David H. Klein

Dissolution of multicomponent microbubbles in the bloodstream: 1. theory

The problem of dissolution of a bubble in the bloodstream is examined. The bubble is assumed to be filled with a mixture of a sparingly water-soluble gas (osmotic agent) and air. The dissolution of the bubble has three definite stages. In Stage 1, the bubble quickly swells in air. The swelling ratio depends on the surface tension, blood pressure, level of oxygen metabolism and initial mole fraction of osmotic agent in the bubble. In Stage 2, the osmotic agent slowly diffuses out of the bubble. The squared radius decreases nearly linearly with time, at a rate proportional to the Ostwald coefficient and diffusivity of the osmotic agent. In Stage 3, the partial pressure of the osmotic agent becomes so high that it condenses into a liquid. In order to prolong the lifetime of 5-micron bubbles in the bloodstream from < 1 s (as found with pure air), the osmotic agent must have a low Ostwald coefficient (< or = 10(-4)) and a relatively high saturated vapor pressure at body temperature (> or = 0.3 atm = 3 x 10(4) Pa).

Dissolution of multicomponent microbubbles in the bloodstream: 2. experiment

The effect of the nature of the filling gas on the persistence of microbubbles in the bloodstream was studied. All the microbubbles were covered with the same shells. Various perfluorocarbons and perfluoropolyethers alone and as mixtures with nitrogen were used as the filling gases. The persistence time of microbubbles in the bloodstream tau increased with the molecular weight of the filling gas, from approximately 2 min for perfluorethane, to > 40 min for perfluorodiglyme, C6F14O3, and then decreased again to 8 min for C6F14O5. An acceptable ultrasound scattering efficacy was exhibited by the filling gases with intermediate molecular weights that possessed both a high saturated vapor pressure and a comparatively low water solubility (Ostwald coefficient). On the basis of the experimental data, it is concluded that the microbubble persistence tau is controlled primarily by the dissolution of microbubbles and not by the removal of the microbubbles by the reticular endothelial system. Although the qualitative experimental trends are in good agreement with the theoretical model developed previously, there are some quantitative differences. Possible reasons for these differences are discussed.

Influence of Perflubron Emulsion Particle Size on Blood Half-Life and Febrile Response in Rats

Perfluorochemical (PFC) emulsions are particulate in nature and, as such, can cause delayed febrile reactions when injected intravenously. This study investigated the influence of emulsion particle size on intravascular retention and on body temperature changes in unrestrained conscious rats. Concentrated (60% to 90% w/v) emulsions based on perflubron (perfluorooctyl bromide [PFOB]) with mean particle sizes ranging from 0.05 microns to 0.63 microns were tested. Rats were fitted with a chronic jugular catheter and an abdominal body temperature telemetry unit. Fully recovered, conscious rats were monitored for 24 hours after infusion (dose = 2.7 g PFC/kg). Emulsion blood half-life (T1/2) was determined from blood perflubron levels measured by gas chromatography. Emulsions with a particle size of 0.2-0.3 microns caused fevers (6 to 8 hour duration) which peaked at 1-1.5 degrees C above normal (approximately 37.5 degrees C). Fevers could be blocked by i.v. treatment with either cyclooxygenase inhibitors (ibuprofen) or corticosteroids (dexamethasone). Both intensity and duration of the temperature response, quantified by area under the temperature curve, was decreased significantly for emulsions with a particle size < or = 0.12 micron. Blood T1/2 varied inversely with particle size, and was 3 to 4 fold longer for emulsions with a mean particle size < or = 0.2 micron. Thus, smaller emulsion particles more effectively evaded the reticuloendothelial system, which resulted in longer intravascular retention, less macrophage activity, and reduced febrile responses.

Development of Highly Fluid, Concentrated and Stable Fluorocarbon Emulsions for Diagnosis and Therapy

A challenging aim in developing injectable fluorocarbon emulsions is to combine good flow characteristics (especially at low shear rates) with the high fluorocarbon concentration required for high oxygen delivery or effective contrast in imaging, long shelf life, and biological acceptability. A good balance of these sometimes conflicting objectives has been achieved with 90% w/v concentrated emulsions of various fluorocarbons, including the radiopaque oxygen carrier perfluorooctylbromide (PFOB, perflubron). The sterile emulsions have viscosities of about 20 cPs at a shear rate of 1 sec-1; the viscosity decreases rapidly with fluorocarbon concentration, and at 60% w/v the viscosity is less than that of human blood. The emulsions are suitable for injection as prepared, and are stable unfrozen for over a year.

Recent developments in pharmacokinetic modeling of perfluorocarbon emulsions.

Perfluorocarbon (PFC) emulsions are potential oxygen carriers. This study is to investigate pharmacokinetic compartment models and physiologically based models, which correlate the distribution of PFC emulsion in the blood, reticuloendothelial system (RES) tissues and non-RES tissues with the excretion data. The models are evaluated by nonlinear regression analysis (using PCNONLIN software) with expiration data from animal following an i.v. injection of a concentrated perflubron emulsion. One model with four compartments (representing PFC emulsion in blood, RES tissues, non-RES tissues, and PFC solubilized in blood) meets the mathematical and physical criteria. The physiological modeling provides insight of physiological mechanisms. The relationship between the compartment model parameters (rate constants) and physiological parameters (tissue volumes, flow rates, etc.) is presented. An advantage of physiological model is that prediction may be made in interspecies scaling. The above two kinds of modeling are useful in many applications, e.g. to describe and predict the time course of PFC disposition throughout the body.

Rheology of Concentrated Perfluorocarbon Emulsions

Oil-in-water emulsions conthing perfluomtylbromide (perflubron; PFOB) at up to about 50 vol.% and stabilized with egg yolk pbospbolipid (EYP) have been prepared and their rheology bas been studied. The emulsions are non-Newtonian, and their viscosities are strongly dependent on the volume fnction of pertlubron. as well as on pmcessing and formulation. Using a controlled-stress rbeometer with double-gap geometry, the viscosity at shear rates less hn 0. I sec-1 an be measured. Tbe viscoelastic properties of the emulsions have been explored using oscilhtion and stress-sweep techniques and an be used for the prediction of emulsion stability. MatPrbls and Metbods Pertluhn and naturnl egg yolk phospholipid were used as purchased without further purification. Bohlin CS (controlled-suess) rheMneter with C25 (concentric cylinder, 12ml sample) or DG (double gap, 30 ml sample) meauring geometry was used for dynamic (stress-sweep and oscillation) and smtic (viscosity, etc.) measurements. BrooWield dplate viscometer (Iml sample) was also used for routine viscosity measurements. Results and Discussion