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Continuous enteral protease inhibition as a novel treatment for experimental trauma/hemorrhagic shock

European Journal of Trauma and Emergency Surgery volume 48, pages 1579–1588 (2022)Cite this article

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

Code availability

Not applicable.

Abbreviations

T/HS:

Trauma/hemorrhagic shock

TXA:

Tranexamic acid

T/HS + TXA:

Trauma/hemorrhagic shock with enteral tranexamic acid (experimental group)

MABP:

Mean arterial blood pressure

HYPVOL:

Hypovolemia (experimental period following blood withdrawal)

REPERF:

Reperfusion (experimental period following resuscitation)

WBC:

White blood cells

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Acknowledgements

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.

Funding

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).

Author information

Authors and Affiliations

  1. Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

    Federico Aletti, Frank A. DeLano, Hao Mu & Geert W. Schmid-Schönbein

  2. Department of Veterinary Medicine, University of Milano, Milan, Italy

    Elisa Maffioli & Gabriella Tedeschi

  3. Cimaina, University of Milano, Milan, Italy

    Elisa Maffioli & Gabriella Tedeschi

  4. Department of Anesthesiology & Critical Care, University of California San Diego, La Jolla, CA, USA

    Erik B. Kistler

  5. Department of Anesthesiology & Critical Care, VA San Diego Healthcare System, San Diego, CA, USA

    Erik B. Kistler

Authors
  1. Federico Aletti
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  2. Frank A. DeLano
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  3. Elisa Maffioli
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  4. Hao Mu
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  5. Geert W. Schmid-Schönbein
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  6. Gabriella Tedeschi
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  7. Erik B. Kistler
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Contributions

FA: study design; animal experiments; data analysis; histological preparations; conception, design, realization and testing of the multilumen catheter; results discussion and interpretation; manuscript draft. FAD: animal experiments; conception of the histological preparations; design and realization of the multilumen catheter; manuscript revision and approval. EM: execution of the peptidomics experiments; peptidomics data analysis, discussion and interpretation; manuscript revision and approval. HM: histological preparations and analysis; manuscript revision and approval. GWSS: study design; design of the multilumen catheter; results discussion and interpretation; manuscript revision and approval. GT: design of the peptidomics experiments; eptidomics data discussion and interpretation; manuscript revision and approval. EKB: study design; critical appraisal of the clinical translational potential of the continuous enteral infusion method; results discussion and interpretation; manuscript revision and approval.

Corresponding author

Correspondence to Federico Aletti.

Ethics declarations

Ethics approval

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 48, 1579–1588 (2022). https://doi.org/10.1007/s00068-020-01591-y

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Keywords

  • Trauma
  • Hemorrhagic shock
  • Enteral infusion
  • Tranexamic acid
  • Protease inhibition
  • Hemodynamics