Cliff Grant

Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration.

UNLABELLED Indicator dilution theory predicts that the first-pass pulmonary and systemic arterial concentrations of a drug will be inversely related to the cardiac output. For high-clearance drugs, these first-pass concentrations may contribute significantly to the measured arterial concentrations, which would therefore also be inversely related to cardiac output. We examined the cardiac output dependence of the initial kinetics of propofol in two separate studies using chronically instrumented sheep in which propofol (100 mg) was infused IV over 2 min. In the first study, steady-state periods of low, medium, and high cardiac output were achieved by altering carbon dioxide tension in six halothane-anesthetized sheep. The initial area under the curve and peak value of the pulmonary artery propofol concentrations were inversely related to cardiac output (R2 = 0.57 and 0.66, respectively). For the systemic arterial concentrations, these R2 values were 0.68 and 0.71, respectively. In our second study, transient reductions in cardiac output were achieved in five conscious sheep by administering a short infusion of metaraminol concurrently with propofol. Cardiac output was lowered by 2.2 L/min, and the area under the curve to 10 min of the arterial concentrations increased to 143% of control. IMPLICATIONS The initial arterial concentrations of propofol after IV administration were shown to be inversely related to cardiac output. This implies that cardiac output may be a determinant of the induction of anesthesia with propofol.

Cortical entropy changes with general anaesthesia: theory and experiment

Commonly used general anaesthetics cause a decrease in the spectral entropy of the electroencephalogram as the patient transits from the conscious to the unconscious state. Although the spectral entropy is a configurational entropy, it is plausible that the spectral entropy may be acting as a reliable indicator of real changes in cortical neuronal interactions. Using a mean field theory, the activity of the cerebral cortex may be modelled as fluctuations in mean soma potential around equilibrium states. In the adiabatic limit, the stochastic differential equations take the form of an Ornstein-Uhlenbeck process. It can be shown that spectral entropy is a logarithmic measure of the rate of synaptic interaction. This model predicts that the spectral entropy should decrease abruptly from values approximately 1.0 to values of approximately 0.7 as the patient becomes unconscious during induction of general anaesthesia, and then not decrease significantly on further deepening of anaesthesia. These predictions were compared with experimental results in which electrocorticograms and brain concentrations of propofol were recorded in seven sheep during induction of anaesthesia with intravenous propofol. The observed changes in spectral entropy agreed with the theoretical predictions. We conclude that spectral entropy may be a sensitive monitor of the consciousness-unconsciousness transition, rather than a progressive indicator of anaesthetic drug effect.

An Ultrasonic Doppler Venous Outflow Method for the Continuous Measurement of Cerebral Blood Flow in Conscious Sheep

A pulsed ultrasonic Doppler venous outflow method was developed for the continuous measurement of global cerebral blood flow (CBF) in conscious sheep. The sheep were prepared under anesthesia with a “suture down”-style ultrasonic flow probe on the dorsal sagittal sinus placed via a trephine hole. Angiographic and dye studies showed that the dorsal sagittal sinus at the point of placement of the probe collected the majority of the blood from the cerebral hemispheres. Studies of the blood velocity profile across the sinus showed that the dimensions of the dorsal sagittal sinus changed minimally with changes in CBF in vivo. The velocity measurements were calibrated under anesthesia against an in vivo direct venous outflow method. Control CBF values for six sheep ranged from 31 to 53 ml/min for the area of brain described above; for two sheep in which the weight of the brain was determined, this gave total CBF values of approximately 34 and 30 ml min−1 100 g−1. The CBF measured varied in the expected manner with changes in the end-tidal CO2 concentration in expired breath and showed transient reductions with the barbiturate thiopentone and transient increases with the opiate alfentanil. It is concluded that the method is simple and accurate.

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

BackgroundThiopental 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. MethodsThe 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. ResultsThe 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. ConclusionsThe 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.

A Comparison of the Effects of Norepinephrine, Epinephrine, and Dopamine on Cerebral Blood Flow and Oxygen Utilisation

The concomitant effects of infusions of catecholamines on cerebral blood flow (CBF), intracranial pressure (ICP), arterio-venous oxygen content difference (AVDO2), and cerebral oxygen utilization (COU) were prospectively studied in an intact cerebral autoregulatory model. Epinephrine, norepinephrine and dopamine were infused at doses used in clinical practice in awake, chronically catheterized sheep (n = 5). Mean arterial pressure (MAP), CBF and ICP were measured continuously, COU was expressed as delta CBF x AVDO2. All 3 drugs significantly increased MAP in a dose dependent manner. Norepinephrine and epinephrine had no significant effects on ICP, CBF, AVDO2 or COU at infusions of 0-60 micrograms/min. Infusions of dopamine from 0-60 micrograms/kg/min resulted in statistically significant increases in ICP (+34.5 +/- 3.7 to +97.2 +/- 6.8) and CBF (+13.3 +/- 3.2 to +52.6 +/- 24.3) (% change baseline +/- SEM, 95% CI, ANOVA), reduction in AVDO2 (3.54 +/- 0.2. to 2.69 +/- 0.2 mg%) and a biphasic response in COU. In the intact physiological model, induced hypertension by epinephrine and norepinephrine is not associated with global changes in CBF, ICP or COU which remain constant. At equivalent doses, dopamine causes cerebral hyperaemia, increased ICP and increased global cerebral oxygen utilization.

Cerebral cortical effects of desflurane in sheep: comparison with isoflurane, sevoflurane and enflurane.

Background:  Different volatile anesthetic agents have differing propensities for inducing seizures. A measure of the predilection to develop seizures is the presence of interictal spike discharges (spikes) on the electrocorticogram (ECoG). In this study, we investigated the propensity of desflurane to induce cortical spikes and made a direct objective comparison with enflurane, isoflurane, and sevoflurane. The ECoG effects of desflurane have not been previously reported.

The Influence of the Bolus Injection Rate of Propofol on Its Cardiovascular Effects and Peak Blood Concentrations in Sheep

The influence of the bolus injection rate of propofol on its cardiovascular effects has not been extensively studied.We therefore examined the influence of the injection rate of IV bolus doses of propofol on its acute cardiovascular effects and peak blood concentrations in seven chronically instrumented sheep. Each received IV propofol (200 mg) over 2 min (slow injection) and 0.5 min (rapid injection) on separate occasions in random order. The rapid injection was associated with more profound decreases in mean arterial blood pressure than slow injection (35.7% vs 23.7% maximal reductions from baseline, respectively; P = 0.02). There were no significant differences between the injection rates for peak reductions in myocardial contractility, increases in heart rate, or degree of respiratory depression. Concurrently, the rapid injections were associated with significantly higher arterial (26.9 vs 11.9 mg/L) propofol concentrations in a manner consistent with indicator dilution principles. There were no differences in the peak coronary sinus concentrations between the injection rates. We conclude that the rapid injection of propofol in the context of the induction of anesthesia produced significantly higher peak arterial propofol concentrations and suggest that it is these higher concentrations that produced relatively greater reductions in arterial blood pressure from rapid injections. Implications: Propofol is injected into a vein to initiate anesthesia. It can cause a rapid decrease in blood pressure, which may be dangerous to the patient. We examined the effect of rapid and slow injection rates of propofol in sheep and found that rapid injection caused a greater decrease in blood pressure. This was because rapid injection caused higher concentrations of propofol in the blood immediately after the injection. We believe that if the same processes occur in humans, there may be little advantage in injecting propofol rapidly. (Anesth Analg 1998;86:1109-15)

The effect of rate of administration on brain concentrations of propofol in sheep.

A marked reduction in the dose of propofol required to achieve the onset of anesthesia with slower administration rates has previously been reported, but the mechanism of this phenomenon is unclear.We used a chronically instrumented sheep preparation to examine the effects of different administration rates of propofol on its distribution in the brain using mass balance principles to calculate brain concentrations. The administration of 100 mg of propofol IV at rates of 200, 50, and 20 mg/min had minimal effect on both the peak brain concentrations of propofol and the total amount of drug entering the brain. The more rapid administration rates increased the rate of uptake into the brain but resulted in large increases in peak arterial blood propofol concentrations. These faster administration rates have previously been associated with high arterial propofol concentrations and an increased risk of hypotension. Simulation of titration to an end point revealed that the dose sparing previously reported at induction with slow administration rates relates only to improved titration to effect, and does not result in more anesthesia for a given dose. Therefore, we conclude that the administration of propofol over 2 min provides a reasonable rate of induction and improved titration to effect, yet avoids excessively high arterial concentrations. Implications: Alterations in the rate of administration of propofol in sheep have been shown to have little effect on the quantity of propofol delivered to the brain. At induction of anesthesia, administration rates of approximately 50 mg/min seem likely to provide improved titration to effect without excessively prolonging induction. (Anesth Analg 1998;86:1301-6)

A method for frequent measurement of sedation and analgesia in sheep using the response to a ramped electrical stimulus.

A method for the frequent, precise measurement of the analgesic and sedative (or anesthetic) effects of drugs after bolus administration to sheep was developed. A ramped pulsed DC electrical stimulus was delivered to the hind limb of sheep via subcutaneous needles by use of a peripheral nerve stimulator modified to allow control of current ramp rate and pulse frequency, and limb withdrawal was used as an endpoint. The optimal stimulus pattern was found to be a pulse frequency of 20 Hz, with a 5-sec ramp time and measurement intervals of 30 sec. The effects of a range of analgesic and sedative drugs on the threshold current to produce limb withdrawal were examined. Administration of the sedative/anesthetic drugs propofol and thiopentone intravenously and of the analgesic xylazine both intravenously and intramuscularly resulted in a reproducible dose-dependent rise in the threshold current required to produce limb withdrawal. Administration of the opioids alfentanil and pethidine produced agitation, making measurements unreliable. It is concluded that this device allows repeated reproducible measurements of analgesia and sedation to be made in sheep at a frequency sufficient to characterize the initial effects of analgesic and sedative drugs, particularly after intravenous administration.

Diffusion-limited, but not perfusion-limited, compartmental models describe cerebral nitrous oxide kinetics at high and low cerebral blood flows.

This study aimed to evaluate the relative importance of diffusion-limited vs. perfusion-limited mechanisms in compartmental models of blood–tissue inert gas exchange in the brain. Nitrous oxide concentrations in arterial and brain efferent blood were determined using gas chromatographic analysis during and after 15 min of nitrous oxide inhalation, at separate low and high steady states of cerebral blood flow (CBF) in five sheep under halothane anesthesia. Parameters and model selection criteria of various perfusion- or diffusion-limited structural models of the brain were estimated by simultaneous fitting of the models to the mean observed brain effluent nitrous oxide concentration for both blood flow states. Perfusion-limited models returned precise, credible estimates of apparent brain volume but fit the low CBF data poorly. Diffusion-limited models provided better overall fit of the data, which was best described by exchange of nitrous oxide between a perfusion-limited brain compartment and an unperfused compartment. In individual animals, during the low CBF state, nitrous oxide kinetics displayed either fast, perfusion-limited behavior or slow, diffusion-limited behavior. This variability was exemplified in the different parameter estimates of the diffusion limited models fitted to the individual animal data sets. Results suggest that a diffusion limitation contributes to cerebral nitrous oxide kinetics.