Blood Propofol Research Articles

An Antibiofouling Electrochemical Sensor Consisting of Amphiphilic Copolymer on CNT-COOH Electrodes for Point-of-Care Monitoring of Propofol Blood Concentration in Surgical Patients

The monitoring of propofol (PPF) blood concentration is vital for the safety of intravenous anesthesia. Electrochemical sensors represent a powerful tool for the detection of PPF. Our previous research has demonstrated that CNT-COOH electrodes exhibit advantages in resisting electrochemical fouling from PPF oxidation products. Nevertheless, biofouling remains a critical challenge hindering the clinical transformation of PPF electrochemical sensors. To address this issue, we employed in-situ electrodeposition to deposit zwitterionic sulfobetaine methacrylate (SBMA) and overoxidation polydopamine (OPDA) onto CNT-COOH screen-printed electrodes (SPEs) and proposed an innovative CNT-COOH/OPDA-SBMA (CNT-COOH/OPS) amphiphilic antifouling biosensor. This amphiphilic electrode, featuring both hydrophilic and hydrophobic properties, demonstrated excellent antifouling performance through electrochemical characterization in ex-vivo blood assays, coupled with commendable sensitivity, stability, and selectivity. CNT-COOH/OPS SPEs were also applied in point-of-care monitoring of the PPF blood concentrations in animals and clinical surgical patients and exhibited good accuracy and linearity (Ipa=0.0084c+0.4458, R2=0.995) with a limit of detection of 2.948μM. Further, the electrodes demonstrated a high recovery and the blood concentrations determined by electrochemical detection had robust negative correlation with the depth of anesthesia. Therefore, CNT-COOH/OPS SPEs hold promise as a significant tool in point-of-care monitoring of PPF, offering patients safer and more personalized medical care.

Molecular displacement approach for the electrochemical detection of protein-bound propofol

Propofol is one of the principal drugs used for the sedation of patients undergoing mechanical ventilation in intensive care units. The correct dosage of such sedative drugs is highly important, but current methods of determining infusion rates are limited and there is a lack of suitable methods for directly determining patient blood propofol concentrations. A significant challenge for the development of propofol sensors is that propofol demonstrates very high protein binding, leading to a low free fraction in blood. Here we present a method for improving the efficacy of an electrochemical propofol sensor by increasing the free fraction via a molecular displacement approach. When used in conjunction with a carbon nanotube/graphene oxide/iron oxide nanoparticle functionalised screen-printed electrode, it was found that this approach dramatically improved the sensor's sensitivity towards propofol. Ibuprofen was found to be the most effective displacement agent, with an optimal concentration of 30 mM. The resultant sensitivity was 2.82 nA/μg/ml/mm2 with a coefficient of variation of 0.07, and the limit of detection was 0.2 μg/ml. This approach demonstrates high specificity towards drugs commonly administered to intensive care patients.

Simple quantification of propofol and its metabolites in blood and urine using gas chromatography–tandem mass spectrometry (GC–MS/MS)

An analytical method which was used for the simultaneous detection and quantification of propofol and its metabolites in human blood and urine by gas chromatography-tandem mass spectrometry (GC–MS/MS) was newly established and applied to authentic human samples obtained from the deceased. The QuEChERS method was employed, and then analyzed by GC–MS/MS. We separately used sulfatase and β-glucuronidase to hydrolyze the urine sample and calculated the increase of propofol and 4-hydroxypropofol before and after the hydrolysis. The results of urinary concentrations in urine from the subject were: 4.88 μg/mL for propofol, 0.53 μg/mL for 4-hydroxypropofol, 3.35 μg/mL for propofol-glucuronide, 0.31 μg/mL for the total concentration of 1-(2,6-diisopropyl-1,4-quinol)-glucuronide plus 4-(2,6-diisopropyl-1,4-quinol)-glucuronide, and 0.39 μg/mL for 4-(2,6- diisopropyl-1,4-quinol)-sulfate. The lower limit of quantification was 10 ng/mL for all determined compounds; the extraction recoveries were not less than 57.2 %. Intraday and interday precisions and accuracies were all less than 10 %. The calibration curves for propofol and 4-hydroxypropofol in human urine showed the correlation values of not less than 0.999; propofol and 4-hydroxypropofol in blood also presented good linearities in the concentration ranges of 0.1–10 μg/mL. The two compounds had good stability within 7 days at 25, 4, and −20 ℃. To our knowledge, this is the first trial to establish a simple and reliable method to simultaneously detect and quantify of propofol and its phase I and II metabolites in human blood and urine samples by GC–MS/MS.

