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Artery-to-vein differences in nitric oxide metabolites are diminished in sepsis*

Morgan, Mary Anne M. MD; Frasier, Lauren M. BS; Stewart, Judith C. MA; Mack, Cynthia M. RN; Gough, Michael S. MD; Graves, Brian T. RN; Apostolakos, Michael J. MD; Doolin, Kathleen P. RN; Darling, Denise C. RRT; Frampton, Mark W. MD; Pietropaoli, Anthony P. MD, MPH

doi: 10.1097/CCM.0b013e3181d16a3e
Clinical Investigations

Objective: Nitric oxide deficiency may contribute to microvascular dysfunction in sepsis. Current physiologic paradigms contend that nitrite and/or S-nitrosohemoglobin mediate intravascular delivery of nitric oxide. These nitric oxide metabolites are purportedly consumed during hemoglobin deoxygenation, producing nitric oxide and coupling intravascular nitric oxide delivery with metabolic demand. Systemic nitrite and S-nitrosohemoglobin consumption can be assessed by comparing their concentrations in arterial vs. venous blood. We hypothesized that arterial vs. venous differences in nitrite and S-nitrosohemoglobin are diminished in sepsis and associated with mortality.

Design: Case-control and prospective cohort study.

Setting: Adult intensive care units of an academic medical center.

Patients and Subjects: Eighty-seven critically ill septic patients and 52 control subjects.

Interventions: None.

Measurements and Main Results: Nitrite and S-nitrosohemoglobin were measured using tri-iodide-based reductive chemiluminescence. In control subjects, arterial plasma, whole blood, and red blood cell nitrite levels were higher than the corresponding venous levels. In contrast, S-nitrosohemoglobin was higher in venous compared to arterial blood. In septic patients, arterial vs. venous red blood cell nitrite and S-nitrosohemoglobin differences were absent. Furthermore, the plasma nitrite arterial vs. venous difference was absent in nonsurvivors.

Conclusions: In health, nitrite levels are higher in arterial vs. venous blood (suggesting systemic nitrite consumption), whereas S-nitrosohemoglobin levels are higher in venous vs. arterial blood (suggesting systemic S-nitrosohemoglobin production). These arterial vs. venous differences are diminished in sepsis, and diminished arterial vs. venous plasma nitrite differences are associated with mortality. These data suggest pathologic disruption of systemic nitrite utilization in sepsis.

From Departments of Medicine (MAMM, LMF, JCS, CMM, MSG, MJA, MWF, APP), Nursing (BTG, KPD), Respiratory Care (DCD), and Environmental Medicine (MWF), University of Rochester Medical Center, Rochester, NY.

NIH K23 HL80077 and UL1 RR 024160 funded this study.

We gratefully acknowledge the trust and generosity of our patients and their families.

The authors have not disclosed any potential conflicts of interest.

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© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins