Repletion of S-Nitrosohemoglobin Improves Organ Function... : Annals of Surgery (original) (raw)

Original Articles

Repletion of _S_-Nitrosohemoglobin Improves Organ Function and Physiological Status in Swine After Brain Death

Yurcisin, Basil M. MD*; Davison, Tara E. BS†; Bibbs, Syreena M. BS†; Collins, Bradley H. MD*; Stamler, Jonathan S. MD‡,¶; Reynolds, James D. PhD§

Departments of *Surgery

†Anesthesiology, Duke University Medical Center, Durham, NC

‡Medicine

§Anesthesiology & Perioperative Medicine; Institute for Transformative Molecular Medicine, Case Western Reserve University, Cleveland, OH

¶Harrington Discovery Institute, and University Hospitals Case Medical Center, Cleveland, OH.

Reprints: James D. Reynolds, PhD, Room 4128, 4th Floor Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106. E-mail: [email protected].

Disclosure: JDR has financial interests in Miach Medical Innovations and N30. JSS has financial interests in LifeHealth, N30, and Vindica Therapeutics. Miach is an early-stage medical device company; the others are all early-stage biotech companies developing nitric oxide-related technologies. These companies had no involvement in this study. The other co-authors declare no conflict of interest. Supported by a grant from the Duke Translational Research Institute (National Institutes of Health National Center for Research Resources Clinical and Translational Science Awards Program KL2RR024127), the Duke Anesthesiology Research Fund, and the Institute for Transformative Molecular Medicine at Case Western Reserve University.

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Objective:

To determine if reduction in nitric oxide bioactivity contributes to the physiological instability that occurs after brain death and, if so, to also determine in this setting whether administration of a renitrosylating agent could improve systemic physiological status.

Background:

Organ function after brain death is negatively impacted by reduced perfusion and increased inflammation; the magnitude of these responses can impact post-graft function. Perfusion and inflammation are normally regulated by protein _S_-nitrosylation but systemic assessments of nitric oxide bioactivity after brain death have not been performed.

Methods:

Brain death was induced in instrumented swine by inflation of a balloon catheter placed under the cranium. The subjects were then serially assigned to receive either standard supportive care or care augmented by 20 ppm of the nitrosylating agent, ethyl nitrite, blended into the ventilation circuit.

Results:

Circulating nitric oxide bioactivity (in the form of _S_-nitrosohemoglobin) was markedly diminished 10 hours after induction of brain death—a decline that was obviated by administration of ethyl nitrite. Maintenance of _S_-nitrosohemoglobin was associated with improvements in tissue blood flow and oxygenation, reductions in markers of immune activation and cellular injury, and preservation of organ function.

Conclusions:

In humans, the parameters monitored in this study are predictive of post-graft function. As such, maintenance of endocrine nitric oxide bioactivity after brain death may provide a novel means to improve the quality of organs available for donation.