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.

Development of a gas chromatography-mass spectrometry method for the quantification of propofol in blood / 法医学杂志

OBJECTIVE@#A rapid and selective method has been developed for the determination of propofol in blood by gas chromatography-mass spectrometry (GC-MS).@*METHODS@#The blood was extrasted with the solution of internal standard, the extracted residue was analyzed by gas chromatography-mass spectrometry using selected-ion monitoring mode.@*RESULTS@#The linear range was 0.1-10 microg/mL. The coefficient(R2) was 0.993 1. The detection limit was 0.05 microg/mL.@*CONCLUSION@#The method is simple and rapid, offering superior sensitivity and selectivity for propofol. The method can be used successfully during clinical and forensic toxicology.

Effect of ketamine and propofol on blood coagulation in dogs [a comparative study]

This study was carried out on 20 dogs of mixed breed and of both sexes weighting 12 - 16 kg. The animals were divided into 2 groups with 10 dogs in each group. Group I received 5.5 mg/kg ketamine. Supplementary doses of 3 mg/kg were given IV at intervals of 30 minutes. Group II received propofol in a dose of 2.5 mg/kg during induction followed by 0.3 mg/kg/min. infusion. Both groups were premedicated by atropine sulfate and diazepam. Heart rate, respiratory rate and temperature were measured before anesthesia and at 15-minute intervals for one hour then 30-minute intervals for another hour following induction of anesthesia. Blood samples for coagulation profile [PT, APTT, fibrinogen concentration and platelet count] were extracted before anesthesia and at the same timing of vital signs recording following induction of anesthesia. It was concluded that propofol and ketamine do not alter blood coagulation