Electroencephalographic Indices for Clinical Endpoints during Propofol Anesthesia in Infants: An Early-phase Propofol Biomarker-finding Study.

BACKGROUND: Unlike expired sevoflurane concentration, propofol lacks a biomarker for its brain effect site concentration, leading to dosing imprecision particularly in infants. Electroencephalography monitoring can serve as a biomarker for propofol effect site concentration, yet proprietary electroencephalography indices are not validated in infants. The authors evaluated spectral edge frequency (SEF95) as a propofol anesthesia biomarker in infants. It was hypothesized that the SEF95 targets will vary for different clinical stimuli and an inverse relationship existed between SEF95 and propofol plasma concentration. METHODS: This prospective study enrolled infants (3 to 12 months) to determine the SEF95 ranges for three clinical endpoints of anesthesia (consciousness-pacifier placement, pain-electrical nerve stimulation, and intubation-laryngoscopy) and correlation between SEF95 and propofol plasma concentration at steady state. Dixon's up-down method was used to determine target SEF95 for each clinical endpoint. Centered isotonic regression determined the dose-response function of SEF95 where 50% and 90% of infants (ED50 and ED90) did not respond to the clinical endpoint. Linear mixed-effect model determined the association of propofol plasma concentration and SEF95. RESULTS: Of 49 enrolled infants, 44 evaluable (90%) showed distinct SEF95 for endpoints: pacifier (ED50, 21.4 Hz; ED90, 19.3 Hz), electrical stimulation (ED50, 12.6 Hz; ED90, 10.4 Hz), and laryngoscopy (ED50, 8.5 Hz; ED90, 5.2 Hz). From propofol 0.5 to 6 µg/ml, a 1-Hz SEF95 increase was linearly correlated to a 0.24 (95% CI, 0.19 to 0.29; P < 0.001) µg/ml decrease in plasma propofol concentration (marginal R2 = 0.55). CONCLUSIONS: SEF95 can be a biomarker for propofol anesthesia depth in infants, potentially improving dosing accuracy and utilization of propofol anesthesia in this population.

Pharmacokinetics of propofol in severely obese surgical patients.

BACKGROUND: Existing PK models of propofol include sparse data from very obese patients. The aim of this study was to develop a PK model based on standardised surgical conditions and spanning from normal-weight up to, and including, a high number of very obese patients. METHODS: Adult patients scheduled for laparoscopic cholecystectomy or bariatric surgery were studied. Anaesthesia was induced with propofol 2 mg/kg adjusted body weight over 2 min followed by 6 mg/kg/h adjusted body weight over 30 min. For the remainder of the operation anaesthesia was maintained with sevoflurane. Remifentanil was dosed according to clinical need. Eight arterial samples were drawn in a randomised block sampling regimen over a span of 24 h. Time-concentration data were analysed by population PK modelling using non-linear mixed-effects modelling. RESULTS: Four hundred and seventy four serum propofol concentrations were collected from 69 patients aged 19-60 years with a BMI 21.6-67.3 kg/m2. Twenty one patients had a BMI above 50 kg/m2. A 3-compartment PK model was produced wherein three different body weight descriptors and sex were included as covariates in the final model. Total body weight was found to be a covariate for clearance and Q3; lean body weight for V1, V2 and Q2; predicted normal weight for V3 and sex for V1. The fixed allometric exponent of 0.75 applied to all clearance parameters improved the performance of the model. Accuracy and precision were 1.4% and 21.7% respectively in post-hoc performance evaluation. CONCLUSION: We have developed a new PK model of propofol that is suitable for all adult weight classes. Specifically, it is based on data from an unprecedented number of individuals with very high BMI.

Altitude effect on Propofol Pharmacokinetics in Rats.

BACKGROUND: Propofol is an intravenous agent for clinical anesthesia. As the influence of the hypobaric-hypoxic environment (Qinghai-Tibetan region, altitude: 2800-4300 m, PaO2: 15.1-12.4 kPa) on the metabolism of Propofol is complex, the research results on the metabolic characteristics of Propofol in high-altitude areas remain unclear. This study aimed to investigate the pharmacokinetic characteristics of Propofol in a high-altitude hypoxic environment using animal experiments. METHODS: Rats were randomly divided into three groups: high-altitude, medium-altitude, and plain groups. The time of disappearance and recovery of the rat righting reflex was recorded as the time of anesthesia induction and awakening, respectively. The plasma concentration of Propofol was determined by gas chromatography-mass spectrometry. A pharmacokinetic analysis software was used to analyze the blood-drug concentrations and obtain the pharmacokinetic parameters. RESULTS: We observed that when Propofol anesthetizes rats, the anesthesia induction time was shortened, and the recovery time was prolonged with increased altitude. Compared with the plain group, the clearance of Propofol decreased, whereas the half-life, area under the concentration-time curve, peak plasma concentration, and average residence time extension increased. CONCLUSION: The pharmacokinetic characteristics of Propofol are significantly altered in high-altitude hypoxic environments.

