Guy L. Ludbrook

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.

Are systemic emboli reduced in computer-assisted knee surgery? A PROSPECTIVE, RANDOMISED, CLINICAL TRIAL

We undertook a prospective, randomised study using a non-invasive transcranial Doppler device to evaluate cranial embolisation in computer-assisted navigated total knee arthroplasty (n = 14) and compared this with a standard conventional surgical technique using intramedullary alignment guides (n = 10). All patients were selected randomly without the knowledge of the patient, anaesthetists (before the onset of the procedure) and ward staff. The operations were performed by a single surgeon at one hospital using a uniform surgical approach, instrumentation, technique and release sequence. The only variable in the two groups of patients was the use of single tracker pins of the imageless navigation system in the tibia and femur of the navigated group and intramedullary femoral and tibial alignment jigs in the non-navigated group. Acetabular Doppler signals were obtained in 14 patients in the computer-assisted group and nine (90%) in the conventional group, in whom high-intensity signals were detected in seven computer-assisted patients (50%) and in all of the non-navigated patients. In the computer-assisted group no patient had more than two detectable emboli, with a mean of 0.64 (SD 0.74). In the non-navigated group the number of emboli ranged from one to 43 and six patients had more than two detectable emboli, with a mean of 10.7 (sd 13.5). The difference between the two groups was highly significant using the Wilcoxon non-parametric test (p = 0.0003).Our findings show that computer-assisted total knee arthroplasty, when compared with conventional jig-based surgery, significantly reduces systemic emboli as detected by transcranial Doppler ultrasonography.

Propofol: relation between brain concentrations, electroencephalogram, middle cerebral artery blood flow velocity, and cerebral oxygen extraction during induction of anesthesia.

Background The potential benefit of propofol dose regimens that use physiologic pharmacokinetic modeling to target the brain has been demonstrated in animals, but no data are available on the rate of propofol distribution to the brain in humans. This study measured the brain uptake of propofol in humans and the simultaneous effects on electroencephalography, cerebral blood flow velocity (Vmca), and cerebral oxygen extraction. Methods Seven subjects had arterial and jugular bulb catheters placed before induction. Electroencephalography and Vmca were recorded during induction with propofol while blood samples were taken from both catheters for later propofol analysis. Brain uptake of propofol was calculated using mass balance principles, with effect compartment modeling used to quantitate the rate of uptake. Results Bispectral index (electroencephalogram) values decreased to a minimum value of approximately 4 at around 7 min from the onset of propofol administration and then slowly recovered. This was accompanied by decreases in Vmca, reaching a minimum value of approximately 40% of baseline. Cerebral oxygen extraction did not change, suggesting parallel changes in cerebral metabolism. There was slow equilibrium of propofol between the blood and the brain (t1/2keo of 6.5 min), with a close relation between brain concentrations and bispectral index, although with considerable interpatient variability. The majority of the decreases in Vmca, and presumably cerebral metabolism, corresponded with bispectral index values reaching 40–50 and the onset of burst suppression. Conclusion Description of brain distribution of propofol will allow development of physiologic pharmacokinetic models for propofol and evaluation of dose regimens that target the brain.

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.

A Physiologically Based, Recirculatory Model of the Kinetics and Dynamics of Propofol in Man

Background:The disposition of propofol in man is commonly described using a three-compartment mamillary model. However, these models do not incorporate blood flows as parameters. This complicates the representation of the changes in blood flows that may occur in surgical patients. In contrast, complex physiologically based models are derived from data sets (e.g., tissue:blood partition coefficients) that may not be readily collected in man. Methods:Alternatively, the authors report a recirculatory model of propofol disposition in a “standard” man that incorporates detailed descriptions of the lungs and brain, but with a lumped description of the remainder of the body. The model was parameterized from data in the literature using a “meta-modeling” approach. The first-pass passage of propofol through the venous vasculature and the lungs was a function of the injected drug mixing with cardiac output and passing through a three-“tank in series” model for the lungs. The brain was represented as a two-compartment model defined by cerebral blood flow and a permeability term. The Bispectral Index was a linear function of the mean brain concentration. The remainder of the body was represented by compartment systems for the liver, fast distribution and slow distribution. Results:The model was a good fit of the data and was able to predict other data not used in the development of the model. Conclusions:The model may ultimately find a role in improving the fidelity of patient simulators currently used to train anesthetists and for clinical practice simulation to optimize dosing and management strategies.

