Does the timing of hypertonic saline resuscitation affect its potential to prevent lung damage?

Hypertonic saline (HS) resuscitation has been reported to prevent lung damage by suppressing neutrophil activation in animal models. Data on the effectiveness of HS to prevent organ damage in the clinical setting are inconsistent. We investigated whether the timing of HS administration relative to neutrophil activation could affect its potential to block neutrophil responses. Different likely clinical circumstances were simulated in vitro by exposing human neutrophils to HS at different time points before and after activation with N-formyl-methionyl-leucyl-phenylalanine (fMLP). The in vivo effect of using HS as a secondary resuscitation fluid was determined with a mouse model of hemorrhage. BALB/c mice were hemorrhaged (40 +/- 5 mmHg) for 1 h and partially resuscitated with HS or Lactated Ringer's (LR) 20 min before completing resuscitation with LR or HS, respectively. Neutrophil activation parameters were determined 2 h after complete resuscitation and lung damage was assessed after 24 h. The length of exposure to physiologically relevant HS levels (20 mM) determined the suppressive effect on in vitro neutrophil superoxide formation. HS treatment caused a transient state of suppression during which neutrophil activation was suppressed; however, HS was unable to suppress cells that were stimulated with fMLP before HS was added. Accordingly, in vivo lung damage was greater in animals that received HS after they had been partially resuscitated with LR compared to mice that received HS before LR (P < 0.05). We conclude that timing of exposure to HS affects neutrophil responses in vitro and may reduce the potential of HS resuscitation to prevent lung injury in vivo.