Brachial artery reactivity in patients with severe sepsis: an observational study.

INTRODUCTION: Ultrasound measurements of brachial artery reactivity in response to stagnant ischemia provide estimates of microvascular function and conduit artery endothelial function. We hypothesized that brachial artery reactivity would independently predict severe sepsis and severe sepsis mortality. METHODS: This was a combined case-control and prospective cohort study. We measured brachial artery reactivity in 95 severe sepsis patients admitted to the medical and surgical intensive care units of an academic medical center and in 52 control subjects without acute illness. Measurements were compared in severe sepsis patients versus control subjects and in severe sepsis survivors versus nonsurvivors. Multivariable analyses were also conducted. RESULTS: Hyperemic velocity (centimeters per cardiac cycle) and flow-mediated dilation (percentage) were significantly lower in severe sepsis patients versus control subjects (hyperemic velocity: severe sepsis = 34 (25 to 48) versus controls = 63 (52 to 81), P < 0.001; flow-mediated dilation: severe sepsis = 2.65 (0.81 to 4.79) versus controls = 4.11 (3.06 to 6.78), P < 0.001; values expressed as median (interquartile range)). Hyperemic velocity, but not flow-mediated dilation, was significantly lower in hospital nonsurvivors versus survivors (hyperemic velocity: nonsurvivors = 25 (16 to 28) versus survivors = 39 (30 to 50), P < 0.001; flow-mediated dilation: nonsurvivors = 1.90 (0.68 to 3.41) versus survivors = 2.96 (0.91 to 4.86), P = 0.12). Lower hyperemic velocity was independently associated with hospital mortality in multivariable analysis (odds ratio = 1.11 (95% confidence interval = 1.04 to 1.19) per 1 cm/cardiac cycle decrease in hyperemic velocity; P = 0.003). CONCLUSIONS: Brachial artery hyperemic blood velocity is a noninvasive index of microvascular function that independently predicts mortality in severe sepsis. In contrast, brachial artery flow-mediated dilation, reflecting conduit artery endothelial function, was not associated with mortality in our severe sepsis cohort. Brachial artery hyperemic velocity may be a useful measurement to identify patients who could benefit from novel therapies designed to reverse microvascular dysfunction in severe sepsis and to assess the physiologic efficacy of these treatments.

The ratio of arginine to dimethylarginines is reduced and predicts outcomes in patients with severe sepsis.

OBJECTIVES: Arginine deficiency may contribute to microvascular dysfunction, but previous studies suggest that arginine supplementation may be harmful in sepsis. Systemic arginine availability can be estimated by measuring the ratio of arginine to its endogenous inhibitors, asymmetric and symmetric dimethylarginine. We hypothesized that the arginine-to-dimethylarginine ratio is reduced in patients with severe sepsis and associated with severity of illness and outcomes. DESIGN: Case-control and prospective cohort study. SETTING: Medical and surgical intensive care units of an academic medical center. PATIENTS AND SUBJECTS: One hundred nine severe sepsis and 50 control subjects. MEASUREMENTS AND MAIN RESULTS: Plasma and urine were obtained in control subjects and within 48 hrs of diagnosis in severe sepsis patients. The arginine-to-dimethylarginine ratio was higher in control subjects vs. sepsis patients (median, 95; interquartile range, 85-114; vs. median, 34; interquartile range, 24-48; p < .001) and in hospital survivors vs. nonsurvivors (median, 39; interquartile range, 26-52; vs. median, 27; interquartile range, 19-32; p = .004). The arginine-to-dimethylarginine ratio was correlated with Acute Physiology and Chronic Health Evaluation II score (Spearman's correlation coefficient [ρ] = - 0.40; p < .001) and organ-failure free days (ρ = 0.30; p = .001). A declining arginine-to-dimethylarginine ratio was independently associated with hospital mortality (odds ratio, 1.63 per quartile; 95% confidence interval, 1.00-2.65; p = .048) and risk of death over the course of 6 months (hazard ratio, 1.41 per quartile; 95% confidence interval, 1.01-1.98; p = .043). The arginine-to-dimethylarginine ratio was correlated with the urinary nitrate-to-creatinine ratio (ρ = 0.46; p < .001). CONCLUSIONS: The arginine-to-dimethylarginine ratio is associated with severe sepsis, severity of illness, and clinical outcomes. The arginine-to-dimethylarginine ratio may be a useful biomarker, and interventions designed to augment systemic arginine availability in severe sepsis may still be worthy of investigation.

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

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.