Recovery of driving skills after endoscopy under propofol sedation: a prospective pilot study to assess the driving skills after endoscopic sedation using driving simulation

BackgroundPatients are recommended not to drive for at least the first 24 h after endoscopy with propofol sedation. However, the evidence underlying these recommendations is scarce. We hypothesized that after endoscopic procedures performed under propofol sedation, the subject’s driving ability was restored in less than 24 h.MethodsWe prospectively enrolled thirty patients between 20 and 70 years possessing a legitimate driver’s license scheduled for endoscopy at our hospital. The sample chosen was a convenience sample. Gastroscopy or colonoscopy was performed with propofol sedation. Before and after endoscopy, the investigator drove the subjects to the laboratory to assess their driving skills using a driving simulation system, which employs 3 driving scenarios designed by professional transportation researchers. The blood propofol concentration was estimated before endoscopy, and 2 and 4 h after endoscopy. The primary outcome was the time required for subjects to recover their driving ability after propofol sedation. The secondary outcome was the blood propofol concentration before and after endoscopic procedures under propofol anesthesia.ResultsThirty volunteers participated in the study and 18 of them completed all the interventions. In the low-risk S-curve scene, the mean acceleration, lane deviation, and number of deviations from the path at baseline (0.016 cm/s2, 42.50 cm, and 0.83, respectively) were significantly less than that at post-2 h (0.029 cm/s2, P = 0.001; 53.80 cm, P = 0.014; 2.06, P = 0.022). In the moderate-(overtaking) and high-risk (emergency collision avoidance) scenes, the tested parameters at baseline and post-2 h were statistically comparable. In the low-, moderate-, and high-risk scenes the tested parameters at baseline and post-4 h were statistically comparable. The total range of propofol was 120-280 mg.The mean blood concentration of propofol at post-2 h was 0.81 ± 0.40 µg/mL, and at post-4 h was below the limit of detection.ConclusionAfter endoscopy performed under propofol sedation, subjects’ driving abilities were completely restored at 4 h when tested on a simulator.

Selective Reagent Ion-Time-of-Flight-Mass Spectrometric Investigations of the Intravenous Anaesthetic Propofol and Its Major Metabolite 2,6-Diisopropyl-1,4-benzoquinone

The first detailed selected reagent ion-time-of-flight-mass spectrometric fundamental investigations of 2,6-diisopropylphenol, more commonly known as propofol (C12H18O), and its metabolite 2,6-diisopropyl-1,4-benzoquinone (C12H16O2) using the reagent ions H3O+, H3O+.H2O, O2+• and NO+ are reported. Protonated propofol is the dominant product ion resulting from the reaction of H3O+ with propofol up to a reduced electric field strength (E/N) of about 170 Td. After 170 Td, collision-induced dissociation leads to protonated 2-(1-methylethyl)-phenol (C9H13O+), resulting from the elimination of C3H6 from protonated propofol. A sequential loss of C3H6 from C9H13O+ also through collision-induced processes leads to protonated phenol (C6H7O+), which becomes the dominant ionic species at E/N values exceeding 170 Td. H3O+.H2O does not react with propofol via a proton transfer process. This is in agreement with our calculated proton affinity of propofol being 770 kJ mol−1. Both O2+• and NO+ react with propofol via a charge transfer process leading to two product ions, C12H18O+ (resulting from non-dissociative charge transfer) and C11H15O+ that results from the elimination of one of the methyl groups from C12H18O+. This dissociative pathway is more pronounced for O2+• than for NO+ throughout the E/N range investigated (approximately 60–210 Td), which reflects the higher recombination energy of O2+• (12.07 eV) compared to that of NO+ (9.3 eV), and hence the higher internal energy deposited into the singly charged propofol. Of the four reagent ions investigated, only H3O+ and H3O+.H2O react with 2,6-diisopropyl-1,4-benzoquinone, resulting in only the protonated parent at all E/N values investigated. The fundamental ion-molecule studies reported here provide underpinning information that is of use for the development of soft chemical ionisation mass spectrometric analytical techniques to monitor propofol and its major metabolite in the breath. The detection of propofol in breath has potential applications for determining propofol blood concentrations during surgery and for elucidating metabolic processes in real time.

