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Biomedical subjects

R N Upton

Publications and source records attributed to R N Upton.

At least 19 recordsLinked to original sources
PubMed2002

Theoretical aspects of P-glycoprotein mediated drug efflux on the distribution volume of anaesthetic-related drugs in the brain.

P-glycoprotein in the membranes of endothelial cells actively transports some drugs out of the brain. The theoretical effect of P-glycoprotein mediated drug efflux on the cerebral distribution volumes of drugs was examined, with particular emphasis on anaesthetic-related drugs (often characterized by moderate to high permeability across the blood brain barrier due to their lipophilicity and intermediate molecular weight). An analytical equation for the cerebral distribution volume in the presence of the efflux was derived, and validated by modelling the same system using differential equations. The efflux was shown to lower both the membrane and intracellular drug concentrations in parallel, and to reduce the time required for brain:blood equilibration. The net effect of the efflux was governed by the ratio of the P-glycoprotein drug clearance from the membrane (Pcl) and the permeability of the membrane (PS). It was therefore a balance between the rate that a drug could be pumped out of the membrane by the efflux system, and the rate that the drug leaked back in due to the permeability of the membrane for the drug. The effect of the efflux was therefore more pronounced for drugs with membrane-limited cerebral kinetics (e.g. morphine), but was nevertheless significant for drugs with more flow-limited kinetics (e.g fentanyl). The cerebral distribution volume was also influenced by the free fraction in blood and the free fraction in the intracellular space in the conventional manner. There are no theoretical limitations to the P-glycoprotein system influencing the cerebral distribution volume of moderately lipophilic anaesthetic-related drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Cerebrovascular carbon dioxide reactivity in sheep: effect of propofol or isoflurane anaesthesia.

Propofol and isoflurane are commonly used in neuroanaesthesia. Some published data suggest that the use of these agents is associated with impaired cerebral blood flow/carbon dioxide (CO2) reactivity. Cerebrovascular CO2 reactivity was therefore measured in three cohorts of adult merino sheep: awake (n=6), anaesthetized with steady-state propofol (15 mg/min; n=6) and anaesthetized with 2% isoflurane (n=6). Changes in cerebral blood flow were measured continuously from changes in velocities of blood in the sagittal sinus via a Doppler probe. Alterations in the partial pressure of carbon dioxide in arterial blood (PaCO2) over the range 18-63 mmHg were achieved by altering either the inspired CO2 concentration or the rate of mechanical ventilation. Cerebral blood flow/CO2 relationships were determined by linear regression analysis, with changes in cerebral blood flow expressed as a percentage of the value for a PaCO2 of 35 mmHg. Propofol decreased cerebral blood flow by 55% relative to pre-anaesthesia values (P=0.0001), while isoflurane did not significantly alter cerebral blood flow (88.45% of baseline, P=0.39). Significant linear relationships between cerebral blood flow and CO2 tension were determined in all individual studies (r2 ranged from 0.72 to 0.99). The slopes of the lines were highly variable between individuals for the awake cohort (mean 4.73, 1.42-7.12, 95% CI). The slopes for the propofol (mean 2.67, 2.06-3.28, 95% CI) and isoflurane (mean 2.82, 219-3.45, 95% CI) cohorts were more predictable. However, there was no significant difference between these anaesthetic agents with respect to the CO2 reactivity of cerebral blood flow.

Anesthetics, Inhalation↗
PubMed2001

Epinephrine, norepinephrine and dopamine infusions decrease propofol concentrations during continuous propofol infusion in an ovine model.

