Enhancing oxygen diffusion during hypovolemic shock

Background: Tissue hypoxia due to reduced tissue perfusion is hallmark pathophysiology of hemorrhagic shock. However, since capillary dysfunction is a common complication during shock, it is unclear whether oxygen diffusion from capillaries to surrounding tissue is also impaired. We hypothesized that oxygen diffusion is impaired during prolonged hemorrhagic shock and that treatment targeting both capillary perfusion and oxygen diffusion can effectively correct tissue hypoxia under hypovolemic conditions. Methods: Male rats were randomized into five groups: Control (saline vehicle), albumin (25%), PEG (polyethylene glycol-20k), XC (PEG + trans-sodium crocetinate), and XCD (XC + 50% dextrose; n = 7-8 for each group). Albumin and PEG were used to enhance capillary perfusion, and trans-sodium crocetinate was applied to increase oxygen diffusion. Trauma was induced in anesthetized (inactin) rats with unilateral muscle injury and fibula fracture, followed by pressure-controlled hemorrhagic shock (mean arterial pressure (MAP) = 55 mmHg) for 45 minutes. Rats then received a single intravenous injection (0.3 ml/kg) of saline, albumin, XC, or XCD. MAP, skeletal muscle perfusion and oxygen partial pressure (PO 2 ), and mortality were monitored for another 2 hours without further resuscitation. The animals were remained under anesthesia and the survived animals were euthanized at the end of the experiment. Results: The hypotensive shock resulted in an about 50% decrease in skeletal muscle capillary perfusion but >80% decrease in the tissue PO 2 compared to the baseline values. Saline had no effect on MAP, tissue perfusion, or PO 2 . All control group animals died approximately one hour after injection with severe hyperlactatemia, hyperkalemia, and renal injury (GFR 0.05 ± 0.01 ml/min/100g with undetectable urinary flow). Survival was markedly improved in all the other treated groups (63% in albumin, 87% in PEG, and 100% in XC and XCD groups). MAP was rapidly improved in albumin, PEG, XC, and XCD groups from 10min to 60min after injection. The capillary flows were similarly improved in these groups to the levels comparable to 85% of baseline for 30 minutes. Tissue PO 2 was slightly and transiently improved (< 50% of baseline for 20 minutes) in albumin and PEG groups, but the increase in PO 2 was more profound and prolonged (up to 75% baseline for 2 hours, P < 0.01) in XC and XCD groups. In addition, the high dose of dextrose in XCD group failed to delay glucose depletion, but the accelerated glycolysis did not increase lactate levels compared to XC group. Conclusion: Our data suggest that tissue hypoxia during hemorrhagic shock is not only due to decreased oxygen delivery but also to impaired oxygen diffusion. XC is effective in maintaining tissue oxygen levels and aerobic metabolism for over 2 hours by improving both tissue perfusion and oxygen diffusion under hypovolemic conditions without resuscitation. Due to its rapid- and long-acting beneficial effects on organ oxygenation, XC may be a potential option to protect organ function and extend survival during prolonged hemorrhagic shock when timely resuscitation with blood and blood products is unavailable. DoD disclaimer: The views expressed in this abstract are those of the author(s) and do not reflect the official policy or position of the U.S. Army Medical Department, Department of the Army, DoD, or the U.S. Government. US Army Medical Research and Development Command This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.