Effects of Si and Sr elements on solidification microstructure and thermal conductivity of Al-Si-based alloys.

Effects of Si and Sr on solidification microstructure and thermal conductivity of Al-Si binary alloys and Al-9Si-Sr ternary were investigated, respectively, with a special focus on the relationship between solidification microstructure and thermal conductivity. It was found that (i) in Al-Si binary alloys, with increasing Si content, α-Al grain size increases and then decreases when Si content is over 7 wt%, while the percentage of eutectic Si continuously increases, which significantly decreases the thermal conductivity and electrical conductivity, and (ii) in Al-9Si-Sr ternary alloys, the presence of Sr has no significant effect on α-Al grain, but effectively modifies eutectic Si and significantly improves the thermal and electrical conductivity. On this basis, two theoretical calculation models [the Maxwell model and the Hashin-Shtrikman (H-S) model] were used to elucidate the relationship between solidification microstructure and thermal conductivity. Compared with the Maxwell model, the H-S model fits better with the measured values. The obtained results are very helpful to the precise composition control during alloy design and recycling of Al-Si-based alloys with the aim to further improve the thermal conductivity of Al-Si-based alloys. Supplementary Information: The online version contains supplementary material available at 10.1007/s10853-022-07045-7.

Novel transcutaneous sensor combining optical tcPO2 and electrochemical tcPCO2 monitoring with reflectance pulse oximetry.

This study investigated the accuracy, drift, and clinical usefulness of a new optical transcutaneous oxygen tension (tcPO2) measuring technique, combined with a conventional electrochemical transcutaneous carbon dioxide (tcPCO2) measurement and reflectance pulse oximetry in the novel transcutaneous OxiVenT™ Sensor. In vitro gas studies were performed to measure accuracy and drift of tcPO2 and tcPCO2. Clinical usefulness for tcPO2 and tcPCO2 monitoring was assessed in neonates. In healthy adult volunteers, measured oxygen saturation values (SpO2) were compared with arterially sampled oxygen saturation values (SaO2) during controlled hypoxemia. In vitro correlation and agreement with gas mixtures of tcPO2 (r = 0.999, bias 3.0 mm Hg, limits of agreement - 6.6 to 4.9 mm Hg) and tcPCO2 (r = 0.999, bias 0.8 mm Hg, limits of agreement - 0.7 to 2.2 mm Hg) were excellent. In vitro drift was negligible for tcPO2 (0.30 (0.63 SD) mm Hg/24 h) and highly acceptable for tcPCO2 (- 2.53 (1.04 SD) mm Hg/12 h). Clinical use in neonates showed good usability and feasibility. SpO2-SaO2 correlation (r = 0.979) and agreement (bias 0.13%, limits of agreement - 3.95 to 4.21%) in healthy adult volunteers were excellent. The investigated combined tcPO2, tcPCO2, and SpO2 sensor with a new oxygen fluorescence quenching technique is clinically usable and provides good overall accuracy and negligible tcPO2 drift. Accurate and low-drift tcPO2 monitoring offers improved measurement validity for long-term monitoring of blood and tissue oxygenation. Graphical abstract.

Revealing heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys.

The heterogeneous nucleation of primary Si and eutectic Si can be attributed to the presence of AlP. Although P, in the form of AlP particles, is usually observed in the centre of primary Si, there is still a lack of detailed investigations on the distribution of P within primary Si and eutectic Si in hypereutectic Al-Si alloys at the atomic scale. Here, we report an atomic-scale experimental investigation on the distribution of P in hypereutectic Al-Si alloys. P, in the form of AlP particles, was observed in the centre of primary Si. However, no significant amount of P was detected within primary Si, eutectic Si and the Al matrix. Instead, P was observed at the interface between the Al matrix and eutectic Si, strongly indicating that P, in the form of AlP particles (or AlP 'patch' dependent on the P concentration), may have nucleated on the surface of the Al matrix and thereby enhanced the heterogeneous nucleation of eutectic Si. The present investigation reveals some novel insights into heterogeneous nucleation of primary Si and eutectic Si by AlP in hypereutectic Al-Si alloys and can be used to further develop heterogeneous nucleation mechanisms based on adsorption.

The roles of Eu during the growth of eutectic Si in Al-Si alloys.

