We investigated the nonlinear dynamics of the pressure vs. hydraulic conductivity (L(p)) relationship in lung microvascular endothelial cells and demonstrate that heparan sulfates, an important component of the endothelial glycocalyx, participate in pressure-sensitive mechanotransduction that results in barrier dysfunction. The pressure vs. L(p) relationship was complex, possessing both time- and pressure-dependent components. Pretreatment of lung capillary endothelial cells with heparanase III completely abolished the pressure-induced increase in L(p). This extends our (7) previous observation regarding heparan sulfates as mechanotransducers for shear stress. Inhibition of nitric oxide (NO) synthase with L-NAME (N(G)-nitro-L-arginine methyl ester HCl) and intracellular scavenging of reactive oxygen species (ROS) by TBAP [tetrakis-(4-benzoic acid) porphorin] significantly attenuated the pressure-induced L(p) response. Intracellular NO/ROS were visualized using the fluorescent dye, 2'7'-dichlorofluorescein diacetate (DCFA), and cells demonstrated a pressure-induced increase in intracellular fluorescence. Heparanase pretreatment significantly reduced the pressure-induced increase in intracellular fluorescence, suggesting that cell-surface heparan sulfates directly participate in mechanotransduction that results in NO/ROS production and increased permeability. This is the first report to demonstrate a role for heparan sulfates in pressure-mediated mechanotransduction and barrier regulation. These observations may have important clinical implications during conditions where pulmonary microvascular pressure is elevated.

Hemorrhagic shock produced minimal changes in the pharmacokinetics and no change in the pharmacodynamics of etomidate in swine. These results suggest that, unlike other sedative hypnotics and opioids, minimal adjustment in the dose of etomidate is required to achieve the same drug effect during hemorrhagic shock.

Hypercapnia, along with hyperventilation, may be used clinically to decrease emergence time from inhaled anesthesia. These time savings might reduce drug costs. In addition, higher PAco2 during emergence may enhance respiratory drive and airway protection after tracheal extubation.

No abstract

Hemorrhagic shock followed by resuscitation with lactated Ringer's solution did not alter the pharmacokinetics but did increase the potency of propofol. These results demonstrate that alterations in propofol pharmacokinetics observed in moderate to severe blood loss can be reversed with resuscitation. These results suggest that a modest reduction in propofol is prudent to achieve a desired drug effect after resuscitation from severe hemorrhagic shock.

The buccal absorption, bioavailability, and permeability of fentanyl are markedly increased as the pH of the fentanyl solution becomes more basic. Most likely, this is because of an increase in the fraction of unionized fentanyl.

We are developing methods for imaging multiple PET tracers in a single scan with staggered injections, where imaging measures for each tracer are separated and recovered using differences in tracer kinetics and radioactive decay. In this work, signal-separation performance for rapid dual-tracer 62 Cu-PTSM (blood flow) + 62 Cu-ATSM (hypoxia) tumor imaging was evaluated in a large animal model. Four dogs with pre-existing tumors received a series of dynamic PET scans with 62 Cu-PTSM and 62 Cu-ATSM, permitting evaluation of a rapid dual-tracer protocol designed by previous simulation work. Several imaging measures were computed from the dual-tracer data and compared with those from separate, single-tracer imaging. Static imaging measures (e.g. SUV) for each tracer were accurately recovered from dual-tracer data. The wash-in (k 1 ) and washout (k 2 ) rate parameters for both tracers were likewise well recovered (r = 0.87 -0.99), but k 3 was not accurately recovered for PTSM (r = 0.19) and moderately well recovered for ATSM (r = 0.70). Some degree of bias was noted, however, which may potentially be overcome through further refinement of the signal-separation algorithms. This work demonstrates that complementary information regarding tumor blood flow and hypoxia can be acquired by a single dual-tracer PET scan, and also that the signal-separation procedure works effectively for real physiologic data with realistic levels of kinetic model-mismatch. Rapid multi-tracer PET has the potential to improve tumor assessment for image-guide therapy and monitoring, and further investigation with these and other tracers is warranted.

Both 201Tl uptake and 99mTc-teboroxime kinetic parameters were well correlated with flow. The 99mTc-teboroxime washin parameters offer semiquantitative flow values and provide greater defect contrast than can be obtained with 201Tl uptake values.