In a 24 h, double-blind, prospective trial, we tested the hypothesis that two 4 mL/kg doses of hypertonic saline dextran (HSD; 7.5% NaCl/6% dextran 70) given in addition to isotonic fluid treatment would produce both immediate and sustained benefit for the heart after large burn injury. 12 instrumented sheep were subjected to a 40% total body surface area full-thickness flame burn under halothane anesthesia. 1 h after burn, when the animals had recovered from anesthesia, the first dose of either HSD (n = 6) or normal saline (NaCl .9%; n = 6) was infused over 30 min. The test solution was immediately followed by lactated Ringer's solution infused to maintain a urine output of 1-2 mL/kg.h throughout the study. The second dose of test solution was started at 12 h and was infused over 5 h. The initial dose of HSD corrected the burn-induced reduction in cardiac output, cardiac work, an index of myocardial contractility, and restored myocardial blood flow, as measured by the colored microsphere technique, to preburn values. Plasma concentrations of troponin I, creatine kinase (CK), and CK isoenzyme CKMB were increased 1 h after burn, but were not altered after HSD treatment. After euthanasia at 24 h, myocardial glutathione concentrations were higher in HSD-treated animals, whereas other markers of oxidative injury in heart or in plasma did not show systematic differences. The maximum contraction force measured in isolated right papillary muscles ex vivo was significantly greater in HSD-treated than normal saline-treated animals. In conclusion, the first dose of 4 mL/kg HSD infused 1 h after burn improved cardiac function, whereas the second dose of HSD infused at 12 h was without apparent effect on dynamic variables. An overall effect of the HSD treatments was a lasting increase in papillary muscle contraction force.