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The current study evaluated the pharmacodynamics of topically applied antimicrobials incorporated into radiolabeled liposomes. Radiolabeled 125I-phenyldecanoic acid was used in the formulation of small unilamellar liposomes. Sephadex (cross-linked dextran beads) G-50 columns were run to determine the per cent of radioactivity incorporated into liposomes and persistence of radioactive tag on the liposome after two weeks (greater than 95 per cent) remained incorporated. On the day of the experiment, 31 adult Sprague Dawley rats were subjected to a 10 per cent total body surface area full thickness burn (Walker burn model). All rats were treated with topical application of 0.3 milliliters of tobramycin entrapped in 125I-liposomes, and burn wounds were covered with Opsite (Winfield Laboratories). This formulation resulted in each rat receiving 14 milligrams per kilogram of tobramycin with a specific activity of 10.41 microcuries. Rats were sacrificed at several time periods after burn injury (nine after 24 hours, 12 after 48 hours, 11 after 72 hours). At these time intervals, serum and tissue tobramycin levels were measured, burn dressing, burn tissue and splanchnic organs were harvested and radioactivity was assessed with a gamma scintillation counter to determine tissue concentration of 125I-liposome tobramycin. Concentration of tobramycin in the serum was negligible at 24, 48 and 72 hours postburn, but was significant in the burn tissues at these times. The radioactive recovery data demonstrated that the majority (greater than 90 per cent) of the recovered liposomes remained at the site of application (the burn wound). No splanchnic organs had greater than 2 per cent of the recovered 125I-liposomes at any time period. These data suggest that, in burn wounds, tobramycin incorporated into liposomes remain at the site of initial application, resulting in high local concentrations with little systemic absorption and confirm that liposomes provide an effective vehicle for delivery of antimicrobials at the site of the burn injury.

Isolated coronary perfused hearts from guinea pigs were used to determine if aging alters left ventricular (LV) intrinsic contractile response to resuscitated burn shock. Parameters measured included LV pressure (LVP) and maximal rate of LVP rise (+dP/dt max) and fall (-dP/dt max) at a constant preload (LV enddiastolic pressure [LVEDP]). Compared with young controls (ten), aged control hearts (ten) showed significantly lower LVP (87.4 +/- 2.53 versus 76.0 +/- 1.5, p,0.001), +dP/dt max (1,351 +/- 51 versus 1,048 +/- 49, p,0.001), and -dP/dt max (1,154 +/- 34 versus 916 +/- 27, p,0.001), at an LVEDP of 10 millimeters of mercury. A 43 +/- 2 per cent third-degree burn (Walker model) was studied in ten young and ten aged guinea pigs. Burned aged hearts showed significantly lower LVP (57.1 +/- 2.1 versus 67.5 +/- 3.7, p,0.01) and -dP/dt max (707 +/- 33 versus 993 +/- 59, p,0.001) at an LVEDP of 10 millimeters of mercury. In addition, LV function curves for burned aged hearts were shifted downward and to the right of curves obtained from young burned hearts (p,0.05). Contractile defects in the aged group were not overcome by altered beating frequency, increased extracellular calcium concentration, nor maximally effective increases in diastolic stretch. Finally, we examined the effects of fluid resuscitation (4 milliliters per kilogram per percentage of burns) on contractile function in an additional ten young and ten aged burned guinea pigs. Contractile deficits persisted in both age groups despite adequate fluid resuscitation. Peak LVP and maximal rate of relaxation (-dP/dt) were uniformly depressed in aged as compared with young burned hearts (52.4 +/- 1.5 versus 63.2 +/- 2.7 and 715 +/- 42 versus 909 +/- 52, p,0.01, respectively). These data suggest that severe myocardial contractile change resulting from a major thermal insult in subjects with already compromised hearts is likely a significant limiting factor in the response to burn shock and adequate fluid resuscitation.