Trauma and hemorrhagic shock (T/HS) is a major cause of morbidity and mortality. Existing treatment options are largely limited to source control and fluid and blood repletion. Previously, we have shown that enteral protease inhibition improves outcomes in experimental models of T/HS by protecting the gut from malperfusion and ischemia. However, enteral protease inhibition was achieved invasively, by laparotomy and direct injection of tranexamic acid (TXA) into the small intestine. In this study, we tested a minimally invasive method of enteral protease inhibitor infusion in experimental T/HS that can be readily adapted for clinical use.
Wistar rats were exsanguinated to a mean arterial blood pressure (MABP) of 40 mmHg, with laparotomy to induce trauma. Hypovolemia was maintained for 120 min and was followed by reperfusion of shed blood. Animals were monitored for an additional 120 min. A modified orogastric multi-lumen tube was developed to enable rapid enteral infusion of a protease inhibitor solution while simultaneously mitigating risk of reflux aspiration into the airways. The catheter was used to deliver TXA (T/HS + TXA) or vehicle (T/HS) continuously into the proximal small intestine, starting 20 min into the ischemic period.
Rats treated with enteral protease inhibition (T/HS + TXA) displayed improved outcomes compared to control animals (T/HS), including significantly improved MABP (p = 0.022) and lactate (p = 0.044). Mass spectrometry-based analysis of the plasma peptidome after T/HS indicated mitigation of systemic proteolysis in T/HS + TXA.
Minimally invasive, continuous enteral protease inhibitor delivery improves outcomes in T/HS and is readily translatable to the clinical arena.
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Availability of data and materials
The datasets analyzed for this study are available from the corresponding author on reasonable request.
- T/HS + TXA:
Trauma/hemorrhagic shock with enteral tranexamic acid (experimental group)
Mean arterial blood pressure
Hypovolemia (experimental period following blood withdrawal)
Reperfusion (experimental period following resuscitation)
White blood cells
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Department of Defense award W81XWH-17-2-0047 (EBK); ‘ShockOmics’ grant #602706, 7th Framework Program of the European Union (GWSS, GT); CelSys Shock” Marie Curie International Outgoing Fellowship PIOF-GA-2012-328796, 7th Framework Program of the European Union (FA). We thank Dr. Rafi Mazor for assistance with the interpretation of the histological images, and Dr. Fernando dos Santos for the critical appraisal of the discussion of the results.
Department of Defense award W81XWH-17–2-0047 (EBK); ‘ShockOmics’ grant #602706, 7th Framework Program of the European Union (GWSS, GTW); CelSys Shock” Marie Curie International Outgoing Fellowship PIOF-GA-2012–328796, 7th Framework Program of the European Union (FA).
The animal protocol was reviewed and approved by the Institutional Animal Care and Use Committee of the University of California, San Diego (protocol number S15117) and conforms to the Guide for the Care and Use of Laboratory Animals, 8th edition, by the National Institutes of Health (2011).
Conflict of interests
FAD and GWSS own stock in Inflammagen Inc., a company that develops new shock treatments.
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Aletti, F., DeLano, F.A., Maffioli, E. et al. Continuous enteral protease inhibition as a novel treatment for experimental trauma/hemorrhagic shock. Eur J Trauma Emerg Surg (2021). https://doi.org/10.1007/s00068-020-01591-y
- Hemorrhagic shock
- Enteral infusion
- Tranexamic acid
- Protease inhibition