OBJECTIVE: To determine the effects of exogenous ramped infusions of epinephrine, norepinephrine and dopamine on arterial and effluent brain blood concentrations of propofol under steady state intravenous anesthesia. DESIGN: Prospective, randomized animal study. SETTING: University research laboratory. SUBJECTS: Five adult female merino sheep. INTERVENTIONS: Induction (5 mg/kg) and continuous infusion of propofol (15 mg/min) with controlled mechanical ventilation to maintain PaCO2 40 mmHg. After 1 h of continuous anesthesia, each animal randomly received ramped infusions of epinephrine, norepinephrine (10, 20, 40 microg/min) and dopamine (10, 20, 40 microg x kg x min) in 3 x 5 min intervals followed by a 30-min washout period. MEASUREMENTS: Arterial and sagittal sinus whole blood for determination of propofol concentrations using high-pressure liquid chromatography. Cardiac output using a thermodilution method. Level of consciousness using an observational scale. MAIN RESULTS: All three drugs significantly and transiently increased cardiac output in a dose-dependent fashion to a maximum of 146-169% of baseline. Baseline arterial and sagittal sinus propofol concentrations were not statistically different prior to catecholamine infusions. All three drugs significantly reduced mean arterial propofol concentrations (95 % CI, p < 0.05): epinephrine to 41.8% of baseline (11.4-72), norepinephrine to 63 % (27-99) and dopamine to 52.9 % (18.5-87.3). There were parallel reductions of concentrations in sagittal sinus blood leaving the brain. The lowest blood concentrations were associated with emergence from anesthesia. Arterial concentrations were inversely related to the simultaneously determined cardiac output (r2 = 0.74, p < 0.0001). Comparison of the data with the predictions of a previously developed recirculatory model of propofol disposition in sheep showed the data were consistent with a mechanism based on increased first pass dilution and clearance of propofol secondary to the increased cardiac output. CONCLUSIONS: Catecholamines produced circulatory changes that reversed propofol anesthesia. These observations have potential clinical implications for the use of propofol in hyperdynamic circulatory conditions, either induced by exogenous catecholamine infusions or pathological states.

Anesthetics, Intravenous↗
PubMed2001

In vivo cerebral pharmacokinetics and pharmacodynamics of diazepam and midazolam after short intravenous infusion administration in sheep.

The cerebral pharmacokinetics and pharmacodynamics of midazolam and diazepam were examined in chronically instrumented sheep via measurements of their arterio-venous concentration difference across the brain during and after 2-min i.v. infusions. Diazepam (30 mg) or midazolam (10 mg) were administered on 5 separate occasions to 4 sheep. For both drugs, rapid cerebral uptake occurred during the infusion, which quickly turned to elution in the postinfusion period. However, this process was more rapid for midazolam than diazepam. The cerebral pharmacokinetics of both was better described by a kinetic model with slight membrane limitation rather than flow limitation. For diazepam, the estimated brain:plasma partition coefficient was 2.67, and the first and second compartments filled with half-lives of 2.2 and 0.5 min, respectively. For midazolam, these values were 0.27, 0.26 and 1.34 min, respectively. In a subset of sheep, pulmonary arterial-arterial gradients were too small to measure suggesting limited metabolism and small distribution volumes for both drugs in the lungs. Simultaneous dynamic measurements of cerebral blood flow and algesimetry lagged behind both the arterial and sagittal sinus blood concentrations. The changes in cerebral blood flow were best described by a previously published a dynamic model that incorporated long half-lives for drug dissociation from the benzodiazepine receptor (13.3 and 5.5 min for midazolam and diazepam, respectively). Effect compartment modeling of the cerebral blood flow data showed apparent effect compartment half-lives (t1/2,keo) that were longer than the half-lives of cerebral equilibration.

Animals↗
PubMed2001

Diffusion-limited tissue equilibration and arteriovenous diffusion shunt describe skeletal muscle nitrous oxide kinetics at high and low blood flows in sheep.