Controlling the growth of eutectic Si and thereby modifying the eutectic Si from flake-like to fibrous is a key factor in improving the properties of Al-Si alloys. To date, it is generally accepted that the impurity-induced twinning (IIT) mechanism and the twin plane re-entrant edge (TPRE) mechanism as well as poisoning of the TPRE mechanism are valid under certain conditions. However, IIT, TPRE or poisoning of the TPRE mechanism cannot be used to interpret all observations. Here, we report an atomic-scale experimental and theoretical investigation on the roles of Eu during the growth of eutectic Si in Al-Si alloys. Both experimental and theoretical investigations reveal three different roles: (i) the adsorption at the intersection of Si facets, inducing IIT mechanism, (ii) the adsorption at the twin plane re-entrant edge, inducing TPRE mechanism or poisoning of the TPRE mechanism, and (iii) the segregation ahead of the growing Si twins, inducing a solute entrainment within eutectic Si. This investigation not only demonstrates a direct experimental support to the well-accepted poisoning of the TPRE and IIT mechanisms, but also provides a full picture about the roles of Eu atoms during the growth of eutectic Si, including the solute entrainment within eutectic Si.

Sevoflurane remifentanil interaction: comparison of different response surface models.

BACKGROUND: Various pharmacodynamic response surface models have been developed to quantitatively describe the relationship between two or more drug concentrations with their combined clinical effect. We examined the interaction of remifentanil and sevoflurane on the probability of tolerance to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy in patients to compare the performance of five different response surface models. METHODS: Forty patients preoperatively received different combined concentrations of remifentanil (0-12 ng/ml) and sevoflurane (0.5-3.5 vol.%) according to a criss-cross design (160 concentration pairs, four per patient). After having reached pseudosteady state, the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy was recorded. For the analysis of the probability of tolerance, five different interaction models were tested: Greco, Reduced Greco, Minto, Scaled C50(O) Hierarchical, and Fixed C50(O) Hierarchical model. All calculations were performed with NONMEM VI (Icon Development Solutions, Ellicott City, MD). RESULTS: The pharmacodynamic interaction between sevoflurane and remifentanil was strongly synergistic for both the hypnotic and the analgesic components of anesthesia. The Greco model did not result in plausible parameter estimates. The Fixed C50(O) Hierarchical model performed slightly better than the Scaled C50(O) Hierarchical and Reduced Greco models, whereas the Minto model fitted less well. CONCLUSION: We showed the importance of exploring various surface model approaches when studying drug interactions. The Fixed C50(O) Hierarchical model fits our data on sevoflurane remifentanil interaction best and appears to be an appropriate model for use in hypnotic-opioid drug interaction.

Noxious stimulation response index: a novel anesthetic state index based on hypnotic-opioid interaction.

BACKGROUND: The noxious stimulation response index (NSRI) is a novel anesthetic depth index ranging between 100 and 0, computed from hypnotic and opioid effect-site concentrations using a hierarchical interaction model. The authors validated the NSRI on previously published data. METHODS: The data encompassed 44 women, American Society of Anesthesiology class I, randomly allocated to three groups receiving remifentanil infusions targeting 0, 2, and 4 ng/ml. Propofol was given at stepwise increasing effect-site target concentrations. At each concentration, the observer assessment of alertness and sedation score, the response to eyelash and tetanic stimulation of the forearm, the bispectral index (BIS), and the acoustic evoked potential index (AAI) were recorded. The authors computed the NSRI for each stimulation and calculated the prediction probabilities (PKs) using a bootstrap technique. The PKs of the different predictors were compared with multiple pairwise comparisons with Bonferroni correction. RESULTS: The median (95% CI) PK of the NSRI, BIS, and AAI for loss of response to tetanic stimulation was 0.87 (0.75-0.96), 0.73 (0.58-0.85), and 0.70 (0.54-0.84), respectively. The PK of effect-site propofol concentration, BIS, and AAI for observer assessment of alertness and sedation score and loss of eyelash reflex were between 0.86 (0.80-0.92) and 0.92 (0.83-0.99), whereas the PKs of NSRI were 0.77 (0.68-0.85) and 0.82 (0.68-0.92). The PK of the NSRI for BIS and AAI was 0.66 (0.58-0.73) and 0.63 (0.55-0.70), respectively. CONCLUSION: The NSRI conveys information that better predicts the analgesic component of anesthesia than AAI, BIS, or predicted propofol or remifentanil concentrations. Prospective validation studies in the clinical setting are needed.

Response surface modeling of the interaction between propofol and sevoflurane.

