First-pass Lung Uptake and Pulmonary Clearance of Propofol: Assessment with a Recirculatory Indocyanine Green Pharmacokinetic Model

Background: The principal site for elimination of propofol is the liver. The clearance of propofol exceeds hepatic blood flow; therefore, extrahepatic clearance is thought to contribute to its elimination. This study examined the pulmonary kinetics of propofol using part of an indocyanine green (ICG) recirculatory model.

Methods: Ten sheep, immobilized in a hammock, received injections of propofol (4 mg/kg) and ICG (25 mg) via two semipermanent catheters in the right internal jugular vein. Arterial blood samples were obtained from the carotid artery. The ICG injection was given for measurement of intravascular recirculatory parameters and determination of differences in propofol and ICG concentration-time profiles. No other medication was given during the experiment, and the sheep were not intubated. The arterial concentration-time curves of ICG were analyzed with a recirculatory model. The pulmonary uptake and elimination of propofol was analyzed with the central part of that model extended with a pulmonary tissue compartment allowing elimination from that compartment.

Results: During the experiment, cardiac output was 3.90 +/- 0.72 l/min (mean +/- SD). The blood volume in heart and lungs, measured with ICG, was 0.66 +/- 0.07 l. A pulmonary tissue compartment of 0.47 +/- 0.16 l was found for propofol. The pulmonary first-pass elimination of propofol was 1.14 +/- 0.23 l/min. Thirty percent of the dose was eliminated during the first pass through the lungs.     

Formulation-dependent Brain and Lung Distribution Kinetics of Propofol in Rats

Background: Propofol when administered by brief infusion in a lipid-free formulation has a slower onset, prolonged offset and greater potency compared with an emulsion formulation. To understand these findings the authors examined propofol brain and lung distribution kinetics in rats.

Methods: Rats were infused with equieffective doses of propofol in emulsion (n = 21) or lipid-free formulation (n = 21). Animals were sacrificed at various times to harvest brain and lung. Arterial blood was sampled repeatedly from each animal until sacrifice. Deconvolution and moment analysis were used to calculate the half-life for propofol brain turnover (BT) and brain:plasma partition coefficient (Kp). Lung concentration-time profiles were compared for the two formulations.

Results: Peak propofol plasma concentrations for the lipid-free formulation were 50% of that observed for emulsion formulation, whereas peak lung concentrations for lipid-free formulation were 300-fold higher than emulsion formulation. Brain Kp calculated from tissue disposition curve and ratio of brain:plasma area under the curves were 8.8 and 13, and 7.2 and 9.1 for emulsion and lipid-free formulations, respectively. BT were 2.4 and 2.5 min for emulsion and lipid-free formulations, respectively.     

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.     

A Bistable Field Model of Cancer Dynamics

Cancer spread is a dynamical process occurring not only in time but also in space which, for solid tumors at least, can be modeled quantitatively by reaction and diffusion equations with a bistable behavior: tumor cell colonization happens in a portion of tissue and propagates, but in some cases the process is stopped. Such a cancer proliferation/extinction dynamics is obtained in many mathematical models as a limit of complicated interacting biological fields. In this article we present a very basic model of cancer proliferation adopting the bistable equation for a single tumor cell dynamics. The reaction-diffusion theory is numerically and analytically studied and then extended in order to take into account dispersal effects in cancer progression in analogy with ecological models based on the porous medium equation. Possible implications of this approach for explanation and prediction of tumor development on the lines of existing studies on brain cancer progression are discussed. The potential role of continuum models in connecting the two predominant interpretative theories about cancer, once formalized in appropriate mathematical terms, is discussed.     

A Model of Ultrafiltration and Glucose Mass Transfer Kinetics in Peritoneal Dialysis

We have investigated the variation with dwell time of dialysate volume and glucose concentration during continuous ambulatory peritoneal dialysis using a one-pool model. No assumption was made regarding the ultrafiltration rate that was calculated by the model. Results show that the volume ultrafiltered during dwell time is an increasing function of peritoneal membrane hydraulic permeability and a decreasing function of glucose mass transfer coefficient (MTC). For large MTC and low initial glucose concentration there is reabsorption of dialysate into the blood at large dwell times. For a 6 h dwell time, glycerol (92 daltons) is a more effective osmotic agent than glucose (198 daltons) at the same weight concentration. These results are in quantitative agreement with published clinical studies.     

