INTRODUCTION: Burn injury alters immune function, increasing the risk of postburn infection. HSD modulates inflammatory responses, and this present study examined the hypothesis that HSD given after an initial insult attenuates the exaggerated inflammation that occurs with a second insult. METHODS AND MATERIALS: Sprague Dawley rats (N=15 per group) were divided into: Group 1 -- sham burn; Group 2 -- burn over 40% TBSA given a bolus of isotonic saline (IS, 4 ml/kg) plus lactated Ringer's (LR, 4 ml/kg/% burn); Group -- 3 burns given hypertonic saline dextran 70 (HSD, 4 ml/kg) + LR; Groups 1-3 were all studied 24 hrs postburn. Additional groups include: Group 4 -- sham burns given intratracheal (IT) vehicle on day 7 post sham burn and studied 24 hours after IT challenge; Group 5 -- burns given isotonic saline plus LR followed by IT vehicle on post burn day 7; Group 6 -- burns given HSD and LR followed by IT vehicle on post burn day 7; Group 7 -- burns given isotonic saline and LR plus intratracheal S. pneumoniae, 4x10⁶ CFU on postburn day 7; and Group 8 -- burns given HSD plus lactated Ringer's plus IT S. pneumoniae, 4x10⁶ CFU on postburn day 7. Groups 4-8 were studied 8 days after the initial burn injury and 24 hours after IT septic (or sham) challenge. Cardiomyocytes (collagenase digestion) or perfused hearts (Langendorff) were studied in vitro 24 hours after IT challenge. RESULTS: Contractile defects occurred 24 hrs postburn in isotonic saline treated burns, Group 2 (LVP: 73±3 mmHg; +dP/dt: 1350±70 mmHg/sec) but not HSD treated burns, Group 3 (LVP: 83±2; +dP/dt : 1970±75) compared to sham burns, Group 1 (LVP: 90±4, +dP/dt: 1990±80). Burn-related cardiac inflammatory responses were evident with isotonic saline treatment, Group 2 (TNF-, 170±10 pg/ml; IL-1, 34±3 pg/ml) but not HSD resuscitation, Group 3 (TNF-, 45±5 pg/ml; IL-1, 12±2 pg/ml) compared to shams, Group 1 (TNF-, 80±15 pg/ml; IL-1, 3±1 pg/ml). Pneumonia-related sepsis 8 days after isotonic saline treated burns (Group 7) exacerbated myocyte inflammatory responses (TNF-, 450±13 pg/ml) and contractile dysfunction (LVP, 65±3 mmHg) compared to that seen after isotonic saline treated burn in the absence of sepsis (Group 2) (p<0.05). Sepsis which occurred in animals given HSD after burn injury and septic challenge on post burn day 7 (Group 8) had less myocyte cytokine secretion (TNF-, 163±7) and better contractile function (LVP, 80±3) than isotonic saline treated burns complicated by sepsis, Group 7, p<0.05. DISCUSSION/CONCLUSION: The data confirm that an initial injury such as burn exacerbates the myocardial inflammation/dysfunction which occurs with a septic insult; providing HSD resuscitation after the initial insult attenuates myocardial inflammation and dysfunction associated with a second hit such as sepsis, suggesting that HSD reduces the post injury risk for infectious complications.