BACKGROUND: Propofol and sevoflurane display additivity for gamma-aminobutyric acid receptor activation, loss of consciousness, and tolerance of skin incision. Information about their interaction regarding electroencephalographic suppression is unavailable. This study examined this interaction as well as the interaction on the probability of tolerance of shake and shout and three noxious stimulations by using a response surface methodology. METHODS: Sixty patients preoperatively received different combined concentrations of propofol (0-12 microg/ml) and sevoflurane (0-3.5 vol.%) according to a crisscross design (274 concentration pairs, 3 to 6 per patient). After having reached pseudo-steady state, the authors recorded bispectral index, state and response entropy and the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy. For the analysis of the probability of tolerance by logistic regression, a Greco interaction model was used. For the separate analysis of bispectral index, state and response entropy suppression, a fractional Emax Greco model was used. All calculations were performed with NONMEM V (GloboMax LLC, Hanover, MD). RESULTS: Additivity was found for all endpoints, the Ce(50, PROP)/Ce(50, SEVO) for bispectral index suppression was 3.68 microg. ml(-1)/ 1.53 vol.%, for tolerance of shake and shout 2.34 microg . ml(-1)/ 1.03 vol.%, tetanic stimulation 5.34 microg . ml(-1)/ 2.11 vol.%, laryngeal mask airway insertion 5.92 microg. ml(-1) / 2.55 vol.%, and laryngoscopy 6.55 microg. ml(-1)/2.83 vol.%. CONCLUSION: For both electroencephalographic suppression and tolerance to stimulation, the interaction of propofol and sevoflurane was identified as additive. The response surface data can be used for more rational dose finding in case of sequential and coadministration of propofol and sevoflurane.

Anesthesia or sedation for gastroenterologic endoscopies.

PURPOSE OF REVIEW: Because propofol is the sedative preferred by gastroenterologists, we focus this review on gastroenterologist-directed propofol sedation, provide simulations of the respiratory depressant effect of different dosing protocols and give a perspective on future developments in computer-assisted sedation techniques. RECENT FINDINGS: Propofol use by nonanesthesiologists remains a contraindication in the package insert of propofol in most countries. Sedation guidelines produced by the American Society of Gastroenterology partially contradict those produced by the American Society of Anesthesiologists for sedation by nonanesthesiologists, whereas the German guidelines were developed with anesthesiologists involved. The use of fospropofol, recently approved by the US Food and Drug Administration for sedation, is considered an alternative to propofol by some gastroenterologists. Methodological errors in earlier pharmacological studies have to be solved before widespread use of fospropofol is justified, however. Our simulations show that dosing protocols with small boluses administered at reasonable intervals induce less respiratory depression than large boluses. Interindividual variability of propofol-induced respiratory depression is illustrated by different pharmacokinetic and dynamic parameter sets used in the simulation. Two computer-assisted propofol infusion systems are currently being investigated. They not only incorporate the target effect but also the side effects, which may limit respiratory depression. SUMMARY: Propofol use by gastroenterologists may be well tolerated if appropriate patient selection, staff training, monitoring and low-dose sedation protocols are applied.

Automatic algorithm for monitoring systolic pressure variation and difference in pulse pressure.

BACKGROUND: Difference in pulse pressure (dPP) reliably predicts fluid responsiveness in patients. We have developed a respiratory variation (RV) monitoring device (RV monitor), which continuously records both airway pressure and arterial blood pressure (ABP). We compared the RV monitor measurements with manual dPP measurements. METHODS: ABP and airway pressure (PAW) from 24 patients were recorded. Data were fed to the RV monitor to calculate dPP and systolic pressure variation in two different ways: (a) considering both ABP and PAW (RV algorithm) and (b) ABP only (RV(slim) algorithm). Additionally, ABP and PAW were recorded intraoperatively in 10-min intervals for later calculation of dPP by manual assessment. Interobserver variability was determined. Manual dPP assessments were used for comparison with automated measurements. To estimate the importance of the PAW signal, RV(slim) measurements were compared with RV measurements. RESULTS: For the 24 patients, 174 measurements (6-10 per patient) were recorded. Six observers assessed dPP manually in the first 8 patients (10-min interval, 53 measurements); no interobserver variability occurred using a computer-assisted method. Bland-Altman analysis showed acceptable bias and limits of agreement of the 2 automated methods compared with the manual method (RV: -0.33% +/- 8.72% and RV(slim): -1.74% +/- 7.97%). The difference between RV measurements and RV(slim) measurements is small (bias -1.05%, limits of agreement 5.67%). CONCLUSIONS: Measurements of the automated device are comparable with measurements obtained by human observers, who use a computer-assisted method. The importance of the PAW signal is questionable.

On the modeling of drug induced respiratory depression in the non-steady-state.

