Inert gas clearance from tissue by co-currently and counter-currently arranged microvessels

To elucidate the clearance of dissolved inert gas from tissues, we have developed numerical models of gas transport in a cylindrical block of tissue supplied by one or two capillaries. With two capillaries, attention is given to the effects of co-current and counter-current flow on tissue gas clearance. Clearance by counter-current flow is compared with clearance by a single capillary or by two co-currently arranged capillaries. Effects of the blood velocity, solubility, and diffusivity of the gas in the tissue are investigated using parameters with physiological values. It is found that under the conditions investigated, almost identical clearances are achieved by a single capillary as by a co-current pair when the total flow per tissue volume in each unit is the same (i.e., flow velocity in the single capillary is twice that in each co-current vessel). For both co-current and counter-current arrangements, approximate linear relations exist between the tissue gas clearance rate and tissue blood perfusion rate. However, the counter-current arrangement of capillaries results in less-efficient clearance of the inert gas from tissues. Furthermore, this difference in efficiency increases at higher blood flow rates. At a given blood flow, the simple conduction-capacitance model, which has been used to estimate tissue blood perfusion rate from inert gas clearance, underestimates gas clearance rates predicted by the numerical models for single vessel or for two vessels with co-current flow. This difference is accounted for in discussion, which also considers the choice of parameters and possible effects of microvascular architecture on the interpretation of tissue inert gas clearance

Do distribution volumes and clearances relate to tissue volumes and blood flows? A computer simulation

BACKGROUND: Kinetics of inhaled agents are often described by physiological models. However, many pharmacokinetic concepts, such as context-sensitive half-times, have been developed for drugs described by classical compartmental models. We derived classical compartmental models that describe the course of the alveolar concentrations (F(A)) generated by the physiological uptake and distribution models used by the Gas Man(® )program, and describe how distribution volumes and clearances relate to tissue volumes and blood flows. METHODS: Gas Man(® )was used to generate F(A )vs. time curves during the wash-in and wash-out period of 115 min each with a high fresh gas flow (8 L.min(-1)), a constant alveolar minute ventilation (4 L.min(-1)), and a constant inspired concentration (F(I)) of halothane (0.75%), isoflurane (1.15%), sevoflurane (2%), or desflurane (6%). With each of these F(I), simulations were ran for a 70 kg patient with 5 different cardiac outputs (CO) (2, 3, 5, 8 and 10 L.min(-1)) and for 5 patients with different weights (40, 55, 70, 85, and 100 kg) but the same CO (5 L.min(-1)). Two and three compartmental models were fitted to F(A )of the individual 9 runs using NONMEM. After testing for parsimony, goodness of fit was evaluated using median prediction error (MDPE) and median absolute prediction error (MDAPE). The model was tested prospectively for a virtual 62 kg patient with a cardiac output of 4.5 L.min(-1 )for three different durations (wash-in and wash-out period of 10, 60, and 180 min each) with an F(I )of 1.5% halothane, 1.5% isoflurane, sevoflurane 4%, or desflurane 12%. RESULTS: A three-compartment model fitted the data best (MDPE = 0% and MDAPE ≤ 0.074%) and performed equally well when tested prospectively (MDPE ≤ 0.51% and MDAPE ≤ 1.51%). The relationship between CO and body weight and the distribution volumes and clearances is complex. CONCLUSION: The kinetics of anesthetic gases can be adequately described e by a mammilary compartmental model. Therefore, concepts that are traditionally thought of as being applicable to the kinetics of intravenous agents can be equally well applied to anesthetic gases. Distribution volumes and clearances cannot be equated to tissue volumes and blood flows respectively

