HSPTX Protects Against Hemorrhagic Shock Resuscitation- Induced Tissue Injury: An Attractive Alternative to Ringer’s Lactate Raul Coimbra, MD, PhD, FACS, Rafael Porcides, MD, William Loomis, BS, Heidi Melbostad, BS, Rohan Lall, MD, Jessica Deree, MD, Paul Wolf, MD, and David B. Hoyt, MD, FACS Background: Conventional fluid re- suscitation with Ringer’s lactated (RL) ac- tivates neutrophils and causes end-organ damage. We have previously shown that HSPTX, a combination of small volume hypertonic saline (HS) and pentoxifylline (PTX), a phosphodiesterase-inhibitor, downregulates in vitro neutrophil activa- tion and proinflammatory mediator syn- thesis. Herein, we hypothesized that HSPTX decreases end-organ injury when compared with RL in an animal model of hemorrhagic shock. Methods: Sprague-Dawley rats were bled to a mean arterial pressure of 35 mm Hg for 1 hour. Animals were divided into 3 groups: sham (no shock, no resuscita- tion, n  7), RL (32 mL/kg, n  7), and HSPTX (7.5% NaCl 4 mL/kg  PTX 25 mg/kg; n  7). Shed blood was infused after fluid resuscitation. Blood pressure was monitored until the end of resuscita- tion. Animals were sacrificed at 24 hour after resuscitation. Bronchoalveolar la- vage fluid (BALF) was obtained for white cell count (total and differential) and TNF- and IL-1 levels were measured by ELISA. Lung and intestinal injury at 24 hour were evaluated by histopathology. Organ damage was graded by a patholo- gist and a score was created (0  no in- jury; 3  severe). Lung neutrophil infil- tration was evaluated by MPO immune staining. Results: There were no differences in mean arterial pressure between groups. At 24 hours, BALF leukocyte count was decreased by 30% in HSPTX animals (p < 0.01). TNF- and IL-1 levels were mark- edly decreased in HSPTX-resuscitated an- imals compared with their RL counter- parts (p < 0.01). HSPTX-resuscitated animals (lung injury score  1.0  0.4) had markedly decreased acute lung injury compared with RL-treated animals (2.5  0.3) (p < 0.01). RL resuscitation led to a two-fold increase in lung neutrophil infil- tration whereas in HSPTX-treated ani- mals, the number of MPO  cells was similar to sham animals (p < 0.001). In- testinal injury was markedly attenuated by HSPTX (1.1  0.3) compared with RL animals (2.6  0.4) (p < 0.001). Conclusions: HSPTX, a small vol- ume resuscitation strategy with marked immunomodulatory potential led to a marked decrease in end-organ damage. HSPTX is an attractive alternative to RL in hemorrhagic shock resuscitation. Key Words: Hemorrhage, Shock, Fluid Resuscitation, Ringer’s lactate, Hy- pertonic saline, Pentoxifylline, Lung in- jury, Myeloperoxidase, Inflammation, Gut injury, Ischemia, Reperfusion. J Trauma. 2006;60:41–51. H emorrhagic shock is the most important cause of early death after major trauma. The relationship between hemorrhagic shock, duration of ischemia and reperfu- sion, and the development of sepsis and MODS has been well studied. Splanchnic ischemia leads to translocation of bacte- ria or bacterial products from the intestinal lumen to the central circulation through the portal venous system and the mesenteric lymphatic circulation. Activation of inflammatory cell populations in target organs then takes place, which, if uncontrolled, causes tissue damage. 1–4 Prompt fluid resuscitation shortening the duration of shock should, theoretically, decrease the inflammatory re- sponse after hemorrhage and trauma. However, there is strong evidence suggesting that the current clinical resusci- tation regimen with Ringer’s lactate (RL) potentiates neutro- phil activation and is associated with increased organ injury, particularly in the lung. 5–8 Alternative resuscitation regimens have been studied recently. Our laboratory has investigated the anti-inflammatory and immune effects of small volume hypertonic saline resuscitation (HS) and pentoxifylline (PTX) following hemorrhagic shock. These two strategies were aimed to modulate shock-induced inflammation and end or- gan injury. 9 –14 The ideal fluid resuscitation regimen would be administered to the patient immediately after the injury or during the initial phase of care in the hospital, would attenuate the inflammatory response decreasing organ injury secondary to uncontrolled in- flammation, and ultimately, would improve survival. Several similarities comparing the effects of HS and PTX on the inflammatory response have been observed. The Submitted for publication September 28, 2005. Accepted for publication November 11, 2005. Copyright © 2006 by Lippincott Williams & Wilkins, Inc. From the Department of Surgery, Division of Trauma and Surgical Critical Care, University of California San Diego School of Medicine, San Diego, California. Presented at the Annual Meeting of the American Association for the Surgery of Trauma, September 22–24, 2005. Atlanta, Georgia. Address for Reprints: Raul Coimbra, MD, PhD, FACS, Division of Trauma and Surgical Critical Care, University of California San Diego, 200 W Arbor Drive, #8896, San Diego, CA, 92103-8896; email: rcoimbra@ucsd.edu. DOI: 10.1097/01.ta.0000197417.03460.0a The Journal of TRAUMA  Injury, Infection, and Critical Care Volume 60 • Number 1 41