The ability of anesthetic agents to provide adequate analgesia and sedation is limited by the ventilatory depression associated with overdosing in spontaneously breathing patients. Therefore, quantitation of drug induced ventilatory depression is a pharmacokinetic-pharmacodynamic problem relevant to the practice of anesthesia. Although several studies describe the effect of respiratory depressant drugs on isolated endpoints, an integrated description of drug induced respiratory depression with parameters identifiable from clinically available data is not available. This study proposes a physiological model of CO2 disposition, ventilatory regulation, and the effects of anesthetic agents on the control of breathing. The predictive performance of the model is evaluated through simulations aimed at reproducing experimental observations of drug induced hypercarbia and hypoventilation associated with intravenous administration of a fast-onset, highly potent anesthetic mu agonist (including previously unpublished experimental data determined after administration of 1 mg alfentanil bolus). The proposed model structure has substantial descriptive capability and can provide clinically relevant predictions of respiratory inhibition in the non-steady-state to enhance safety of drug delivery in the anesthetic practice.

Effect of constant and variable domain glycosylation on pharmacokinetics of therapeutic antibodies in mice.

Previous studies on the effect of glycosylation on the elimination rate of antibodies have produced conflicting results. Here, we performed pharmacokinetic studies in mice with two preparations of a monoclonal IgG1 antibody enriched for complex type or high mannose type oligosaccharides at the Fc glycosylation site. No significant difference in the serum half-life was found between the two antibody glycoforms, nor was any difference observed in the serum half-lives of different complex type glycoforms. To evaluate the influence of glycosylation within the variable domain, a second monoclonal antibody, glycosylated in both the Fc and Fv domains, was separated into fractions containing different amounts of Fv-associated sialic acid and administered to mice. Again, no significant difference was found in the clearance rates of variants carrying different amounts of Fv-associated sialic acid or lacking Fv-glycosylation. These results suggest that glycosylation has little or no impact on the pharmacokinetic behavior of these two monoclonal antibodies in mice.

Drug-induced respiratory depression: an integrated model of drug effects on the hypercapnic and hypoxic drive.

Drug-induced respiratory depression is a common side effect of the agents used in anesthesia practice to provide analgesia and sedation. Depression of the ventilatory drive in the spontaneously breathing patient can lead to severe cardiorespiratory events and it is considered a primary cause of morbidity. Reliable predictions of respiratory inhibition in the clinical setting would therefore provide a valuable means to improve the safety of drug delivery. Although multiple studies investigated the regulation of breathing in man both in the presence and absence of ventilatory depressant drugs, a unified description of respiratory pharmacodynamics is not available. This study proposes a mathematical model of human metabolism and cardiorespiratory regulation integrating several isolated physiological and pharmacological aspects of acute drug-induced ventilatory depression into a single theoretical framework. The description of respiratory regulation has a parsimonious yet comprehensive structure with substantial predictive capability. Simulations relative to the synergistic interaction of the hypercarbic and hypoxic respiratory drive and the global effect of drugs on the control of breathing are in good agreement with published experimental data. Besides providing clinically relevant predictions of respiratory depression, the model can also serve as a test bed to investigate issues of drug tolerability and dose finding/control under non-steady-state conditions.

The well-being model: a new drug interaction model for positive and negative effects.

BACKGROUND: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. METHODS: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs. RESULTS: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed. CONCLUSIONS: The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.

Control of muscle relaxation during anesthesia: a novel approach for clinical routine.

During general anesthesia drugs are administered to provide hypnosis, ensure analgesia, and skeletal muscle relaxation. In this paper, the main components of a newly developed controller for skeletal muscle relaxation are described. Muscle relaxation is controlled by administration of neuromuscular blocking agents. The degree of relaxation is assessed by supramaximal train-of-four stimulation of the ulnar nerve and measuring the electromyogram response of the adductor pollicis muscle. For closed-loop control purposes, a physiologically based pharmacokinetic and pharmacodynamic model of the neuromuscular blocking agent mivacurium is derived. The model is used to design an observer-based state feedback controller. Contrary to similar automatic systems described in the literature this controller makes use of two different measures obtained in the train-of-four measurement to maintain the desired level of relaxation. The controller is validated in a clinical study comparing the performance of the controller to the performance of the anesthesiologist. As presented, the controller was able to maintain a preselected degree of muscle relaxation with excellent precision while minimizing drug administration. The controller performed at least equally well as the anesthesiologist.

Compartmental pharmacokinetics of dantrolene in adults: do malignant hyperthermia association dosing guidelines work?

