The immunomodulatory effects of hypertonic saline resuscitation in patients sustaining traumatic hemorrhagic shock: a randomized, controlled, double-blinded trial

Abstract

Objective: To investigate the potential immunologic and anti-inflammatory effects of hypertonic saline plus dextran (HSD) in hemorrhagic trauma patients.

Background: Unbalanced inflammation triggered by shock has been linked to multiorgan dysfunction (MOD) and death. In animal and cellular models, HSD alters the inflammatory response to shock, attenuating MOD and improving outcome. It remains untested whether HSD has similar effects in humans.

Methods: A single 250-mL dose of either HSD (7.5% NaCl, 6% dextran-70) or placebo (0.9% NaCl) was administered to adult blunt trauma patients in hemorrhagic shock. The primary outcome was to measure changes in immune/inflammatory markers, including neutrophil activation, monocyte subset redistribution, cytokine production, and neuroendocrine changes. Patient demographics, fluid requirements, organ dysfunction, infection, and death were recorded.

Results: A total of 27 patients were enrolled (13 HSD) with no significant differences in clinical measurements. Hyperosmolarity was modest and transient, whereas the immunologic/anti-inflammatory effects persisted for 24 hours. HSD blunted neutrophil activation by abolishing shock-induced CD11b up-regulation and causing CD62L shedding. HSD altered the shock-induced monocyte redistribution pattern by reducing the drop in "classic" CD14 and the expansion of the "pro-inflammatory" CD14CD16 subsets. In parallel, HSD significantly reduced pro-inflammatory tumor necrosis factor (TNF)-alpha production while increasing anti-inflammatory IL-1ra and IL-10. HSD prevented shock-induced norepinephrine surge with no effect on adrenal steroids.

Conclusions: This first human trial evaluating the immunologic/anti-inflammatory effects of hypertonic resuscitation in trauma patients demonstrates that HSD promotes a more balanced inflammatory response to hemorrhagic shock, raising the possibility that similar to experimental models, HSD might also attenuate post-trauma MOD.

FIGURE 1. Neutrophil cell-surface and soluble adhesion molecule expression. HSD (7.5% NaCl, 6% Dextran-70) significantly decreased neutrophil surface expression of the adhesion molecules CD11b (A) and CD62L (B) on unstimulated (•, control; ○, HSD) and LPS-stimulated (▪, control; □, HSD) cells up to 24 hours. Data are expressed as percentage change in mean fluorescence intensity (ΔMFI) compared with baseline conditions (set at 100%). C, HSD caused an increase in the soluble form of CD62L that paralleled its reduction on the neutrophil surface. Serum concentrations (ng/mL) were measured by ELISA. Significant differences: *P < 0.05 versus baseline values within a treatment group; †P < 0.05 versus time-matched control values.

FIGURE 2. Monocyte cell-surface adhesion molecule expression. HSD (7.5% NaCl, 6% Dextran-70) significantly altered monocyte surface expression of CD11b (A) and CD62L (B) on unstimulated (•, control; ○, HSD) and LPS-stimulated (▪, control; □, HSD) cells up to 24 hours. Data are expressed as percentage change in mean fluorescence intensity (ΔMFI) compared with baseline conditions (set at 100%). Significant differences: *P < 0.05 versus baseline values within a treatment group; †P < 0.05 versus time-matched control values.

FIGURE 3. Monocyte intracellular cytokine expression. HSD (7.5% NaCl, 6% Dextran-70) significantly inhibited tumor necrosis factor (TNF)-α (A, B) but enhanced IL-10 (C, D) and IL-1ra (E, F) production in unstimulated (•, control; ○, HSD) and LPS-stimulated (▪, control; □, HSD) “classic” (CD14⁺⁺CD16−) and “pro-inflammatory” (CD14⁺CD16⁺) monocyte subsets, respectively. Intracellular cytokines were detected by flow cytometry. Data are expressed as percentage change in mean fluorescence intensity (ΔMFI) compared with baseline conditions (set at 100%). Significant differences: *P < 0.05 versus baseline values within a treatment group; †P < 0.05 versus time-matched control values.

FIGURE 4. Circulating catecholamine concentrations. HSD significantly blunted the rise in circulating norepinephrine concentration (NE; A) compared with control, without altering epinephrine concentrations (Epi; B). Plasma concentrations (mean ± SE, pg/mL) were measured in control (○) and HSD (▪) groups by mass spectroscopy. Significant differences: *P < 0.05 versus baseline values within a treatment group; †P < 0.05 versus time-matched control values.