Remotely controlled drug release in deep brain regions of non-human primates.

Many areas of science and medicine would benefit from selective release of drugs in specific regions. Nanoparticle drug carriers activated by focused ultrasound-remotely applied, depth-penetrating energy-may provide such selective interventions. Here, we developed stable, ultrasound-responsive nanoparticles that can be used to release drugs effectively and safely in non-human primates. The nanoparticles were used to release propofol in deep brain visual regions. The release reversibly modulated the subjects' visual choice behavior and was specific to the targeted region and to the released drug. Gadolinium-enhanced MR imaging suggested an intact blood-brain barrier. Blood draws showed normal clinical chemistry and hematology. In summary, this study provides a safe and effective approach to release drugs on demand in selected deep brain regions at levels sufficient to modulate behavior.

Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations.

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Application of a pharmacokinetics-pharmacodynamics approach to the free propofol plasma levels during coronary artery bypass grafting surgery with hypothermic cardiopulmonary bypass

OBJECTIVES: The objective of this study was to apply a pharmacokinetics-pharmacodynamics approach to investigate the free propofol plasma levels in patients undergoing coronary artery bypass grafting under hypothermic conditions compared with the off-pump procedure. METHODS: Nineteen patients scheduled for on-pump coronary artery bypass grafting under hypothermic conditions (n=10) or the equivalent off-pump surgery (n=9) were anesthetized with sufentanil and propofol target-controlled infusion (2 μg/mL) during surgery. The propofol concentration was then reduced to 1 μg/mL, and a pharmacokinetics-pharmacodynamics analysis using the maximum-effect-sigmoid model obtained by plotting the bispectral index values against the free propofol plasma levels was performed. RESULTS: Significant increases (two- to five-fold) in the free propofol plasma levels were observed in the patients subjected to coronary artery bypass grafting under hypothermic conditions. The pharmacokinetics of propofol varied according to the free drug levels in the hypothermic on-pump group versus the off-pump group. After hypothermic coronary artery bypass was initiated, the distribution volume increased, and the distribution half-life was prolonged. Propofol target-controlled infusion was discontinued when orotracheal extubation was indicated, and the time to patient extubation was significantly higher in the hypothermic on-pump group than in the off-pump group (459 versus 273 min, p=0.0048). CONCLUSIONS: The orotracheal intubation time was significantly longer in the hypothermic on-pump group than in the off-pump group. Additionally, residual hypnosis was identified through the pharmacokinetics-pharmacodynamics approach based on decreases in drug plasma protein binding in the hypothermic on-pump group, which could explain the increased hypnosis observed with this drug in this group of patients.

Sedation in colonoscopy by using three different propofol infusion methods and analysis of plasma concentration levels: a prospective comparative study / Sedação em colonoscopia: utilização do propofol em estudo comparativo entre três diferentes modos de administração

ABSTRACT Background: The propofolemia becomes directly linked to the clinical effects of this anesthetic and is the focus for studies comparing propofol clinical use, in different administration methods routinely used in endoscopy units where sedation is widely administered to patients. Aim: To evaluate the effects of three different regimens of intravenous propofol infusion in colonoscopies. Methods: A total of 50 patients that underwent colonoscopies were consecutively assigned to three groups: 1) intermittent bolus infusion; 2) continuous manually controlled infusion; 3) continuous automatic infusion. Patients were monitored with Bispectral IndexTM (BIS) and propofol serum levels were collected at three different timepoints. The development of an original dilution of propofol and an inventive capnography catheter were necessary. Results: Regarding clinical outcomes, statistical differences in agitation (higher in group 1, p=0.001) and initial blood pressure (p=0.008) were found. As for propofol serum levels, findings were similar in consumption per minute (p=0.748) and over time (p=0.830). In terms of cost analysis, group 1 cost was R$7.00 (approximately US$2,25); group2, R$17.50 (approximately US$5,64); and group 3, R$112.70 (approximately US$36,35, p<0.001). Capnography was able to predict 100% of the oxygen saturation drop (below 90%). Conclusion: The use of propofol bolus administration for colonoscopies, through continuous manually controlled infusion or automatic infusion are similar regarding propofolemia and the clinical outcomes evaluated. The use of an innovative capnography catheter is liable and low-cost solution for the early detection of airway obstruction.

