Plasma Nitric Oxide Consumption Is Elevated and Associated With Adverse Outcomes in Critically Ill Patients

by Dony, Christina A.; Illipparambil, Lijo C.; Maeda, Tetsuro; Mroczek, Susan K.; Rovitelli, Amy; Wexler, Orren; Malnoske, Michelle; Bice, Tristan; Fe, Alex Z.; Storms, Casey R.; Zhang, Jimmy; Schultz, Rebecca D.; Pietropaoli, Anthony P. 

Critical Care Medicine:  August 18, 2023.

OBJECTIVES: 

Impaired nitric oxide (NO) bioavailability may contribute to microvascular dysfunction in sepsis. Excessive plasma NO consumption has been attributed to scavenging by circulating cell-free hemoglobin. This may be a mechanism for NO deficiency in sepsis and critical illness. We hypothesized that plasma NO consumption is high in critically ill patients, particularly those with sepsis, acute respiratory distress syndrome (ARDS), shock, and in hospital nonsurvivors. We further hypothesized that plasma NO consumption is correlated with plasma cell-free hemoglobin concentration.

DESIGN: 

Retrospective cohort study.

SETTING: 

Adult ICUs of an academic medical center.

PATIENTS AND SUBJECTS: 

Three hundred sixty-two critically ill patients and 46 healthy control subjects.

INTERVENTIONS: 

None.

MEASUREMENTS AND MAIN RESULTS: 

Plasma NO consumption was measured using reductive chemiluminescence and cell-free hemoglobin was measured with a colorimetric assay. Mean (95% CI) plasma NO consumption (µM) was higher in critically ill patients versus healthy control subjects (3.9 [3.7–4.1] vs 2.1 [1.8–2.5]), septic versus nonseptic patients (4.1 [3.8–4.3] vs 3.6 [3.3–3.8]), ARDS versus non-ARDS patients (4.4 [4.0–4.9] vs 3.7 [3.6–3.9]), shock vs nonshock patients (4.4 [4.0–4.8] vs 3.6 [3.4–3.8]), and hospital nonsurvivors versus survivors (5.3 [4.4–6.4] vs 3.7 [3.6–3.9]). These relationships remained significant in multivariable analyses. Plasma cell-free hemoglobin was weakly correlated with plasma NO consumption.

CONCLUSIONS: 

Plasma NO consumption is elevated in critically ill patients and independently associated with sepsis, ARDS, shock, and hospital death. These data suggest that excessive intravascular NO scavenging characterizes sepsis and adverse outcomes of critical illness.