Clinical pharmacokinetics and pharmacodynamics of propofol

Propofol is an intravenous hypnotic drug that is used for induction and maintenance of sedation and general anaesthesia. It exerts its effects through potentiation of the inhibitory neurotransmitter -aminobutyric acid (GABA) at the GABA(A) receptor, and has gained widespread use due to its favourable drug effect profile. The main adverse effects are disturbances in cardiopulmonary physiology. Due to its narrow therapeutic margin, propofol should only be administered by practitioners trained and experienced in providing general anaesthesia. Many pharmacokinetic (PK) and pharmacodynamic (PD) models for propofol exist. Some are used to inform drug dosing guidelines, and some are also implemented in so-called target-controlled infusion devices, to calculate the infusion rates required for user-defined target plasma or effect-site concentrations. Most of the models were designed for use in a specific and well-defined patient category. However, models applicable in a more general population have recently been developed and published. The most recent example is the general purpose propofol model developed by Eleveld and colleagues. Retrospective predictive performance evaluations show that this model performs as well as, or even better than, PK models developed for specific populations, such as adults, children or the obese; however, prospective evaluation of the model is still required. Propofol undergoes extensive PK and PD interactions with both other hypnotic drugs and opioids. PD interactions are the most clinically significant, and, with other hypnotics, tend to be additive, whereas interactions with opioids tend to be highly synergistic. Response surface modelling provides a tool to gain understanding and explore these complex interactions. Visual displays illustrating the effect of these interactions in real time can aid clinicians in optimal drug dosing while minimizing adverse effects. In this review, we provide an overview of the PK and PD of propofol in order to refresh readers' knowledge of its clinical applications, while discussing the main avenues of research where significant recent advances have been made

Intraoperative monitoring of the central and peripheral nervous systems:a narrative review

The central and peripheral nervous systems are the primary target organs during anaesthesia. At the time of the inception of the British Journal of Anaesthesia, monitoring of the central nervous system comprised clinical observation, which provided only limited information. During the 100 yr since then, and particularly in the past few decades, significant progress has been made, providing anaesthetists with tools to obtain real-time assessments of cerebral neurophysiology during surgical procedures. In this narrative review article, we discuss the rationale and uses of electroencephalography, evoked potentials, near-infrared spectroscopy, and transcranial Doppler ultrasonography for intraoperative monitoring of the central and peripheral nervous systems.</p

Surviving the storm:manual vs. mechanical chest compressions onboard a lifeboat during bad weather conditions

Objective: It is challenging for rescuers to perform cardiopulmonary resuscitation (CPR) onboard lifeboats, particularly during rough weather. A mechanical chest compression device (MCD) may provide better quality chest compressions. The aim of this study was to compare the quality of chest compressions performed by lifeboat-crewmembers with those of a MCD during rough-sea conditions.Methods: Lifeboat-crewmembers were scheduled to provide compression-onlyCPR on a resuscitation-mannequin during two sets of five 6-min epochs on alifeboat at sea in two different weather-conditions. Simultaneously a MCD wasused for compression-only CPR on another mannequin onboard the lifeboat. Ona third occasion compressions by MCD only were measured due to COVID-19restrictions. The primary outcome variable was the quality of chest compression,evaluated using published variables and standards (mean compression depthand compression frequency, percentage correct compression depth, percentageof not leaning on the thorax, percentage of correct hand placement on thethorax, hands-off-time).Results: Six male lifeboat-crewmembers (mean age 35 years) performed CPRduring two different weather conditions. In weather-conditions one (wind∼6–7 Beaufort/wave-height: 100–150 cm) quality of manual compressions wassignificantly worse than mechanical compressions for mean compression depth(p &lt; 0.05) and compression frequency (p &lt; 0.05), percentage correct compression depth (p &lt; 0.05), percentage of not leaning on the thorax (p &lt; 0.05), and hands off time (p &lt; 0.05). Crewmembers could only perform CPR for a limited time-period (sea-conditions/seasickness) and after one set of five epochs measurements were halted. In weather-condition two (wind ∼9 Beaufort/wave-height ∼200 cm) similar results were found during two epochs, after which measurements were halted (sea-conditions/seasickness). In weather-condition three (wind ∼7 Beaufort/wave-height ∼300–400 cm) MCD compressions were according to resuscitation-guidelines except for three epochs during which the MCD was displaced.Conclusion: Crewmembers were only able to perform chest-compressions for alimited time because of the weather-conditions. The MCD was able to providegood quality chest compressions during all but three epochs during the studyperiod. More research is needed to determine whether MCD-use in real-lifecircumstances improves outcome. Inclusion of data on use of a MCD on lifeboatsshould be considered in future revisions of the USFD and resuscitation guidelines