RESUMO Racional: A propofolemia está diretamente relacionada com os efeitos clínicos desse anestésico e é foco de diversos estudos comparando os usos clínicos do propofol e os diferentes métodos de administração, como realizado amplamente nos centros de endoscopia. Objetivo: Avaliar os efeitos de três diferentes regimes de infusão de propofol intravenoso em colonoscopias. Métodos: Ao todo 50 pacientes que foram submetidos à colonoscopia foram consecutivamente divididos em três grupos: 1) infusão em bolus intermitente; 2) perfusão contínua controlada manualmente; 3) infusão automática contínua. Os pacientes foram monitorados com Bispectral IndexTM (BIS) e os níveis séricos de propofol foram coletados em três momentos diferentes. Foi necessário a preparação de uma diluição específica de propofol e o desenvolvimento de um cateter de capnografia original manufaturado para a realização do estudo. Resultados: Em relação aos desfechos clínicos, houve diferença estatística na agitação (maior no grupo 1, p=0,001) e pressão arterial inicial (p=0,008). Com relação aos níveis séricos de propofol, os resultados foram semelhantes no consumo por minuto (p=0,748) e ao longo do tempo (p=0,830). Em termos de análise de custo, no grupo 1 o custo foi de R$ 7,00 (aproximadamente US$ 2,25); grupo 2, R$ 17,50 (aproximadamente US$ 5,64); e grupo 3, R$ 112,70 (cerca de US$ 36,35, p<0,001). A capnografia foi capaz de diagnosticar 100% das dessaturações de oxigênio (abaixo de 90%). Conclusão: O uso de propofol em bolus para colonoscopias, por meio de infusão contínua controlada manualmente ou infusão automática são semelhantes quanto à propofolemia e os resultados clínicos avaliados. Além disso, o uso de um cateter de capnografia inovador é solução de baixo custo para a detecção precoce da obstrução da via aérea.

Sedação em colonoscopia: utilização do propofol em estudo comparativo entre três diferentes modos de administração / Sedation in colonoscopy: use of propofol in a comparative study of three different administration methods

O uso do propofol em sedação para colonoscopia e outros procedimentos endoscópicos é cada vez mais frequente, devido ao seu rápido início de efeito e curto período de recuperação, com poucos efeitos residuais, o que o torna um anestésico ideal para o uso em condutas médicas realizadas em regime ambulatorial. Seu perfil farmacológico o posiciona como um anestésico adequado a métodos de administração endovenosa contínuos ou titulados, possibilitando maior controle na sua concentração plasmática. Devido à sua alta lipossolubilidade, o propofol difunde-se rapidamente ao sistema nervoso e outros tecidos aonde exercerá seu efeito clínico, intimamente ligado à propofolemia, com diminuição da atividade do sistema nervoso central, que determinará tanto a sedação nos seus diversos níveis, quanto os indesejados efeitos depressores do sistema cardiovascular e respiratório, podendo levar a uma diminuição importante do débito cardíaco e pressão arterial e também a uma depressão central do sistema regulatório da respiração, que pode gerar apneia ou hipoventilação significativas. O presente estudo teve como objetivo avaliar clinicamente, e com dosagem sérica, o propofol em três esquemas diferentes de infusão endovenosa. Foram avaliados aleatoriamente 50 pacientes submetidos à colonoscopia nos Serviços de Endoscopia do Hospital Ana Costa (Santos - SP) e no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (São Paulo-SP). Os pacientes foram divididos em três grupos, conforme o esquema de sedação que foi utilizado. O Grupo 1 recebeu fentanil no início, uma dose inicial de propofol de um miligrama por quilo em um minuto na indução, posteriormente recebeu propofol em infusão intermitente de doses fracionadas de 30 mg (bolus) conforme necessidade clínica durante o exame. O Grupo 2 recebeu fentanil no início, uma dose inicial de propofol de 1 mg/kg em um minuto na indução, após essa, recebeu propofol contínuo em uma solução diluída a 0,2% em solução...

The use of propofol sedation for colonoscopies and other endoscopic procedures is increasing due to the rapid onset of effect and short recovery time with few residual effects, which makes it an ideal anesthetic for usingin outpatient medical procedures. Its pharmacological profile places it as a suitable anesthetic to continuous or titred intravenous administration, providing increased control in its plasma levels. Due to its high liposolubility, propofol diffuses rapidly to the central nervous system and other tissues where it shall perform its clinical effects, closely related to plasma concentration, and providing sedation at different levels, as much as the unwanted depressant effects of the cardiovascular and respiratory system, it may lead to a significant reduction in cardiac output and blood pressure and also a central regulatory breathing system depression, that can result in significant apnea or hypoventilation. This study aimed to evaluate clinically and serum, propofol in three different regimens of intravenous infusion. 50 patients submitted to colonoscopy in the endoscopy centers at Hospital Ana Costa (Santos - SP), and Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (São Paulo-SP), have been randomly assessed. Such patients were divided into three groups, according to the sedation scheme that was used for them. Group 1 received fentanyl at first, then a one milligram per kilogram propofol dose, at induction, in a minute, later they received intermittent infusion of propofol in fractionated doses of 30 mg (Bolus) according to clinical needs during the test. Group 2 received fentanyl in the beginning, a starting dose of propofol 1 mg/kg at induction in one minute, after that received propofol in a 0.2% solution diluted in 5% glucose solution at an initial 1 drop/kg of patient weight dose, equivalent to about one 100 u100/min, manually controlled and changed according to clinical need of the...