Cytochrome P450 2B6 Amperometric Biosensor for Continuous Monitoring of Propofol

Despite the growing evidence of improved patient outcomes and of a substantially reduced environmental impact of propofol-based total intravenous anesthesia when compared to volatile-based techniques, the vast majority of general anesthetics still use volatile agents for the maintenance phase. A significant reason for this is the lack of suitable point-of-care, real-time blood propofol measurement techniques. Here we present an enzyme-based electrochemical biosensor for the detection of propofol. Deactivated yeast cells expressing the enzyme cytochrome P450 2B6 are immobilized, alongside gold nanoparticles, within a chitosan film upon the surface of a screen printed electrode. In the presence of the cofactor NADPH, the enzyme converts propofol to a quinone/quinol redox pair that can be detected using simple electrochemistry. This approach avoids the issue of electrode fouling that commonly renders electrochemical propofol sensors impractical. The sensor has a limit of detection of 67 ± 7 ng/ml and a sensitivity of 4.2 ± 0.2 nA/ <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mu \text{g}$ </tex-math></inline-formula> /ml/mm <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$^{\mathbf {2}}$ </tex-math></inline-formula> . It has been successfully demonstrated in a serum-like solution and has shown a linear response across the therapeutic range of propofol (1 – <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$10~\mu \text{g}$ </tex-math></inline-formula> /ml). Additionally, the sensor has shown good specificity with regards to potential interfering compounds.

Propofol Autocoinduction and Midazolam Co-induction for Propofol Induction

Intoduction: The problem with induction during anaesthesia is decrease in blood pressure, apnea which could be detrimental to patient. Co-induction and autocoinduction are one of the modalities that are developed to overcome hypotension during induction. The study was carried out to observe heart rate, blood pressure response and propofol consumption following midazolam as co-induction or propofol autocoiniduction for propofol induction. Methods: This study was a conducted in 52 patients of ASA I and ASA II undergoing elective surgical procedures with general anesthesia. Patients were randomly allocated and group P received 0.5 mg/ kg of propofol and group M received 0.04 mg/ kg of midazolam intravenously as autocoindution and coinduction respectively. Results: The two groups were identical regarding age, weight, ASA status and base line vitals. This study showed that there was significant difference between 2 groups in terms of blood pressure. Decrease in blood pressure from baseline is more in Midazolam group compared to propofol. In terms of Heart Rate there was no statistically significant between two groups at any time of observation. Decrease in HR from baseline was almost similar in both groups. Consumption of Propofol was not statistically significant different between two groups. Propofol group required 8% lesser Propofol than Midazolam group. Conclusions: Our study concluded that blood pressure was decreased significantly in Midazolam group compared to Propofol group but heart rate was decreased almost similar in both groups and was not statistically significant. Consumption of Propofol was not statistically significant but Propofol group had 8 % lesser Propofol consumption than Midazolam group.

A "Smart" Biosensor-Enabled Intravascular Catheter and Platform for Dynamic Delivery of Propofol to "Close the Loop" for Total Intravenous Anesthesia.