Propofol, bradycardia and the Bezold-Jarisch reflex in rabbits

Propofol may cause profound bradycardia and asystole, which are mediated indirectly via cardiac innervation but could involve direct effects on the sino-atrial (SA) node and the conducting system of the heart. To test the hypothesis that propofol may also activate Bezold- Jarisch reflexes to cause bradycardia, 5-hydroxytryptamine (5-HT), veratridine and propofol were injected into the left ventricle of the heart in both intact and vagotomized rabbits. 5-HT and veratridine produced an acute, rapid, dose-dependent decrease in mean heart rate (delta HR) and a decrease in mean arterial pressure (delta MAP) together with transient but severe depression and abolition of renal sympathetic nerve activity (RSNA). Bilateral vagotomy greatly attenuated these responses; for example, at the highest dose of 5-HT (8 micrograms kg-1), delta HR, delta MAP and duration of abolition of RSNA were reduced by 57% (P < 0.001), 53% (P < 0.05) and 79% (P < 0.05), respectively. In contrast, reductions in delta HR and delta MAP produced by propofol were statistically significant only at very high doses (8 mg kg-1). Propofol depressed but did not abolish RSNA, and bilateral vagotomy had no effect on any of these responses. These results indicate that the cause of acute bradycardia after administration of propofol does not involve the Bezold-Jarisch reflex.      

Recirculatory and compartmental pharmacokinetic modeling of alfentanil in pigs: the influence of cardiac output

BACKGROUND: Cardiac output (CO) is likely to influence the pharmacokinetics of anesthetic drugs and should be accounted for in pharmacokinetic models. The influence of CO on the pharmacokinetic parameters of alfentanil in pigs was evaluated using compartmental and recirculatory models. METHODS: Twenty-four premedicated pigs were evaluated during halothane (0.6-2%) anesthesia. They were assigned randomly to one of three groups. One group served as control. In the other groups, the baseline CO was decreased or increased by 40% by pharmacologic intervention (propranolol or dobutamine). Boluses of alfentanil (2 mg) and indocyanine green (25 mg) were injected into the right atrium. Blood samples were taken for 150 min from the right atrium and aortic root. Arterial concentration-time curves of indocyanine green and alfentanil were analyzed using compartmental models (two-stage and mixed-effects approach) and a recirculatory model, which can describe lung uptake and early distribution. RESULTS: The CO of individual pigs varied from 1.33 to 6.44 l/min. Three-compartmental modeling showed that CO is a determinant of the central compartment volume (V1, r2 = 0.54), fast peripheral compartment volume (V2, r2 = 0.29), steady state distribution volume (Vss, r2 = 0.29), fast distribution clearance (Cl12, r2 = 0.39), and elimination clearance (Cl10, r2 = 0.51). Recirculatory modeling showed that CO is a determinant of total distribution volume (r2 = 0.48), elimination clearance (r2 = 0.54), and some distribution clearances. The pulmonary distribution volume was independent of CO. CONCLUSIONS: Cardiac output markedly influences the pharmacokinetics of alfentanil in pigs. Therefore, accounting for CO enhances the predictive value of pharmacokinetic models of alfentanil.     

Kinetics and Extravascular Retention of Acetated Ringer's Solution during Isoflurane or Propofol Anesthesia for Thyroid Surgery

Background: In sheep, isoflurane causes extravascular accumulation of infused crystalloid fluid. The current study evaluates whether isoflurane has a greater tendency than propofol to cause extravascular retention in surgical patients.

Methods: Thirty patients undergoing thyroid surgery lasting for 143 +/- 32 min (mean +/- SD) received an intravenous infusion of 25 ml/kg acetated Ringer's solution over 30 min. Anesthesia was randomized to consist of isoflurane or propofol supplemented by fentanyl. The distribution and elimination of the infused fluid was estimated using volume kinetics based on the fractional dilution of blood hemoglobin over 150 min. Extravascular retention of infused fluid was taken as the difference between the model-predicted elimination and the urinary excretion. The sodium and fluid balances were measured.

Results: The fractional plasma dilution increased gradually to approximately 30% during the infusion and thereafter remained at 15-20%. Urinary excretion averaged 11% of the infused volume. Mean arterial pressure was 10 mmHg lower in the isoflurane group (P < 0.001). The excess fluid volumes in the central and peripheral functional body fluid spaces were virtually identical in the groups. The sum of water losses by evaporation and extravascular fluid retention amounted to 2.0 +/- 2.5 ml/min for isoflurane and 2.2 +/- 2.1 ml/min for propofol. The sodium balance refuted that major fluid shifts occurred between the extracellular and intracellular spaces.     

Changes in the Auditory Evoked Potentials and the Bispectral Index following Propofol or Propofol and Alfentanil

Background: Midlatency auditory evoked potentials (MLAEP) show graded changes with increasing doses of hypnotics but little change with opioids. The effect of their combination on the MLAEP was evaluated. Also, the bispectral index (BIS) was compared with the ability of MLAEP to correlate with sedation and predict loss of consciousness.

Methods: Twenty healthy volunteers were randomly assigned to receive stepped increases in propofol concentration (10 subjects) or propofol plus alfentanil 100 ng/ml (10 subjects). At baseline and at each targeted effect site concentration the mean MLAEP, BIS, measures of sedation, and drug concentration were obtained. The relation among MLAEP, BIS, and sedation score was determined. The prediction probability (Pk) was calculated and compared for BIS and MLAEP.

