Repletion of S-nitrosohemoglobin improves organ function and physiological status in swine after brain death - PubMed (original) (raw)

Repletion of S-nitrosohemoglobin improves organ function and physiological status in swine after brain death

Basil M Yurcisin et al. Ann Surg. 2013 May.

Abstract

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.

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Conflict of interest statement

Conflicts of Interest

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. There are no conflicts to report for the other co-authors.

Figures

Figure 1

Figure 1

Cardiovascular status. Mean (± SD) time courses for cardiac output, mean arterial pressure, and heart rate after the determination of brain death for the untreated (solid line) and ethyl nitrite (ENO) exposed (small dashes) cohorts. Within each graph, baseline mean (± SD) values are depicted by the bar and arrows. These parameters met the United Network Organ Sharing guidelines for donor maintenance with cardiac output > 3.8 l/min and mean arterial pressure > 60 mm Hg. Assessing for cardiovascular treatment differences was not a component of this study.

Figure 2

Figure 2

Oxygen utilization and tissue oxygenation. Median (± QD) changes in arterial/venous (A/V) oxygen content differences along with mean (± SD) tissue oxygenation and tissue hemoglobin (a measure of blood flow) percent changes from baseline after the determination of brain death for the untreated (solid line) and ethyl nitrite (ENO) exposed (small dashes) cohorts. A/V values were determined by the formula A/Vexperimental – A/Vbaseline. Negative values, as seen in the control group, reflect an increase in venous blood oxygen content following brain death and thus a reduction in oxygen utilization since arterial oxygen content was constant. The positive values, as seen with the ENO treatment, indicate a decrease in venous blood oxygen content and thus an increase in oxygen utilization. Tissue oxygenation and tissue hemoglobin were both significantly increased by 20 ppm ENO compared to the control values.

Figure 3

Figure 3

Kidney function and serum creatinine. Mean (± SD) serum creatinine (top panel), calculated individual glomerular filtration rates (GFR; middle panel), and individual inulin plasma/urine ratios (bottom panel) before and 10 h after determination of brain death. The group means for GFR and inulin ratios are demarcated with bars. Serum creatinine and the plasma/urine inulin ratios significantly increased and GFR significantly decreased in the untreated control cohort after brain death (p < 0.05; brackets with asterisks). In the 20 ppm ethyl nitrite (ENO) treatment group, the before and after brain death values for all three parameters were not statistically different.

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