Target-controlled infusion anesthesia is used worldwide to provide user-defined, stable, blood concentrations of propofol for sedation and anesthesia. The drug infusion is controlled by a microprocessor that uses population-based pharmacokinetic data and patient biometrics to estimate the required infusion rate to replace losses from the blood compartment due to drug distribution and metabolism. The objective of the research was to develop and validate a method to detect and quantify propofol levels in the blood, to improve the safety of propofol use, and to demonstrate a pathway for regulatory approval for its use in the USA. We conceptualized and prototyped a novel "smart" biosensor-enabled intravenous catheter capable of quantifying propofol at physiologic levels in the blood, in real time. The clinical embodiment of the platform is comprised of a "smart" biosensor-enabled catheter prototype, a signal generation/detection readout display, and a driving electronics software. The biosensor was validated in vitro using a variety of electrochemical methods in both static and flow systems with biofluids, including blood. We present data demonstrating the experimental detection and quantification of propofol at sub-micromolar concentrations using this biosensor and method. Detection of the drug is rapid and stable with negligible biofouling due to the sensor coating. It shows a linear correlation with mass spectroscopy methods. An intuitive graphical user interface was developed to: (1) detect and quantify the propofol sensor signal, (2) determine the difference between targeted and actual propofol concentration, (3) communicate the variance in real time, and (4) use the output of the controller to drive drug delivery from an in-line syringe pump. The automated delivery and maintenance of propofol levels was demonstrated in a modeled benchtop "patient" applying the known pharmacokinetics of the drug using published algorithms. We present a proof-of-concept and in vitro validation of accurate electrochemical quantification of propofol directly from the blood and the design and prototyping of a "smart," indwelling, biosensor-enabled catheter and demonstrate feedback hardware and software architecture permitting accurate measurement of propofol in blood in real time. The controller platform is shown to permit autonomous, "closed-loop" delivery of the drug and maintenance of user-defined propofol levels in a dynamic flow model.

Application of a benchtop colorimetric method for quantification of blood propofol levels.

Quantification of plasma propofol (2,6-diisopropylphenol) in the context of clinical anaesthesia is challenging because of the need for offline blood sample processing using specialised laboratory equipment and techniques. In this study we sought to refine a simple procedure using solid phase extraction and colorimetric analysis into a benchtop protocol for accurate blood propofol measurement.The colorimetric method based on the reaction of phenols (e.g. propofol) with Gibbs reagent was first tested in 10% methanol samples (n = 50) containing 0.5-6.0µg/mL propofol. Subsequently, whole blood samples (n = 15) were spiked to known propofol concentrations and processed using reverse phase solid phase extraction (SPE) and colorimetric analysis.The standard deviation of the difference between known and measured propofol concentrations in the methanol samples was 0.11µg/mL, with limits of agreement of - 0.21 to 0.22µg/mL. For the blood-processed samples, the standard deviation of the difference between known and measured propofol concentrations was 0.09µg/mL, with limits of agreement - 0.18 to 0.17µg/mL.Quantification of plasma propofol with an error of less than 0.2µg/mL is achievable with a simple and inexpensive benchtop method.

Rapid quantitative determination of blood propofol concentration throughout perioperative period by negative photoionization ion mobility spectrometer with solvent-assisted neutral desorption

Rapid and quantitative determination of blood propofol concentration is important for anesthesiologists to accurately control intraoperative propofol dose, timely monitor physiological statuses of patients and greatly improve the safety of surgery. Herein, a dopant-assisted negative photoionization ion mobility spectrometer with the optimized ionization region structure and the three-way inlet design was developed, increasing the generation ratio of the reactant ions O2−, and improving the ionization efficiency of propofol molecules. Besides, the addition of methanol-anisole solution during injection promoted the neutral desorption of propofol in blood, further improving the detection sensitivity by an order of magnitude, eliminating any sample pretreatment and effectively reducing the single analysis time to less than 1 min compared to the previous article. The dual calibration quantitative method, i.e. the method of calibrating the O2− concentration and the sample concentration changes during the entire process of detecting propofol through the integral value of M·O2− and the maximum signal intensity of O2−, successfully achieved accurate quantification of blood propofol. And the linear calibration curve of propofol was obtained with the range of 0.1–15 ng μL−1 and with the limit of detection of 0.03 ng μL−1, which was fulfilled to conduct propofol determination throughout the perioperative period. Finally, this method was applied to clinically measure the blood propofol concentration in patients newly regained consciousness with concentrations ranging from 0.2 ng μL−1 to 3 ng μL−1, and it turned out that the older patient had the lower propofol concentration in blood.