Dantrolene is the only drug proven effective for prevention and treatment of malignant hyperthermia (MH). Current dosing recommendations are based on noncompartmental analyses and are largely empiric. They are also divergent, as evidenced by differing recommendations from the Malignant Hyperthermia Association of the United States (MHAUS) and European Sources. We determined the compartmental pharmacokinetics of dantrolene, simulated the concentration time course based on currently recommended dosing, and suggest an optimal regimen. Nine volunteers (55-89 kg) received IV infusions of dantrolene (5 mg/kg over 30 min followed by 0.05 mg.kg(-1) . h(-1) for 5 h). Venous blood samples were drawn for up to 60 h, and dantrolene plasma concentrations were determined by reverse phase, high-performance liquid chromatography. One, two, and three compartmental models were fitted to the data, and a covariate analysis was performed. All calculations were performed with NONMEM using the population approach. The data were adequately described by a two-compartment model with the following typical variable values (median +/- se): volumes of distribution V1= 3.24 +/- 0.61 L; V2= 22.9 +/- 1.53 L; plasma clearance CL el= 0.03 +/- 0.003 L/min; and distributional clearance CL dist= 1.24 +/- 0.22 L/min. All parameters were scaled linearly with weight. Simulations of European recommendations for treatment of MH lead to plasma concentrations converging to 14-18 mg/L within 24 h. Simulating MHAUS guidelines (intermittent bolus administration) yielded peak and trough plasma concentrations ranging from 6.7-22.6 mg/L. Based on our findings, we propose an infusion regimen adjusted to the initial bolus dose(s) required to control symptoms. This strategy maintains the individualized therapeutic concentrations and improves stability of plasma concentrations.

On-line estimation of propofol pharmacodynamic parameters.

A novel advisory system, the Anesthesia Advisory Display (AAD) has been recently developed. It displays information about actual and future predictions of anesthetic drug concentrations mapped to clinical end-points such as BIS, basing on the actual infusion rate combined with population pharmacokinetic and interaction pharmacodynamic (PKPD) models. According to the large variability observed among patients in clinical end-points to the same dosing history, a population model could fail in predicting the real patient's behavior: an "individualized" model is then necessary. An on-line estimation of the model's parameter for the single patients has been developed, basing on the extended Kalman filter algorithm. The method has been tested on data of 40 patients from a previous clinical study and the prediction of the individual models have been compared with the population model's.

A new model for drug interactions and optimal drug dosing.

Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. We propose a new method to study drug interactions considering also their side effects and to identify optimal drug dosing. The model is consistent with clinical knowledge and can explain previously published experimental results, improving our understanding of the characteristics of drug combinations used in clinical practice.

A new closed-loop control system for isoflurane using bispectral index outperforms manual control.

BACKGROUND: Automatic control of depth of hypnosis using the Bispectral Index (BIS) can help to reduce phases of inadequate control. Automated BIS control with propofol or isoflurane administration via an infusion system has recently been described, a comparable study with isoflurane administration via a vaporizer had not been conducted yet. Our hypothesis was that our new model based closed-loop control system can safely be applied clinically and maintains the BIS within a defined target range better than manual control. METHODS: Twenty-three patients, American Society of Anesthesiologists risk class I-III, scheduled for decompressive spinal surgery were randomized into groups with either closed-loop or manual control of BIS using isoflurane. An alfentanil target-controlled infusion was adjusted according to standard clinical practice. The BIS target was set to 50 during the operation. The necessity of human intervention in the control system and events of inadequate sedation (BIS <40 or BIS >60) were counted. The number of phases of inadequate control, defined as BIS >/=65 for more than 3 min, were recorded. The performance of the controller was assessed by several indicators (mean absolute deviation and median absolute performance error) and measured during the skin incision phase, the subsequent low flow phase, and the wound closure phase. Recovery profiles of both groups were compared. RESULTS: No human intervention was necessary in the closed-loop control group. The occurrence of inadequate BIS was quantified with the mean and median values of the area under the curve and amounted to 0.360 and 0.088 for the manual control group and 0.049 and 0.017 for the closed-loop control group, respectively. In the manual control group nine phases of inadequate control were recorded, compared with one in the closed-loop control group, 10.3% to 0.5% of all observed anesthesia time. During all phases the averages of the performance parameters (mean absolute deviation and median absolute performance error) were more than 30% smaller in closed-loop control than in manual control (P < 0.05 between groups). CONCLUSIONS: Closed-loop control with BIS using isoflurane can safely be applied clinically and performs significantly better than manual control, even in phases with abrupt changes of stimulation that cannot be foreseen by the control system.