This study evaluated the relative importance of perfusion and diffusion mechanisms in compartmental models of blood : tissue inert gas exchange in skeletal muscle. Nitrous oxide kinetics in a hind limb skeletal muscle bed were determined during and after 20 min of nitrous oxide inhalation, at separate low and high steady states of hind limb blood flow in five sheep under halothane anaesthesia. Nitrous oxide concentrations in arterial and femoral vein blood were determined using gas chromatographic analysis and femoral vein blood flow was monitored continuously. Parameters and model selection criteria of various perfusion- or diffusion-limited structural models of skeletal muscle were estimated by simultaneous fitting of the models to the mean observed femoral vein nitrous oxide concentration for both blood flow states. Purely perfusion-limited models fit the data poorly. Models that allowed a diffusion-limited exchange of nitrous oxide between a perfusion-limited tissue compartment and an unperfused deep compartment provided better overall fit of the data and credible parameter estimates. The data was best described by allowing, in addition to diffusion-limited tissue equilibration, counter current diffusion of nitrous oxide between arterial and venous blood. The level of tissue blood flow modifies the magnitudes of both these diffusion effects. These results suggest a dual role of diffusion in blood : tissue inert gas equilibration in skeletal muscle.

Algorithms↗
PubMed2001

A mixture of alfentanil and morphine for rapid postoperative loading with opioid: theoretical basis and initial clinical investigation.

Pharmacokinetic modelling of estimated central nervous system concentrations was used to devise the optimal mixture of morphine and alfentanil for the treatment of postoperative pain. Modelling revealed that an intravenous opioid pain protocol using an alfentanil-morphine mixture in the proportions 0.75 : 10 mg would provide a profile of analgesia of rapid onset, yet slow offset. The regimen was evaluated in 58 patients in the recovery ward who were randomly allocated to receive analgesia using pain protocols with either morphine or the mixture. Groups were well matched for age, weight and initial pain scores. The mean (SD) time to patient comfort was 27.6 (20.2) min for the mixture and 41.2 (18.6) min for morphine (p = 0.01). Multiple regression analysis revealed that that initial pain score (p = 0.009) and drug group (p = 0.02), but not age, weight or gender were independent predictors of the time to comfort. Drug group was not a significant predictor of adverse effects.

Adult↗
PubMed2001

Increased cerebral blood flow and cardiac output following cerebral arterial air embolism in sheep.

1. The effects of cerebral arterial gas embolism on cerebral blood flow and systemic cardiovascular parameters were assessed in anaesthetized sheep. 2. Six sheep received a 2.5 mL injection of air simultaneously into each common carotid artery over 5 s. Mean arterial blood pressure, heart rate, end-tidal carbon dioxide and an ultrasonic Doppler index of cerebral blood flow were monitored continuously. Cardiac output was determined by periodic thermodilution. 3. Intracarotid injection of air produced an immediate drop in mean cerebral blood flow. This drop was transient and mean cerebral blood flow subsequently increased to 151% before declining slowly to baseline. Coincident with the increased cerebral blood flow was a sustained increase in mean cardiac output to 161% of baseline. Mean arterial blood pressure, heart rate and end-tidal carbon dioxide were not significantly altered by the intracarotid injection of air. 4. The increased cardiac output is a pathological response to impact of arterial air bubbles on the brain, possibly the brainstem. The increased cerebral blood flow is probably the result of the increased cardiac output and dilation of cerebral resistance vessels caused by the passage of air bubbles.

Animals↗
PubMed2001

The anti-nociceptive efficacy of low dose intramuscular xylazine in lambs.

The anti-nociceptive effects of 50 microg kg(-1)of intramuscular xylazine were examined in seven lambs of 4-6 weeks of age using an electrical nociceptive testing method. Lamb anti-nociception increased from an average baseline of 5.88+/-0.72 mA to an average peak value of 13.66+/-1.49 mA at 21 minutes (mean+/-SEM) after the dose, and remained above baseline for the duration of the experimental period (60 minutes). All values were significantly above baseline from 5 minutes post-xylazine administration onwards. These data were also compared with previously published data from adult sheep undergoing the same treatment. There were no differences in the analgesic response between the adult or lamb groups suggesting xylazine dose requirements scale with bodyweight and are unaffected by age over this range. These findings support the use of xylazine as an effective analgesic in sheep with comparable effects and consistent dosing requirements per unit body weight between adult sheep and lambs.