Performance of Basic Life Support by Lifeboat Crewmembers While Wearing a Survival Suit and Life Vest:A Randomized Controlled Trial

Introduction: Crewmembers of the “Royal Netherlands Sea Rescue Institution” (KNRM) lifeboats must wear heavy survival suits with integrated lifejackets. This and the challenging environment onboard (boat movements, limited space) might influence Basic Life Support (BLS) performance. The primary objective of this study was to assess the impact of the protective gear on single-rescuer BLS-quality. Material and Methods: Sixty-five active KNRM crewmembers who had recently undergone a BLS-refresher course were randomized to wear either their protective gear (n = 32) or their civilian clothes (n = 33; control group) and performed five 2-min sessions of single rescuer BLS on a mannequin on dry land. BLS-quality was assessed according to Dutch and European Resuscitation guidelines. A between group analysis (Mann-Whitney U) and a repeated within group analysis of both groups (Friedman test) were performed. Results: There were no major demographic differences between the groups. The protective gear did not significant impair BLS-quality. It was also not associated with a significant increase in the perceived exertion of BLS (Borg's Rating scale). Compression depth, compression frequency, the percentage of correct compression depth and of not leaning on the thorax, and ventilation volumes in both groups were suboptimal when evaluated according to the BLS-guidelines. Conclusions: The protective gear worn by KNRM lifeboat-crewmembers does not have a significant influence on BLS-quality under controlled study conditions. The impact and significance on outcome in real life situations needs to be studied further. This study provides valuable input for optimizing the BLS-skills of lifeboat crewmembers

The influence of depth of anesthesia and blood pressure on muscle recorded motor evoked potentials in spinal surgery. A prospective observational study protocol

For high-risk spinal surgeries, intraoperative neurophysiological monitoring (IONM) is used to detect and prevent intraoperative neurological injury. The motor tracts are monitored by recording and analyzing muscle transcranial electrical stimulation motor evoked potentials (mTc-MEPs). A mTc-MEP amplitude decrease of 50-80% is the most common warning criterion for possible neurological injury. However, these warning criteria often result in false positive warnings. False positives may be caused by inadequate depth of anesthesia and blood pressure on mTc-MEP amplitudes. The aim of this paper is to validate the study protocol in which the goal is to investigate the effects of depth of anesthesia (part 1) and blood pressure (part 2) on mTc-MEPs. Per part, 25 patients will be included. In order to investigate the effects of depth of anesthesia, a processed electroencephalogram (pEEG) monitor will be used. At pEEG values of 30, 40 and 50, mTc-MEP measurements will be performed. To examine the effect of blood pressure on mTc-MEPs the mean arterial pressure will be elevated from 60 to 100 mmHg during which mTc-MEP measurements will be performed. We hypothesize that by understanding the effects of depth of anesthesia and blood pressure on mTc-MEPs, the mTc-MEP monitoring can be interpreted more reliably. This may contribute to fewer false positive warnings. By performing this study after induction and prior to incision, this protocol provides a unique opportunity to study the effects of depths of anesthesia and blood pressure on mTc-MEPs alone with as little confounders as possible. Trial registration number NL7772

