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Development and validation of brain target controlled infusion of propofol in mice.

ABSTRACT: Mechanisms through which anesthetics disrupt neuronal activity are incompletely understood. In order to study anesthetic mechanisms in the intact brain, tight control over anesthetic pharmacology in a genetically and neurophysiologically accessible animal model is essential. Here, we developed a pharmacokinetic model that quantitatively describes propofol distribution into and elimination out of the brain. To develop the model, we used jugular venous catheters to infuse propofol in mice and measured propofol concentration in serial timed brain and blood samples using high performance liquid chromatography (HPLC). We then used adaptive fitting procedures to find parameters of a three compartment pharmacokinetic model such that all measurements collected in the blood and in the brain across different infusion schemes are fit by a single model. The purpose of the model was to develop target controlled infusion (TCI) capable of maintaining constant brain propofol concentration at the desired level. We validated the model for two different targeted concentrations in independent cohorts of experiments not used for model fitting. The predictions made by the model were unbiased, and the measured brain concentration was indistinguishable from the targeted concentration. We also verified that at the targeted concentration, state of anesthesia evidenced by slowing of the electroencephalogram and behavioral unresponsiveness was attained. Thus, we developed a useful tool for performing experiments necessitating use of anesthetics and for the investigation of mechanisms of action of propofol in mice.

SUBMITTER: Shortal BP

PROVIDER: S-EPMC5912730 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Development and validation of brain target controlled infusion of propofol in mice.

Shortal Brenna P BP Reitz Sarah L SL Aggarwal Adeeti A Meng Qing C QC McKinstry-Wu Andrew R AR Kelz Max B MB Proekt Alex A

PloS one 20180423 4

Mechanisms through which anesthetics disrupt neuronal activity are incompletely understood. In order to study anesthetic mechanisms in the intact brain, tight control over anesthetic pharmacology in a genetically and neurophysiologically accessible animal model is essential. Here, we developed a pharmacokinetic model that quantitatively describes propofol distribution into and elimination out of the brain. To develop the model, we used jugular venous catheters to infuse propofol in mice and meas ...[more]

PMID: 29684039

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Project description:Target-controlled infusion (TCI) provides precise pharmacokinetic control of propofol concentration in the effect-site (Ce), eg. brain. This pilot study aims to evaluate the feasibility and optimal TCI regimen for flexible bronchoscopy (FB) sedation.After alfentanil bolus, initial induction Ce of propofol was targeted at 2 ?g/ml. Patients were randomized into three titration groups (i.e., by 0.5, 0.2 and 0.1 ?g/ml, respectively) to maintain stable sedation levels and vital signs. Adverse events, frequency of adjustments, drug doses, and induction and recovery times were recorded.The study was closed early due to significantly severe hypoxemia events (oxyhemoglobin saturation <70%) in the group titrated at 0.5 ?g/ml. Forty-nine, 49 and 46 patients were enrolled into the 3 respective groups before study closure. The proportion of patients with hypoxemia events differed significantly between groups (67.3 vs. 46.9 vs. 41.3%, p?=?0.027). Hypotension events, induction and recovery time and propofol doses were not different. The Ce of induction differed significantly between groups (2.4±0.5 vs. 2.1±0.4 vs. 2.1±0.3 ?g/ml, p?=?0.005) and the Ce of procedures was higher at 0.5 ?g/ml titration (2.4±0.5 vs. 2.1±0.4 vs. 2.2±0.3 ?g/ml, p?=?0.006). The adjustment frequency tended to be higher for titration at 0.1 ?g/ml but was not statistically significant (2 (0?6) vs. 3 (0?6) vs. 3 (0?11)). Subgroup analysis revealed 14% of all patients required no further adjustment during the whole sedation. Comparing patients requiring at least one adjustment with those who did not, they were observed to have a shorter induction time (87.6±34.9 vs. 226.9±147.9 sec, p<0.001), a smaller induction dose and Ce (32.5±4.1 vs. 56.8±22.7 mg, p<0.001; 1.76±0.17 vs. 2.28 ±0.41, p<0.001, respectively), and less hypoxemia and hypotension (15.8 vs.56.9%, p?=?0.001; 0 vs. 24.1%, p?=?0.008, respectively).Titration at 0.5 ?g/ml is risky for FB sedation. A subgroup of patients required no more TCI adjustment with fewer complications. Further studies are warranted to determine the optimal regimen of TCI for FB sedation.ClinicalTrials.gov NCT01101477.