Rapid determination and continuous monitoring of propofol in microliter whole blood sample during anesthesia by paper spray ionization-mass spectrometry.

Propofol is a widely used intravenous anesthetic agent in sedation and general anesthesia. To improve the safety and maintain the depth of anesthesia, it is important to develop a rapid, sensitive, and reliable method to monitor the concentration of propofol in blood during anesthesia continuously. Here, we present a novel strategy based on paper spray ionization-mass spectrometry (PSI-MS) to detect propofol. Samples (in 10μL) were mixed with methanol as protein precipitation solvent and 2,6-dimethylphenol as internal standard. Protein micro-precipitation was achieved with methanol by vortexing and centrifuging for 5s each, and propofol was extracted to the supernatant. PSI-MS was performed in negative ionization mode, and MS signal lasted for 1min. The analysis of a single sample was completed within 2min. The area ratios of propofol to internal standard were calculated for quantification. Limit of detection of 5.5ngmL-1 and limit of quantification of 18.2ngmL-1 were achieved for propofol in whole blood. Calibration curve was linear in the range of 0.02-10μgmL-1. The developed method was used successfully in monitoring the propofol concentration in 3 patients' whole blood during anesthesia, showing its further application in controlling and feeding-back target concentration infusion. Graphical abstract.

Research progress on rapid detection of propofol

Propofol is a main representative of intravenous anesthetics, with the advantages of rapid onset, rapid awakening, and perfect function recovery. However, at present, there is no clinical method for monitoring its concentration in a real-time manner. Due to the disadvantages of traditional methods, such as complex sample pretreatment, long-time measurement, and large equipment in some assays which is unable to be placed in the operating room, increasing attention has been drawn towards rapid detection of propofol. The current paper is designed to comprehensively describe how to perform rapid detection of propofol concentrations. This article mainly discusses the rapid detection methods and principles of blood propofol concentrations and exhaled concentrations, so as to facilitate clinical application and to instruct anesthesiologists for evaluating anesthesia depth in a fast and real-time manner. Key words: Propofol; Drug concentration; Blood concentration; Expiratory gas; Rapid detection

Multi-drug therapy for epilepsy influenced bispectral index after a bolus propofol administration without affecting propofol\u2019s pharmacokinetics: a prospective cohort study

Some previous studies have indicated that valproate (VPA) might change the pharmacokinetics and enhance the effects of propofol. We evaluated whether clinical VPA therapy affected the propofol blood level, the protein-unbound free propofol level, and/or the anesthetic effects of propofol in the clinical setting. The subjects were divided into the control group (not medicated with antiepileptics), the mono-VPA group (medicated with VPA alone), and the poly-VPA group (medicated with VPA, other antiepileptics, and/or psychoactive drugs). General anesthesia was induced via the administration of a single bolus of propofol and a remifentanil infusion, and when the bispectral index (BIS) exceeded 60 sevoflurane was started. There were no significant differences in the total blood propofol level at 5, 10, 15, and 20 min or the protein-unbound free propofol level at 5 min after the intravenous administration of propofol between the 3 groups. However, the minimum BIS was significantly lower and the time until the BIS exceeded 60 was significantly longer in the poly-VPA group. In the multivariate regression analysis, belonging to the poly-VPA group was found to be independently associated with the minimum BIS value and the time until the BIS exceeded 60. Clinical VPA therapy did not influence the pharmacokinetics of propofol. However, multi-drug therapy involving VPA might enhance the anesthetic effects of propofol.