Characterization of LINE-1 Ribonucleoprotein Particles

The average human genome contains a small cohort of active L1 retrotransposons that encode two proteins (ORF1p and ORF2p) required for their mobility (i.e., retrotransposition). Prior studies demonstrated that human ORF1p, L1 RNA, and an ORF2p-encoded reverse transcriptase activity are present in ribonucleoprotein (RNP) complexes. However, the inability to physically detect ORF2p from engineered human L1 constructs has remained a technical challenge in the field. Here, we have employed an epitope/RNA tagging strategy with engineered human L1 retrotransposons to identify ORF1p, ORF2p, and L1 RNA in a RNP complex. We next used this system to assess how mutations in ORF1p and/or ORF2p impact RNP formation. Importantly, we demonstrate that mutations in the coiled-coil domain and RNA recognition motif of ORF1p, as well as the cysteine-rich domain of ORF2p, reduce the levels of ORF1p and/or ORF2p in L1 RNPs. Finally, we used this tagging strategy to localize the L1–encoded proteins and L1 RNA to cytoplasmic foci that often were associated with stress granules. Thus, we conclude that a precise interplay among ORF1p, ORF2p, and L1 RNA is critical for L1 RNP assembly, function, and L1 retrotransposition

Administration and monitoring of intravenous anesthetics

Purpose of review The importance of accuracy in controlling the dose-response relation for intravenous anesthetics is directly related to the importance of optimizing the efficacy and quality of anesthesia while minimizing adverse drug effects. Therefore, it is important to measure and control all steps of the pharmacokinetic and dynamic cascade influencing this dose-effect relationship. Recent findings The ultimate goal when administering a particular dose of a drug is to obtain the desired clinical effect, taking into account interindividual pharmacokinetic and dynamic variability. Recent findings suggest that effect compartment-controlled target-controlled infusion systems and measurement of (surrogate) clinical drug effects might be helpful in an attempt to optimize the administration intravenous anesthetics and opioids. Additionally, recent findings suggest that the pharmacokinetic and dynamic interaction between anesthetics and opioids is important and such be taking into account when optimizing drug administration. Hereby, feedback control technology and advisory displays depicting these interactions have been studied. Summary Anesthetic drug administration might be optimized by applying knowledge from clinical pharmacokinetics and dynamics

Optimizing intravenous drug administration by applying pharmacokinetic/pharmacodynamic concepts

This review discusses the ways in which anaesthetists can optimize anaesthetic-analgesic drug administration by utilizing pharmacokinetic and pharmacodynamic information. We therefore focus on the dose-response relationship and the interactions between i.v. hypnotics and opioids. For i.v. hypnotics and opioids, models that accurately predict the time course of drug disposition and effect can be applied. Various commercial or experimental drug effect measures have been developed and can be implemented to further fine-tune individual patient-drug titration. The development of advisory and closed-loop feedback systems, which combine and integrate all sources of pharmacological and effect monitoring, has taken the existing kinetic-based administration technology forwards closer to total coverage of the dose-response relationship

Feasibility and optimal choice of stimulation parameters for supramaximal stimulation of motor evoked potentials

Purpose: The aim was to investigate the feasibility and optimal stimulation parameters for supramaximal stimulation of muscle recorded transcranial electrical stimulation motor evoked potentials (mTc-MEP). Methods: Forty-seven consecutive patients that underwent scoliosis surgery were included. First, the feasibility of supramaximal stimulation was assessed for two settings (setting 1: pulse duration 0.075ms, interstimulus interval (ISI) 1.5ms; setting 2: pulse duration 0.300ms, ISI 3ms). Thereafter, three mTc-MEP parameters were considered for both settings; (1) elicitability, (2) amplitude, and (3) if supramaximal stimulation was achieved with ≥ 20 V below maximum output. Finally, ISIs (1ms–4ms) were optimized for setting 1. Results: Nine patients (19.15%) were excluded. Of the remaining patients, supramaximal stimulation was achieved in all patients for setting 1, and in 26 (68.42%) for setting 2. In one patient, mTc-MEPs were elicitable in more muscles for setting (1) Amplitudes were not significantly different. Stimulation voltage could be increased ≥ 20 V in all 38 patients for setting 1 and in 10 (38.46%) for setting (2) Optimal ISI’s differed widely. Conclusion: We recommend using setting 1 when monitoring mTc-MEPs with supramaximal stimulation, after which an individualized ISI optimization can be performed. Moreover, when using supramaximal stimulation, short ISI’s (i.e. 1ms or 1.5ms) can be the optimal ISI for obtaining the highest mTc-MEP amplitude