Results: The BIS and MLAEP patterns showed significant changes (Pa and Nb decreased in amplitude and increased in latency) with increasing level of sedation (P < 0.0001). The BIS correlated better with sedation scores (0.884) than did the MLAEP (P < 0.05). Pa and Nb latencies showed the best correlation with sedation levels (0.685 and 0.658, respectively). The addition of alfentanil did not affect the relation between MLAEP and loss of consciousness (P > 0.15). The BIS (Pk = 0.952) was a better predictor of loss of consciousness than were Pa and Nb amplitude (P < 0.05) but were comparable to Pa and Nb latency (Pk = 0.869 and 0.873, respectively).     

A Population Model to Describe the Distribution and Seasonal Dynamics of the Tick Hyalomma marginatum in the Mediterranean Basin

A dynamic population model of Hyalomma marginatum, the vector of several pathogens in the western Palearctic, was developed to simulate effects of temperature and water vapour deficit (VD) on tick survival, development rates and seasonality. Base tick survival and development rates were obtained from laboratory‐controlled experiments or calculated from reported data. These rates were modelled as temperature‐dependant time delays or accumulated mortality by temperature and water VD stress. Using daily data derived from a gridded data set at 10‐min resolution, the model reached stable and cyclical equilibria in an area that corresponds largely with the reported distribution of the tick in western Palearctic. The model did not identify a potential range of suitable climate for the tick out of the known distribution area, implying that under current climate conditions, there is no potential to spread at the spatial scale of the model. Tick die‐out at northern latitudes was attributed to a steady increase in duration of the development rates of engorged nymphs to adults and hence increased mortality in this stage. Low developmental rates in northern latitudes produced the accumulation of most of the nymphal stock in late summer and early autumn, which cannot moult to adults because of the low temperatures of late autumn and winter. The tick did not produced self‐sustained populations in areas where yearly accumulated temperatures were below 3000–4000°C, a limit roughly found at latitudes north of 47ºN. Tick die‐out in sites southern to 34ºN was attributed to the mortality rates of engorged nymphs, which moult in late spring and summer, in the season where temperatures and water vapour stresses were highest. These findings and future applications of the model in investigating the dynamics of pathogens potentially transmitted by H. marginatum are discussed.     

Recirculatory and Compartmental Pharmacokinetic Modeling of Alfentanil in Pigs: The Influence of Cardiac Output

Background: Cardiac output (CO) is likely to influence the pharmacokinetics of anesthetic drugs and should be accounted for in pharmacokinetic models. The influence of CO on the pharmacokinetic parameters of alfentanil in pigs was evaluated using compartmental and recirculatory models.

Methods: Twenty-four premedicated pigs were evaluated during halothane (0.6-2%) anesthesia. They were assigned randomly to one of three groups. One group served as control. In the other groups, the baseline CO was decreased or increased by 40% by pharmacologic intervention (propranolol or dobutamine). Boluses of alfentanil (2 mg) and indocyanine green (25 mg) were injected into the right atrium. Blood samples were taken for 150 min from the right atrium and aortic root. Arterial concentration-time curves of indocyanine green and alfentanil were analyzed using compartmental models (two-stage and mixed-effects approach) and a recirculatory model, which can describe lung uptake and early distribution.

Results: The CO of individual pigs varied from 1.33 to 6.44 l/min. Three-compartmental modeling showed that CO is a determinant of the central compartment volume (V1, r2 = 0.54), fast peripheral compartment volume (V2, r2 = 0.29), steady state distribution volume (Vss, r2 = 0.29), fast distribution clearance (Cl12, r2 = 0.39), and elimination clearance (Cl10, r2 = 0.51). Recirculatory modeling showed that CO is a determinant of total distribution volume (r2 = 0.48), elimination clearance (r2 = 0.54), and some distribution clearances. The pulmonary distribution volume was independent of CO.     

Refining the Model of Urea Kinetics: Compartment Effects

A 70-year-old female with chronic congestive heart failure requires maintenance hemodialysis because of end-stage diabetic nephropathy. She is dialyzed on Monday, Wednesday, and Friday for 2 hours using a dialyzer with an average urea clearance of 250 ml/min. Dry weight is 50 kg. Predialysis blood urea nitrogen (BUN) on Wednesday is 50 mg/dl; postdialysis BUN is 15 mg/dl. A single-compartment, variable-volume model of urea kinetics revealed the following: 1.5 hours of dialysis are sufficient to maintain Kt/V at 1.1/dialysis; protein catabolism is 0.92 g/kg/day; her volume of urea distribution is 43% of body weight. Provided the blood access device and dialysis equipment are functioning properly and the blood specimens are drawn and measured correctly, are the model predictions valid?