Online monitoring of end-tidal propofol in balanced anesthesia by anisole assisted positive photoionization ion mobility spectrometer

Online measuring end-tidal propofol concentration during balanced anesthesia is important for anesthetists to learn the patient's anesthesia depth as exhaled propofol concentration is well related to blood propofol concentration. In previous work, exhaled propofol was detected using acetone assisted negative photoionization ion mobility spectrometer, however, the existence of high concentration sevoflurane interfered the response of propofol. In this work, an anisole assisted photoionization ion mobility spectrometer operated in positive mode was developed to sensitively and selectively measure the end-tidal propofol by eliminating the interferences of exhaled humidity and sevoflurane during balanced anesthesia. Anisole molecular ion is stable enough not to go under proton transfer reaction with water presents in the exhaled breath. Hence, the exhaled humidity related peaks were eliminated and only one propofol product ion peak (K0 = 1.50 cm2 V−1 s−1) was observed. The relative standard deviation (RSD) ranging from 0.64%–0.91% showed good repeatability and the quantitative range was 0.2–40 ppbv with a response time of 4 s. Finally, the performance of the proposed method was demonstrated by monitoring end-tidal propofol of balanced anesthetized patients during gastric cancer surgery.

Rapid determination of intraoperative blood propofol concentration in operating theatre by dopant-enhanced neutral release and negative photoionization ion mobility spectrometry

The concentration of propofol in blood is an important indicator for anesthesiologists to monitor and regulate the anesthesia depth of patients during surgery. Herein, a negative photoionization ion mobility spectrometry with acetone as the dopant was developed for rapid and direct determination of intraoperative blood propofol concentration in the operating theatre. High concentration of acetone molecules in the carrier gas was used not only to enhance neutral desorption and release free propofol molecules from the whole blood, but also to increase the intensity of reactant O2− and reduce the amount of non-reactive CO3− ions simultaneously, which allowed to measure trace propofol in less than 2 min without any tedious pretreatment. Under optimized conditions, a linear calibration curve of propofol was obtained with the range of 0.5–20 ng μL−1 and with a limit of detection of 0.14 ng μL−1, which met the clinical requirements and correlated well with standard HPLC methods. Finally, the method was applied to detect intraoperative blood propofol concentration in nearly 100 surgical patients, demonstrating its excellent detection capability and facilitating the study of propofol pharmacokinetics.

The number and kind of antiepileptics affect propofol dose requirement for anesthesia: observational study.

The propofol dose requirement and the emergence time are affected by antiepileptic use. The effects on anesthesia of the number and kind of antiepileptic agents have not been reported. We investigated the relationship between the kind and number of antiepileptic agents and the propofol dose requirement for anesthesia and emergence time in intravenous general anesthesia for dental treatment for patients with neurological disorders. We studied 247 patients with neurological disorders who underwent dental treatment under intravenous general anesthesia. Patients were categorized according to the number of antiepileptics (none, single agent, two kinds, and three or more kinds of antiepileptics) and the kind of antiepileptic (carbamazepine, valproate, phenobarbital, phenytoin, zonisamide, clobazam, or topiramate) being received. The propofol dose requirement for anesthesia, emergence time, and predicted blood propofol concentration at emergence were evaluated. Patients on three or more kinds of antiepileptics had significantly lower propofol dose requirement (reduction in 25%, compare with no use) and predicted blood propofol concentration at emergence (reduction in 41%) and significantly longer emergence time (extension in 50%) (P < 0.05). Valproate and clobazam reduced the propofol dose (valproate 9% and clobazam 19%) and predicted blood propofol concentration at emergence (valproate 18% and clobazam 33%), while phenobarbital increased these parameters (30% and 125%) (P < 0.05). The number and kind of antiepileptics effects propofol dose requirement. In particular, valproate and clobazam reduce the propofol dose requirement, while phenobarbital increases this.Clinical trial registration UMIN No. UMIN000014179.