Effect of nitrous oxide on cisatracurium infusion demands: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Recent studies have questioned our previous understanding on the effect of nitrous oxide on muscle relaxants, since nitrous oxide has been shown to potentiate the action of bolus doses of mivacurium, rocuronium and vecuronium. This study was aimed to investigate the possible effect of nitrous oxide on the infusion requirements of cisatracurium.</p> <p>Methods</p> <p>70 ASA physical status I-III patients aged 18-75 years were enrolled in this randomized trial. The patients were undergoing elective surgery requiring general anesthesia with a duration of at least 90 minutes. Patients were randomized to receive propofol and remifentanil by target controlled infusion in combination with either a mixture of oxygen and nitrous oxide (Nitrous oxide/TIVA group) or oxygen in air (Air/TIVA group). A 0.1 mg/kg initial bolus of cisatracurium was administered before tracheal intubation, followed by a closed-loop computer controlled infusion of cisatracurium to produce and maintain a 90% neuromuscular block. Cumulative dose requirements of cisatracurium during the 90-min study period after bolus administration were measured and the asymptotic steady state rate of infusion to produce a constant 90% block was determined by applying nonlinear curve fitting to the data on the cumulative dose requirement during the study period.</p> <p>Results</p> <p>Controller performance, i.e. the ability of the controller to maintain neuromuscular block constant at the setpoint and patient characteristics were similar in both groups. The administration of nitrous oxide did not affect cisatracurium infusion requirements. The mean steady-state rates of infusion were 0.072 +/- 0.018 and 0.066 +/- 0.017 mg * kg-1 * h-1 in Air/TIVA and Nitrous oxide/TIVA groups, respectively.</p> <p>Conclusions</p> <p>Nitrous oxide does not affect the infusion requirements of cisatracurium.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT01152905; European Clinical Trials Database at <url>http://eudract.emea.eu.int/2006-006037-41</url>.</p

Protocol for the "Michigan Awareness Control Study": A prospective, randomized, controlled trial comparing electronic alerts based on bispectral index monitoring or minimum alveolar concentration for the prevention of intraoperative awareness

<p>Abstract</p> <p>Background</p> <p>The incidence of intraoperative awareness with explicit recall is 1-2/1000 cases in the United States. The Bispectral Index monitor is an electroencephalographic method of assessing anesthetic depth that has been shown in one prospective study to reduce the incidence of awareness in the high-risk population. In the B-Aware trial, the number needed to treat in order to prevent one case of awareness in the high-risk population was 138. Since the number needed to treat and the associated cost of treatment would be much higher in the general population, the efficacy of the Bispectral Index monitor in preventing awareness in all anesthetized patients needs to be clearly established. This is especially true given the findings of the B-Unaware trial, which demonstrated no significant difference between protocols based on the Bispectral Index monitor or minimum alveolar concentration for the reduction of awareness in high risk patients.</p> <p>Methods/Design</p> <p>To evaluate efficacy in the general population, we are conducting a prospective, randomized, controlled trial comparing the Bispectral Index monitor to a non-electroencephalographic gauge of anesthetic depth. The total recruitment for the study is targeted for 30,000 patients at both low and high risk for awareness. We have developed a novel algorithm that is capable of real-time analysis of our electronic perioperative information system. In one arm of the study, anesthesia providers will receive an electronic page if the Bispectral Index value is >60. In the other arm of the study, anesthesia providers will receive a page if the age-adjusted minimum alveolar concentration is <0.5. Our minimum alveolar concentration algorithm is sensitive to both inhalational anesthetics and intravenous sedative-hypnotic agents.</p> <p>Discussion</p> <p>Awareness during general anesthesia is a persistent problem and the role of the Bispectral Index monitor in its prevention is still unclear. The Michigan Awareness Control Study is the largest prospective trial of awareness prevention ever conducted.</p> <p>Trial Registration</p> <p>Clinical Trial NCT00689091</p

Protocol for the BAG-RECALL clinical trial: a prospective, multi-center, randomized, controlled trial to determine whether a bispectral index-guided protocol is superior to an anesthesia gas-guided protocol in reducing intraoperative awareness with explicit recall in high risk surgical patients