Adrenergic alpha-Agonists↗
PubMed2001

Cardiovascular and haemodynamic effects of intramuscular doses of xylazine in conscious sheep.

OBJECTIVE: To determine if a commonly used analgesic dose of xylazine has detrimental cardiovascular or haemodynamic effects in sheep. DESIGN: A physiological study following intramuscular administration of xylazine. PROCEDURE: Xylazine (50 micrograms/kg) was injected intramuscularly into six healthy Merino ewes. For 60 min heart rate, mean arterial blood pressure and cardiac output were recorded; arterial blood samples for the measurement of blood gas tensions were also collected. RESULTS: There were no significant changes in heart rate, mean arterial blood pressure, cardiac output or arterial carbon dioxide tension. A slight degree of arterial hypoxaemia was noted with a 10% reduction in arterial oxygen tension values at 30 min. CONCLUSION: The minimal changes to cardiovascular and respiratory values in this study verify the safety of previously suggested analgesic dosing regimens for sheep. Previously reported hypoxaemic effects in sheep as a result of intravenous xylazine administration appear to be reduced as a result of intramuscular administration.

Adrenergic alpha-Agonists↗
PubMed2001

The cerebral and systemic kinetics of thiopentone and propofol in halothane anaesthetized sheep.

The cerebral and systemic kinetics of intravenous thiopentone (250 mg over 2 minutes, n=5) and propofol (100 mg over 2 minutes, n=6) were determined in sheep anaesthetized with halothane (2.0%) and mechanically ventilated to an end-expired carbon dioxide tension of 40 mmHg. The sheep were previously instrumented with arterial and sagittal sinus (effluent from the brain) blood sampling catheters. Systemic kinetics were inferred from the time-course of the arterial blood concentrations, and cerebral kinetics from the time-course of the arterio-sagittal sinus concentration difference across the brain. Under halothane anaesthesia, the peak arterial concentrations of each drug occurred at the end of the two-minute infusion, and was 42.3 mg/l and 12.3 mg/l for thiopentone and propofol, respectively. Propofol had a significantly larger systemic clearance (3.19 l/min) than thiopentone (0.99 l/min). The brain concentrations of propofol equilibrated more slowly with the arterial concentrations than those of thiopentone. The extraction ratio across the brain near the end of the infusions (1.5 min) were 0.85 and 0.46 respectively. These data were also compared to analogous previously published data for initially conscious sheep. The systemic kinetics of thiopentone were little affected by halothane anaesthesia. For propofol, halothane anaesthesia was associated with a statistically significant reduction in clearance (50% of awake), a slower initial half-life (247% of awake), and the emergence of a second slower half-life in some sheep. The cerebral kinetics of both drugs were subtly altered by halothane anaesthesia.

Anesthesia, Inhalation↗
PubMed2001

Acute cardiovascular effects of magnesium and their relationship to systemic and myocardial magnesium concentrations after short infusion in awake sheep.

The temporal relationship between the systemic and myocardial concentrations of magnesium and some of its acute cardiovascular effects were examined after short i.v. infusion administration of magnesium (30 mmol over 2 min) in five awake chronically instrumented sheep. Magnesium decreased mean arterial blood pressure and systemic vascular resistance (SVR) by 23 and 41% from baseline, respectively. These hemodynamic changes were consistent with magnesium producing primary reductions in SVR with partial heart rate (HR)-mediated compensation of blood pressure. Cardiac output and HR increased by 38 and 38% from baseline, respectively. Magnesium had little effect on myocardial contractility, but substantially increased myocardial blood flow (MBF, 77% above baseline) primarily due to direct myocardial vasodilation. The peak arterial and coronary sinus serum magnesium concentrations were 6.94 +/- 0.26 (mean +/- S.E.M.) and 6.51 +/- 0.20 mM, respectively, at 2 min. Both arterial and coronary sinus magnesium concentrations at the end of the study were still more than 3 mM, whereas all the cardiovascular effects were back to baseline. The myocardial kinetics of magnesium was consistent with rapid equilibration of magnesium (half-life 0.4 min) with a small distribution volume (71 ml) consistent with the extracellular space of the heart. In conclusion, magnesium was shown to have a rapid equilibration between the plasma/serum concentrations of magnesium and its extracellular concentration in the myocardium. However, the primary cardiovascular effect of magnesium (reductions in SVR) preceded its extracellular concentrations, and was a direct function of its arterial concentration. A "threshold" model for changes in SVR was preferred when linked to the arterial magnesium concentration.