Multimodal cardioprotective strategy in cardiac surgery (the ProCCard trial): Study protocol for a multicenter randomized controlled trial

BackgroundMyocardial damage in patients undergoing cardiac surgery increases both morbidity and mortality. Different protective strategies dealing with either preconditioning or postconditioning or assessing a single aspect of cardioprotection have shown conflicting results. We tested the hypothesis that a multimodal approach would improve cardioprotection and limit myocardial damage following cardiac surgery with cardiopulmonary bypass.MethodsThis study is a pragmatic multicenter (six French institutions), prospective, randomized, single-blinded, controlled trial. The randomization is stratified by centers. In the study, 210 patients scheduled for aortic valve surgery with or without coronary artery bypass grafting will be assigned to a control or a treatment group (105 patients in each group). In the control group, patients receive total intravenous anesthesia with propofol and liberal intraoperative blood glucose management (initiation of insulin infusion when blood glucose, measured every 60 min, is greater than 180 mg/dl), as a standard of care. The treatment group receives a bundle of care combining five techniques of cardioprotection: (1) remote ischemic preconditioning applied before aortic cross-clamping; (2) maintenance of anesthesia with sevoflurane; (3) tight intraoperative blood glucose management (initiation of insulin infusion when blood glucose, measured every 30 min, is greater than 140 mg/dl); (4) moderate respiratory acidosis (pH 7.30) at the end of cardiopulmonary bypass; and (5) a gentle reperfusion protocol following aortic unclamping. The primary outcome is myocardial damage measured by postoperative 72-h area under the curve of high-sensitivity cardiac troponin I.DiscussionThe ProCCard study will be the first multicenter randomized controlled trial aiming to assess the role of a bundle of care combining several cardioprotective strategies to reduce myocardial damage in patients undergoing cardiac surgery with cardiopulmonary bypass.Trial registrationClinicalTrials.gov, NCT03230136. Registered on July 26, 2017. Last updated on April 17, 2019.

A manual propofol infusion regimen for neonates and infants.

Manual propofol infusion regimens for neonates and infants have been determined from clinical observations in children under the age of 3years undergoing anesthesia. We assessed the performance of these regimens using reported age-specific pharmacokinetic parameters for propofol. Where performance was poor, we propose alternative dosing regimens. Simulations using a reported general purpose pharmacokinetic propofol model were used to predict propofol blood plasma concentrations during manual infusion regimens recommended for children 0-3years. Simulated steady state concentrations were 6-8µg.mL-1 in the first 30minutes that were not sustained during 100minutes infusions. Pooled clinical data (n=161, 1902 plasma concentrations) were used to determine an alternative pharmacokinetic parameter set for propofol using nonlinear mixed effects models. A new manual infusion regimen for propofol that achieves a steady-state concentration of 3µg.mL-1 was determined using a heuristic approach. A manual dosing regimen predicted to achieve steady-state plasma concentration of 3µg.mL-1 comprised a loading dose of 2mg.kg-1 followed by an infusion rate of 9mg.kg-1 .h-1 for the first 15minutes, 7mg.kg-1 .h-1 from 15 to 30minutes, 6mg.kg-1 .h-1 from 30 to 60minutes, 5mg.kg-1 .h-1 from 1 to 2hours in neonates (38-44weeks postmenstrual age). Dose increased with age in those aged 1-2years with a loading dose of 2.5mg.kg-1 followed by an infusion rate of 13mg.kg-1 .h-1 for the first 15minutes, 12mg.kg-1 .h-1 from 15 to 30minutes, 11mg.kg-1 .h-1 from 30 to 60minutes, and 10mg.kg-1 .h-1 from 1 to 2hours. Propofol clearance increases throughout infancy to reach 92% that reported in adults (1.93L.min.70kg-1 ) by 6months postnatal age and infusion regimens should reflect clearance maturation and be cognizant of adverse effects from concentrations greater than the target plasma concentration. Predicted concentrations using a published general purpose pharmacokinetic propofol model were similar to those determined using a new parameter set using richer neonatal and infant data.

