidine infusion. Use of these known pharmacokinetic parameters and covariate information for the pediatric patient could readily be incorporated into commercial target‐controlled infusion pumps to allow effective and safe open‐loop administration of dexmedetomidine in children.
Journal of Clinical Medicine, 2021
The parameters for a three-compartment model described by Morse and colleagues [...].
Pediatric Anesthesia, 2021
Pharmacokinetic simulation was used to characterize levobupivacaine disposition after regional an... more Pharmacokinetic simulation was used to characterize levobupivacaine disposition after regional anesthetic rescue for failed spinal anesthesia in neonates and infants.
Journal of the Endocrine Society, 2021
Purpose Latin American reports on pheochromocytomas and paragangliomas (PPGLs) are scarce. Recent... more 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)...
Journal of Clinical Medicine, 2020
A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postm... more A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1–152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universa...
Frontiers in Pharmacology, 2020
Dexmedetomidine (DEX) is a highly selective a2-adrenergic agonist with sedative and analgesic pro... more Dexmedetomidine (DEX) is a highly selective a2-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.
Pediatric Anesthesia, 2019
What is already known about this subject: Propofol infusion regimens for neonates and infants hav... more What is already known about this subject: Propofol infusion regimens for neonates and infants have been developed from clinical observations in children 0-3 years undergoing anesthesia. These regimens have not been reviewed using published neonatal and infant pharmacokinetic parameters. What this study adds: A pharmacokinetic parameter set using current propofol infusion regimens in neonates predicted propofol plasma concentrations 6-8 µg.mL-1 in the first 30 min that were not sustained during 100 min infusions. Re-evaluation of propofol plasma time-concentration profiles led to alternative dose regimens that achieve a target plasma concentration of 3 µg.mL-1. Neonates (38-44 weeks postmenstrual age) required a loading dose of 2 mg.kg-1 followed by an infusion rate of 9 mg.kg-1 .h-1 for the first 15 min, 7 mg.kg-1 .h-1 from 15 to 30 min, 6 mg.kg-1 .h-1 from 30 to 60 min, 5 mg.kg-1 .h-1 from 1 to 2 hours.
F1000 - Post-publication peer review of the biomedical literature, 2017
F1000 - Post-publication peer review of the biomedical literature, 2015