Project description:BACKGROUND:Propofol sedation is effective for gastrointestinal endoscopic procedures, but its narrow therapeutic window highlights the importance of identifying an optimal administration technique regarding effectiveness and safety. This study aimed to determine the incidence of significant adverse events in adult patients scheduled for gastrointestinal endoscopy under anaesthetist-performed sedation using propofol target-controlled infusion and determine the existence of associations between these events and potentially related variables. METHODS:This single-centre, retrospective cohort study took place in a tertiary referral university hospital. Medical records of 823 patients (age?>?18?years, American Society of Anesthesiologists physical status classification scores I-III) who had undergone elective gastrointestinal endoscopy under propofol target-controlled infusion sedation during September 2018 were reviewed. Outcomes included hypoxia, hypotension, and bradycardia events, requirement of vasoactive drugs, unplanned tracheal intubation or supraglottic device insertion, and need for advanced cardiac life support. RESULTS:The most frequently encountered adverse event was oxygen desaturation <?95% with an incidence of 22.35%. Vasoactive drug administration, hypotension, and oxygen desaturation <?90% followed, with incidences of 19.2, 12.64, and 9.92%, respectively. Only 0.5% of patients required advanced airway management. Multivariate analysis revealed an association between hypotension events, colonoscopic procedures, and propofol doses (odds ratio: 3.08, 95% confidence interval: 1.43 to 6.61; P?=?0.004 and odds ratio: 1.14, 95% confidence interval: 1.00 to 1.29; P?=?0.046). A strong dose-effect relationship was found between hypoxia and obesity; patients with body mass index ?40 were nine times (odds ratio: 10.22, 95% confidence interval: 2.83 to 36.99) more likely to experience oxygen desaturation <?90% events. CONCLUSIONS:Propofol sedation using target-controlled infusion appears to be a safe and effective anaesthetic technique for gastrointestinal endoscopic procedures with acceptable rates of adverse events and could be more widely adopted in clinical practice.

Project description:BackgroundThe effects of circadian rhythms on drug metabolism and efficacy are being increasingly recognized. However, the extent to which they affect general anesthesia remains unclear. This study aims to investigate the effects of circadian rhythms on anesthetic depth and the concentrations of propofol target-controlled infusion (TCI).MethodsSixty patients undergoing laparoscopic surgeries were sequentially assigned to four groups. Group ND (n = 15): Propofol TCI with Narcotrend monitor during the day (8:00-18:00), Group NN (n = 15): Propofol TCI with Narcotrend monitor during the night (22:00-5:00), Group CLTD (n = 15): Propofol closed-loop TCI guided by bispectral index (BIS) during the day (8:00-18:00), Group CLTN (n = 15): Propofol closed-loop TCI guided by BIS during the night (22:00-5:00). The Narcotrend index, mean arterial pressure (MAP) and heart rate (HR) were compared between group ND and NN at 7 time points, from 5 min before induction to the end of operation. The propofol TCI concentrations, MAP and HR were compared between group CLTD and CLTN at 7 time points, from 5 min after induction to the end of operation.ResultsThe Narcotrend index, MAP, and HR in group NN were lower than those in group ND from the beginning of mechanical ventilation to the end of operation (p < 0.05). The propofol TCI concentrations in group CLTN were lower than those in group CLTD from the beginning of operation to the end of operation (p < 0.05).ConclusionCircadian rhythms have a significant effect on the depth of anesthesia and drug infusion concentrations during propofol TCI. When using general anesthesia during night surgery, the propofol infusion concentration should be appropriately reduced compared to surgery during the day.Trial registrationThe present study was registered on the ClinicalTrials.gov website ( NCT02440269 ) and approved by the Medical Ethics Committee of Southwest Hospital of Third Military Medical University (ethics lot number: 2016 Research No. 93). All patients provided informed written consent to participate in the study.

Dataset Information

Development and validation of brain target controlled infusion of propofol in mice.

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Development and validation of brain target controlled infusion of propofol in mice.

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