Animals↗
PubMed2000

Relationships between steady state blood concentrations and cardiac output during intravenous infusions.

The blood concentration of a drug at steady state can be calculated from the ratio of infusion rate over the total body drug clearance. When the blood is assumed to be a homogenous pool, the clearance is not usually referenced to any particular site within the circulation. In contrast, in recirculating systems, the relative sites of an infusion, the lungs and organs of elimination, and dilution in the cardiac output, produce concentration gradients in the blood. Equations that describe the relationship between the steady state concentrations of a drug in arterial, pulmonary artery, mixed venous and eliminating organ (e.g. liver or kidney) blood and the intrinsic clearance of the drug in the lungs and the eliminating organ were derived analytically. The concentrations at all sites were shown to be cardiac output dependent with the following exceptions: (1) in arterial blood, when the drug is highly extracted by the lungs, and (2) in eliminating organ blood when there is no lung clearance of the drug. The arterial and pulmonary artery concentrations will be least affected by cardiac output in the absence of lung clearance, and if the intrinsic clearance in the eliminating organ is substantially less than cardiac output.

Blood Circulation↗
PubMed2000

In vivo manipulation and continuous measurement of muscle blood flow with venous effluent sampling.

1. An acute in vivo hindlimb skeletal muscle preparation was developed in anaesthetized sheep in order to facilitate studies of the effects of altered blood flow states on drug kinetics in skeletal muscle. 2. A continuous index of blood flow was recorded via ultrasonic Doppler probes on the femoral artery and vein. Skeletal muscle effluent blood was sampled via a catheter in the femoral vein proximal to the probe. Low- and high-blood flow states were achieved by direct femoral artery infusion of adrenaline (0.002-0.006 mg/min) or magnesium (0.4-1 mmol/min), which produced mean (+/-SD) stable flow states of 25+/-12 and 185+/-56% (both n = 5) of baseline, respectively. The correlation coefficients between arterial and venous Doppler frequency shifts in five sheep during and after adrenaline infusion were 0.96 (indicating these vessels probably supplied and drained common tissue). 3. The venous Doppler frequency shifts were calibrated against timed collections of the femoral vein outflow to provide estimates of the low and normal blood flow states (mean flows of 2.8+/-1.7 and 9.3+/-5.7mL/100 g per min; both n = 3) and against an indirect Kety-Schmidt method during low- and high-blood flow states (mean flows of 2.2+/-1.3 and 18.2+/-7.0 mL/100 g per min; both n = 5). There was a generally good agreement between the two methods. 4. The tissue was neither hypoxic nor acidotic in the low- or high-flow states and altering the flow produced no change in muscle oxygen consumption, suggesting the flow changes were largely due to changes in resistance vessel tone. 5. Postmortem femoral artery dye injection and dissection of stained tissues showed the artery supplied 657+/-96 g (n = 5) of skeletal muscle and 42+/-20 g (n = 5) of other tissues. 6. It is concluded that the method is suitable for sampling predominantly muscle effluent blood at low- or high-blood flow states according to experimental requirements.

Animals↗
PubMed2000

Skeletal muscle kinetics of propofol in anaesthetized sheep: effect of altered muscle blood flow.