Effects of cardiopulmonary bypass on propofol pharmacokinetics and bispectral index during coronary surgery

PURPOSE: Cardiopulmonary bypass is known to alter propofol pharmacokinetics in patients undergoing cardiac surgery. However, few studies have evaluated the impact of these alterations on postoperative pharmacodynamics. This study was designed to test the hypothesis that changes in propofol pharmacokinetics increase hypnotic effects after cardiopulmonary bypass. METHODS: Twenty patients scheduled for on-pump coronary artery bypass graft (group, n=10) or off-pump coronary artery bypass graft (group, n=10) coronary artery bypass grafts were anesthetized with sufentanil and a propofol target controlled infusion (2.0 µg/mL). Depth of hypnosis was monitored using the bispectral index. Blood samples were collected from the induction of anesthesia up to 12 hours after the end of propofol infusion, at predetermined intervals. Plasma propofol concentrations were measured using high-performance liquid chromatography, followed by a non-compartmental propofol pharmacokinetic analysis. Data were analyzed using ANOVA, considering p<0.05 as significant. RESULTS: After cardiopulmonary bypass, despite similar plasma propofol concentrations in both groups, bispectral index values were lower in the on-pump coronary artery bypass graft group. Time to extubation after the end of propofol infusion was greater in the on-pump coronary artery bypass graft group (334 ± 117 vs. 216 ± 85 min, p = 0.04). Patients undergoing cardiopulmonary bypass had shorter biological (1.82 ± 0.5 vs. 3.67 ± 1.15h, p < 0.01) and terminal elimination (6.27 ± 1.29 vs. 10.5h ± 2.18, p < 0.01) half-life values, as well as higher total plasma clearance (28.36 ± 11.40 vs.18.29 ± 7.67 mL/kg/min, p = 0.03), compared to patients in the off-pump coronary artery bypass graft group. CONCLUSION: Aside from the increased sensitivity of the brain to anesthetics after cardiopulmonary bypass, changes in propofol pharmacokinetics may contribute to its central nervous system effects.

Propofol: nuevas formulaciones / Propofol: new formulations

Desde el punto de vista farmacológico en los últimosaños no han aparecido nuevos fármacos anestésicos,pero si se han producido grandes avances en la farmacologíade alguno de ellos, es el caso del propofol. Estosavances se han producido en aras de minimizar o evitarlos efectos adversos colaterales que van asociados a laadministración de la formulación original de propofol(comercializada por Astra-Zéneca). Los efectos no deseadosque se han intentado solventar son: el dolor a lainyección intravenosa del fármaco, la elevación de laconcentración sérica de triglicéridos y el riesgo de contaminaciónbacteriana. Para ello han aparecido formulacionesque contienen excipientes con acción bactericidacomo es el propofol con EDTA o con metabisulfito, formulacionesque sustituyen el intralipid por lipuro, o formulacionesmás avanzadas como es el propofol en ciclodextrinao que utilizan tecnología de nanopartículascomo el IDD-propofol. Para llegar a comprender lasdiferencias farmacológicas de las distintas formulacioneses preciso conocer las características farmacocinéticas yfarmacodinámicas de la fórmula original, que es la basede estudio del resto de ellas

Few pharmacologically new anesthetics have appearedin recent years, but great progress has been madetoward improving some existing ones. Such is the casewith propofol. New formulations have been developed toreduce or avoid adverse side effects associated with theoriginal drug produced by Astra-Zeneca. The unwantedeffects for which solutions have been sought are painupon intravenous injection of the drug, elevated serumconcentrations of triglycerides, and the risk of bacterialcontamination. Some new formulations contain excipientswith bactericidal action, such as propofol withethylenediaminetetraacetic acid or metabisulfite, andothers use lipuro rather than intralipid. Other moreadvanced products are propofol in cyclodextrin or IDDDpropofol, which makes use of nanoparticle technology.A grasp of the pharmacokinetics and pharmacodynamicsof the original formulation must be the basisfor understanding the differences between these newproducts