Humidified gas prevents hypothermia induced by laparoscopic insufflation : A randomized controlled study in a pig model

AbstractBackground: This experimental study evaluated whether humidification of warmed insufflated CO2 during laparoscopic procedures would resolve the problem of laparoscopy-induced hypothermia. Methods: Changes in core temperature were quantified over a 3-h period of high-flow CO2 insufflation in a randomized, controlled trial of five pigs. Each animal was anesthetized and studied on three occasions under standardized conditions, acting as its own control by insufflation with no gas compared with insufflation by cool dry gas and heated humidified gas. Results: Core temperatures after insufflation with heated humidified gas were no different from that of controls. After insufflation with cool dry gas, core temperature dropped by 1.8°C, which was significantly more than the 0.6°C drop experienced by control animals and those insufflated with heated humidified gas (p < 0.01). Calculations of the heat expended in evaporation of water were also performed. The temperature drop due to water evaporation alone in pigs insufflated with cool dry gas was calculated to be 1.5°C. This compares favorably with the measured 1.2°C temperature difference between these animals and the control group. Conclusions: The majority of heat lost during laparoscopic insufflation is due to water evaporation, and laparoscopic hypothermia may be prevented by using heated and humidified gas insufflation.

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.

Crisis management during anaesthesia: bronchospasm

Background: Bronchospasm in association with anaesthesia may appear as an entity in its own right or be a component of another problem such as anaphylaxis. It may present with expiratory wheeze, prolonged exhalation or, in severe cases, complete silence on auscultation. Objectives: To examine the role of a previously described core algorithm “COVER ABCD–A SWIFT CHECK”, supplemented by a specific sub-algorithm for bronchospasm, in the diagnosis and management of bronchospasm occurring in association with anaesthesia. Methods: The potential performance of this structured approach for each of the relevant incidents among the first 4000 reported to the Australian Incident Monitoring Study (AIMS) was compared with the actual management as reported by anaesthetists involved. Results: There were 103 relevant incidents among the first 4000 AIMS reports, 22 of which were associated with allergy or anaphylaxis. Common presenting signs, in addition to wheeze, were decreased pulmonary compliance and falling oxygen saturation. Of the non-allergy/anaphylaxis related incidents, 80% occurred during induction or maintenance of anaesthesia. Of these, the principal causes of bronchospasm were airway irritation (35%), problems with the endotracheal tube (23%), and aspiration of gastric contents (14%). It was considered that, properly used, the structured approach recommended would have led to earlier recognition and/or better management of the problem in 10% of cases, and would not have harmed any patient had it been applied in all of them. Conclusion: Bronchospasm may present in a variety of ways and may be associated with other life threatening conditions. Although most cases are handled appropriately by the attending anaesthetist, the use of a structured approach to its diagnosis and management would lead to earlier recognition and/or better management in 10% of cases.

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.

The pharmacokinetics and pharmacodynamics of liposome bupivacaine administered via a single epidural injection to healthy volunteers

Background and Objectives The objective of this study was to assess the pharmacokinetics, sensory/motor effects, and safety of epidurally administered liposome bupivacaine versus bupivacaine HCl in healthy volunteers. Methods Thirty subjects were randomized to receive liposome bupivacaine 89, 155, or 266 mg, or bupivacaine HCl 50 mg in a double-blind fashion. Occurrence/duration of motor blockade, pinprick/cold sensitivity, and plasma bupivacaine levels were assessed for 96 hours after study drug administration. Tolerability parameters were also assessed. Results All doses of liposome bupivacaine resulted in greater area under the curve and a longer time to observed maximum plasma concentration and terminal elimination half-life than bupivacaine HCl 50 mg. Mean maximum plasma concentration with liposome bupivacaine 89 and 155 mg (but not 266 mg) was statistically significantly lower than with bupivacaine HCl 50 mg (P < 0.001). Median duration of motor blockade with liposome bupivacaine 266 mg was 1 hour versus 2.8 hours for bupivacaine HCl. Of subjects who received liposome bupivacaine 266 mg, 29% (2/7) were unable to ambulate at 4 hours postdose versus 67% (4/6) of those receiving bupivacaine HCl. Median durations of pinprick/cold sensitivity loss were 36 and 69 hours, respectively, in the liposome bupivacaine 266-mg group versus 12 hours for both pinprick and cold in the bupivacaine HCl group. Liposome bupivacaine was well tolerated; the most common adverse event in all treatment groups was injection site pain, which resolved within 30 days for most subjects. Conclusions Epidurally administered liposome bupivacaine 266 mg resulted in a longer duration of sensory blockade than liposome bupivacaine 89 or 155 mg or bupivacaine HCl 50 mg. Duration of motor blockade was shorter with liposome bupivacaine 266 mg versus bupivacaine HCl.