1. The kinetics of propofol were studied in vivo in a skeletal muscle bed of the hindlimb of the anaesthetized sheep at normal and low rates of blood flow. 2. Propofol kinetics in muscle were determined during and after a 20-min i.v. infusion of propofol (10 mg min-1) via paired arteriofemoral venous blood sampling. One-and-a-half hours later, the study was repeated but with a concurrent left femoral artery infusion of adrenaline (0.004 mg min-1) to lower the muscle blood flow by vasoconstriction. 3. Muscle blood flow in the low flow state was 28% of that in the normal state. The kinetics were poorly described by a single flow-limited compartment model, but were better described by a model with a flow-limited component and a deeper distribution component. There were no significant differences in muscle retention of propofol between normal and low flow states. 4. There was an apparent arteriovenous shunt of approximately 24% of total muscle blood flow for the low flow state, but not for the normal blood flow state.

Adrenergic Agonists↗
PubMed2000

The effect of altered cerebral blood flow on the cerebral kinetics of thiopental and propofol in sheep.

BACKGROUND: Thiopental and propofol are highly lipid-soluble, and their entry into the brain often is assumed to be limited by cerebral blood flow rather than by a diffusion barrier. However, there is little direct experimental evidence for this assumption. METHODS: The cerebral kinetics of thiopental and propofol were examined over a range of cerebral blood flows using five and six chronically instrumented sheep, respectively. Using anesthesia (2.0% halothane), three steady state levels of cerebral blood flow (low, medium, and high) were achieved in random order by altering arterial carbon dioxide tension. For each flow state, 250 mg thiopental or 100 mg propofol was infused intravenously over 2 min. To quantify cerebral kinetics, arterial and sagittal sinus blood was sampled rapidly for 20 min from the start of the infusion, and 1.5 h was allowed between consecutive infusions. Various models of cerebral kinetics were examined for their ability to account for the data. RESULTS: The mean baseline cerebral blood flows for the "high" flow state were over threefold greater than those for the low. For the high-flow state the normalized arteriovenous concentration difference across the brain was smaller than for the low-flow state, for both drugs. The data were better described by a model with partial membrane limitation than those with only flow limitation or dispersion. CONCLUSIONS: The cerebral kinetics of thiopental and propofol after bolus injection were dependent on cerebral blood flow, despite partial diffusion limitation. Higher flows produce higher peak cerebral concentrations.

Anesthetics, Intravenous↗
PubMed2000

Development and validation of a recirculatory physiological model of the myocardial concentrations of lignocaine after intravenous administration in sheep.

A recirculatory physiological model of the determinants of the myocardial concentrations of lignocaine after intravenous administration was developed in sheep and validated with the intention of analysing and predicting the outcome of altered dose regimens and various pathophysiological states on the initial myocardial concentrations of lignocaine. The structure and parameters of the model were determined by hybrid modelling of the time-courses of the pulmonary artery, arterial and coronary sinus concentrations of lignocaine after the intravenous administration of 100 mg of lignocaine over 5 min to 5 chronically instrumented sheep. The model accounted for the determinants of the myocardial concentrations via compartments for venous mixing, the lung (a single-compartment model with a first-order loss) and the heart (a single flow-limited compartment). Recirculation and the remainder of the body were represented as a single tissue pool with a clearance term. The distribution volume of the heart was 0.42+/-0.009 L, which gave a half-time of myocardium:blood equilibration of 2.37 min. The distribution volume of the lungs was 5.40+/-0.23 L, with an apparent first-order loss of 1.02 L min(-1) representing deep distribution or metabolism. The validity of the model was tested by comparing the predictions of the model with the equivalent data collected in 6 sheep when lignocaine (89 mg) was administered via a complex dose regimen with a faster initial rate of infusion (39.1 mg min(-1)), declining exponentially to basal infusion rate (7.02 mg min(-1)) over 8 min. The predictions of the model were in general agreement with these data. It is concluded that the model was sufficient to account for the effect of altered dose regimens of lignocaine on the time-course of its myocardial concentrations.

Anesthetics, Local↗
PubMed1999

A compartmental analysis of the pharmacokinetics of propofol in sheep.

Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid i.v. administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after i.v. administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.

Anesthetics, Intravenous↗