<p>Abstract</p> <p>Background</p> <p>Awareness with explicit recall of intra-operative events is a rare and distressing complication that may lead to severe psychological symptoms. Candidate depth of anesthesia monitors have been developed, partly with the aim of preventing this complication. Despite conflicting results from clinical trials and the lack of incisive validation, such monitors have enjoyed widespread clinical adoption, in particular the bispectral index. The American Society of Anesthesiologists has called for adequately powered and rigorously designed clinical trials to determine whether the use of such monitors decreases the incidence of awareness in various settings. The aim of this study is to determine with increased precision whether incorporating the bispectral index into a structured general anesthesia protocol decreases the incidence of awareness with explicit recall among a subset of surgical patients at increased risk for awareness and scheduled to receive an inhalation gas-based general anesthetic.</p> <p>Methods/Design</p> <p>BAG-RECALL is a multi-center, randomized, controlled clinical trial, in which 6,000 patients are being assigned to bispectral index-guided anesthesia (target range, 40 to 60) or end-tidal anesthetic gas-guided anesthesia (target range, 0.7 to 1.3 age-adjusted minimum alveolar concentration). Postoperatively, patients are being assessed for explicit recall at two intervals (0 to 72 hours, and 30 days after extubation). The primary outcome of the trial is awareness with explicit recall. Secondary outcomes include postoperative mortality, psychological symptoms, intensive care and hospital length of stay, average anesthetic gas administration, postoperative pain and nausea and vomiting, duration of stay in the recovery area, intra-operative dreaming, and postoperative delirium.</p> <p>Discussion</p> <p>This trial has been designed to complement two other clinical trials: B-Unaware and MACS (ClinicalTrials.gov numbers, NCT00281489 and NCT00689091). With the large patient numbers and complementary rigorous designs, it is envisaged that pre-specified meta-analyses will address some of the outstanding controversies and questions relating to processed electroencephalography monitoring.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: NCT00682825</p

Heterogeneity of human adipose blood flow

BACKGROUND: The long time pharmacokinetics of highly lipid soluble compounds is dominated by blood-adipose tissue exchange and depends on the magnitude and heterogeneity of adipose blood flow. Because the adipose tissue is an infinite sink at short times (hours), the kinetics must be followed for days in order to determine if the adipose perfusion is heterogeneous. The purpose of this paper is to quantitate human adipose blood flow heterogeneity and determine its importance for human pharmacokinetics. METHODS: The heterogeneity was determined using a physiologically based pharmacokinetic model (PBPK) to describe the 6 day volatile anesthetic data previously published by Yasuda et. al. The analysis uses the freely available software PKQuest and incorporates perfusion-ventilation mismatch and time dependent parameters that varied from the anesthetized to the ambulatory period. This heterogeneous adipose perfusion PBPK model was then tested by applying it to the previously published cannabidiol data of Ohlsson et. al. and the cannabinol data of Johansson et. al. RESULTS: The volatile anesthetic kinetics at early times have only a weak dependence on adipose blood flow while at long times the pharmacokinetics are dominated by the adipose flow and are independent of muscle blood flow. At least 2 adipose compartments with different perfusion rates (0.074 and 0.014 l/kg/min) were needed to describe the anesthetic data. This heterogeneous adipose PBPK model also provided a good fit to the cannabinol data. CONCLUSION: Human adipose blood flow is markedly heterogeneous, varying by at least 5 fold. This heterogeneity significantly influences the long time pharmacokinetics of the volatile anesthetics and tetrahydrocannabinol. In contrast, using this same PBPK model it can be shown that the long time pharmacokinetics of the persistent lipophilic compounds (dioxins, PCBs) do not depend on adipose blood flow. The ability of the same PBPK model to describe both the anesthetic and cannabinol kinetics provides direct qualitative evidence that their kinetics are flow limited and that there is no significant adipose tissue diffusion limitation

Mapping the contribution of β3-containing GABA(A )receptors to volatile and intravenous general anesthetic actions

BACKGROUND: Agents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by β3-containing GABA(A )receptors. This was determined by using the β3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABA(A )receptors. In this communication, we analyzed the contribution of β3-containing GABA(A )receptors to the pharmacological actions of isoflurane, etomidate and propofol by means of β3(N265M) mice. RESULTS: Isoflurane decreased core body temperature and heart rate to a smaller degree in β3(N265M) mice than in wild type mice, indicating a minor but significant role of β3-containing GABA(A )receptors in these actions. Prolonged time intervals in the ECG and increased heart rate variability were indistinguishable between genotypes, suggesting no involvement of β3-containing GABA(A )receptors. The anterograde amnesic action of propofol was indistinguishable in β3(N265M) and wild type mice, suggesting that it is independent of β3-containing GABA(A )receptors. The increase of heart rate variability and prolongation of ECG intervals by etomidate and propofol were also less pronounced in β3(N265M) mice than in wild type mice, pointing to a limited involvement of β3-containing GABA(A )receptors in these actions. The lack of etomidate- and propofol-induced immobilization in β3(N265M) mice was also observed in congenic 129X1/SvJ and C57BL/6J backgrounds, indicating that this phenotype is stable across different backgrounds. CONCLUSION: Our results provide evidence for a defined role of β3-containing GABA(A )receptors in mediating some, but not all, of the actions of general anesthetics, and confirm the multisite model of general anesthetic action. This pharmacological separation of anesthetic endpoints also suggests that subtype-selective substances with an improved side-effect profile may be developed

