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Extracorporeal life support without systemic anticoagulation: a nitric oxide-based non-thrombogenic circuit for the artificial placenta in an ovine model

Pediatric Research volume 95, pages 93–101 (2024)Cite this article

Abstract

Background

Clinical translation of the extracorporeal artificial placenta (AP) is impeded by the high risk for intracranial hemorrhage in extremely premature newborns. The Nitric Oxide Surface Anticoagulation (NOSA) system is a novel non-thrombogenic extracorporeal circuit. This study aims to test the NOSA system in the AP without systemic anticoagulation.

Methods

Ten extremely premature lambs were delivered and connected to the AP. For the NOSA group, the circuit was coated with DBHD-N2O2/argatroban, 100 ppm nitric oxide was blended into the sweep gas, and no systemic anticoagulation was given. For the Heparin control group, a non-coated circuit was used and systemic anticoagulation was administered.

Results

Animals survived 6.8 ± 0.6 days with normal hemodynamics and gas exchange. Neither group had any hemorrhagic or thrombotic complications. ACT (194 ± 53 vs. 261 ± 86 s; p < 0.001) and aPTT (39 ± 7 vs. 69 ± 23 s; p < 0.001) were significantly lower in the NOSA group than the Heparin group. Platelet and leukocyte activation did not differ significantly from baseline in the NOSA group. Methemoglobin was 3.2 ± 1.1% in the NOSA group compared to 1.6 ± 0.6% in the Heparin group (p < 0.001).

Conclusions

The AP with the NOSA system successfully supported extremely premature lambs for 7 days without significant bleeding or thrombosis.

Impact

  • The Nitric Oxide Surface Anticoagulation (NOSA) system provides effective circuit-based anticoagulation in a fetal sheep model of the extracorporeal artificial placenta (AP) for 7 days.

  • The NOSA system is the first non-thrombogenic circuit to consistently obviate the need for systemic anticoagulation in an extracorporeal circuit for up to 7 days.

  • The NOSA system may allow the AP to be implemented clinically without systemic anticoagulation, thus greatly reducing the intracranial hemorrhage risk for extremely low gestational age newborns.

  • The NOSA system could potentially be applied to any form of extracorporeal life support to reduce or avoid systemic anticoagulation.

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Fig. 1: Artificial placenta (AP) circuit.
Fig. 2: Circuit and oxygenator performance.
Fig. 3: Coagulation profile.
Fig. 4: Platelets.
Fig. 5: Leukocytes.
Fig. 6: NOSA circuit after 7 days of AP support.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank Mark Jeakle and Joseph Hill for performing much of the laboratory testing for this manuscript.

Funding

This study was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD073475; PI: G.B.M.).

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Authors and Affiliations

  1. Department of Surgery, ECLS Laboratory, University of Michigan Medical School, Ann Arbor, MI, USA

    Brian P. Fallon, Orsolya Lautner-Csorba, Terry C. Major, Gergely Lautner, Stephen L. Harvey, Mark W. Langley, Matthew D. Johnson, Claudia Saveski, Alvaro Rojas-Pena & Robert H. Bartlett

  2. Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA

    Niki Matusko

  3. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    Raja Rabah

  4. Department of Surgery, Section of Transplantation, University of Michigan Medical School, Ann Arbor, MI, USA

    Alvaro Rojas-Pena

  5. Department of Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA

    Mark E. Meyerhoff

  6. Department of Surgery, Section of Pediatric Surgery, University of Michigan Medical School, Ann Arbor, MI, USA

    George B. Mychaliska

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Contributions

B.P.F., O.L.-C., T.C.M., and G.L. made substantial contributions to the conception or design of the work; the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agree to be accountable for all aspects of the work. S.L.H., M.W.L., M.D.J., C.S., N.M., and R.R. made substantial contributions to the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agree to be accountable for all aspects of the work. A.R.-P., M.E.M., R.H.B., and G.B.M. made substantial contributions to the conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agree to be accountable for all aspects of the work.

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Correspondence to Brian P. Fallon.

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Fallon, B.P., Lautner-Csorba, O., Major, T.C. et al. Extracorporeal life support without systemic anticoagulation: a nitric oxide-based non-thrombogenic circuit for the artificial placenta in an ovine model. Pediatr Res 95, 93–101 (2024). https://doi.org/10.1038/s41390-023-02605-2

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