Lethal self-administration of propofol and atracurium: Two case reports and literature review

Propofol is an intravenous anesthetic agent widely used in the induction and maintenance of general anesthesia. Acute intoxications with propofol are rare and remain primarily related to the acquisition of the product in hospital. If propofol can induce fatal respiratory depression alone, in a number of cases the clinical situation is exacerbated by the presence of other drugs like neuromuscular-blocking agents. Laudanosine, the circulating form of atracurium or cisatracurium, two non-depolarizing neuromuscular-blocking agents, is more frequently observed in toxicology. Such agents are widely used for tracheal intubations. Laudanosine has no pharmacological activity, which is exclusively due to the parent drugs. These agents can be fatal at any concentration, due to respiratory failure. Here, two cases of anesthesiologists’ suicide following self-administration of propofol-atracurium combination are reported. Case 1: a 48-years-old anesthesiologist was found without vital signs at his office. The drugs and paraphernalia used for delivery were discovered at the scene. Case 2: a 61-years-old anesthesiologist was found dead at home with a cannula connected to an infusion set at the bend of the elbow. Next to the body several empty ampoules of Diprivan ® and Atracurium besylate ® were found. For both cases, several biological specimens were collected for toxicological investigation. Comprehensive screenings of drugs and toxic compounds were performed using LC-DAD and GC-MS. Ethanol concentrations were determined using GC-FID. Laudanosine was quantified using LC-DAD. Propofol was quantified using GC-MS and LC-MS/MS. Propofol blood concentrations were 1 and 1.91 mg/L for case 1 and case 2, respectively (therapeutic range: 2–8 mg/L). Laudanosine blood concentrations were 0.13 and 1.18 mg/L for case 1 and case 2, respectively. Paroxetine, N-demethyldiazepam and ethanol were detected in the first case. Hydroxyzine was detected in the second case. In both cases, levels of these substances could not explain the death. Propofol related fatalities are rare, even more when combined with neuromuscular- blocking agents [1] . Propofol and atracurium concentrations documented here, are in agreement with those reported in the literature, these being characterized by a high inter-individual variability [2] . However, the concentrations observed in suicide cases compared to those observed in accidental fatalities (chronic abusers) appear to be much higher. In fact, three manners of death have been described with propofol: suicide, accidental overdose in chronic abusers, and more exceptionally, murder [3] . In the cases described here, circumstances and the use of atracurium suggest suicide. It should be noted that the concentrations of laudanosine and propofol observed here are in the usual anesthetic range. Albeit, it should be pointed out that for anesthetic agents, therapeutic concentrations are established for patients being supported respiratory-wise, while in non-supported or non-intubated patients such concentrations may be fatal. Therefore, the interpretation of the blood concentration in the forensic toxicological analysis must take into account the context and the circumstances of the death.

Maternal and neonatal wellbeing during elective C-section induced with a combination of propofol and dexmedetomidine: How effective is the placental barrier in dogs?

Anaesthetics administered during C-section (CS) can cross the placenta and the foetal blood-brain barrier contributing to distress up to neonatal mortality. Therefore, to prevent neonatal risks, sedatives and analgesics are not commonly administered to the bitch until all pups are delivered. This study aims to evaluate the effect of a new anaesthetic and analgesic protocol for elective CS in dogs, focused on both maternal and neonatal wellbeing. General anaesthesia was induced by a combination of propofol (PPF) and dexmedetomidine (DEX) and maintained with isoflurane. DEX was added to PPF in order to provide analgesia and to reduce PPF dose. Propofol and DEX concentrations in maternal blood, amniotic fluid, and placenta were correlated to maternal and neonatal parameters. Maternal pain score was assessed with Glasgow Composite Measure Pain Scale short-form. Nine healthy purebred dogs scheduled for elective CS delivered 54 pups. The 77.8% of pups were vigorous at birth and assigned to the highest Apgar score (AS). The lowest AS was recorded in pups from mothers receiving additional doses of PPF (p < 0.001). Apgar scores improved with the increase in time between induction and pups' extraction, starting from 30 min after induction (p < 0.01). This study could contribute to clarify the controversy about the optimal extraction's time of pups after induction i.e. the best time between PPF administration and birth. No bitch showed post-operative pain or required additional analgesic doses based on their pain score. Maternal blood PPF and DEX, as well as placental PPF concentrations, decreased over time (p < 0.01). Conversely, placental DEX was fair uniformly detected in littermate pups. Both PPF and DEX were not detectable in amniotic fluid. Placenta resulted an effective barrier against foetal DEX exposure, making this protocol safe, analgesic and advisable for elective CS in dogs.