A systematic review of physiological methods in rodent pharmacological MRI studies

Rationale: Pharmacological magnetic resonance imaging (phMRI) provides an approach to study effects of drug challenges on brain processes. Elucidating mechanisms of drug action helps us to better understand the workings of neurotransmitter systems, map brain function or facilitate drug development. phMRI is increasingly used in preclinical research employing rodent models; however, data interpretation and integration are complicated by the use of different experimental approaches between laboratories. In particular, the effects of different anaesthetic regimes upon neuronal and haemodynamic processes and baseline physiology could be problematic. Objectives: This paper investigates how differences in phMRI research methodologies are manifested and considers associated implications, placing particular emphasis on choice of anaesthetic regimes. Methods: A systematic review of rodent phMRI studies was conducted. Factors such as those describing anaesthetic regimes (e.g. agent, dosage) and parameters relating to physiological maintenance (e.g. ventilatory gases) and MRI method were recorded. Results: We identified 126 eligible studies and found that the volatile agents isoflurane (43.7 %) and halothane (33.3 %) were most commonly used for anaesthesia, but dosage and mixture of ventilatory gases varied substantially between laboratories. Relevant physiological parameters were usually recorded, although 32 % of studies did not provide cardiovascular measures. Conclusions: Anaesthesia and animal preparation can influence phMRI data profoundly. The variation of anaesthetic type, dosage regime and ventilatory gases makes consolidation of research findings (e.g. within a specific neurotransmitter system) difficult. Standardisation of a small(er) number of preclinical phMRI research methodologies and/or increased consideration of approaches that do not require anaesthesia is necessary to address these challenges

Combining Nitrous Oxide with Carbon Dioxide Decreases the Time to Loss of Consciousness during Euthanasia in Mice — Refinement of Animal Welfare?

Carbon dioxide (CO2) is the most commonly used euthanasia agent for rodents despite potentially causing pain and distress. Nitrous oxide is used in man to speed induction of anaesthesia with volatile anaesthetics, via a mechanism referred to as the “second gas” effect. We therefore evaluated the addition of Nitrous Oxide (N2O) to a rising CO2 concentration could be used as a welfare refinement of the euthanasia process in mice, by shortening the duration of conscious exposure to CO2. Firstly, to assess the effect of N2O on the induction of anaesthesia in mice, 12 female C57Bl/6 mice were anaesthetized in a crossover protocol with the following combinations: Isoflurane (5%)+O2 (95%); Isoflurane (5%)+N2O (75%)+O2 (25%) and N2O (75%)+O2 (25%) with a total flow rate of 3l/min (into a 7l induction chamber). The addition of N2O to isoflurane reduced the time to loss of the righting reflex by 17.6%. Secondly, 18 C57Bl/6 and 18 CD1 mice were individually euthanized by gradually filling the induction chamber with either: CO2 (20% of the chamber volume.min−1); CO2+N2O (20 and 60% of the chamber volume.min−1 respectively); or CO2+Nitrogen (N2) (20 and 60% of the chamber volume.min−1). Arterial partial pressure (Pa) of O2 and CO2 were measured as well as blood pH and lactate. When compared to the gradually rising CO2 euthanasia, addition of a high concentration of N2O to CO2 lowered the time to loss of righting reflex by 10.3% (P<0.001), lead to a lower PaO2 (12.55±3.67 mmHg, P<0.001), a higher lactataemia (4.64±1.04 mmol.l−1, P = 0.026), without any behaviour indicative of distress. Nitrous oxide reduces the time of conscious exposure to gradually rising CO2 during euthanasia and hence may reduce the duration of any stress or distress to which mice are exposed during euthanasia