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

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.

Methionine Metabolites in Patients With Sepsis.

OBJECTIVE: Sepsis is characterized by microvascular dysfunction and thrombophilia. Several methionine metabolites may be relevant to this sepsis pathophysiology. S-adenosylmethionine (SAM) serves as the methyl donor for trans-methylation reactions. S-adenosylhomocysteine (SAH) is the by-product of these reactions and serves as the precursor to homocysteine. Relationships between plasma total homocysteine concentrations (tHcy) and vascular disease and thrombosis are firmly established. We hypothesized that SAM, SAH, and tHcy levels are elevated in patients with sepsis and associated with mortality. METHODS: This was a combined case-control and prospective cohort study consisting of 109 patients with sepsis and 50 control participants without acute illness. The study was conducted in the medical and surgical intensive care units of the University of Rochester Medical Center. Methionine, SAM, SAH, and tHcy concentrations were compared in patients with sepsis versus control participants and in sepsis survivors versus nonsurvivors. RESULTS: Patients with sepsis had significantly higher plasma SAM and SAH concentrations than control participants (SAM: 164 [107-227] vs73 [59-87 nM], P < .001; SAH: 99 [60-165] vs 35 [28-45] nM, P < .001). In contrast, plasma tHcy concentrations were lower in sepsis patients compared to healthy control participants (4 [2-6]) vs 7 [5-9] µM; P = .04). In multivariable analysis, quartiles of SAM, SAH, and tHcy were independently associated with sepsis ( P = .006, P = .05, and P < .001, respectively). Sepsis nonsurvivors had significantly higher plasma SAM and SAH concentrations than survivors (SAM: 223 [125-260] vs 136 [96-187] nM; P = .01; SAH: 139 [81-197] vs 86 [55-130] nM, P = .006). Plasma tHcy levels were similar in survivors vs nonsurvivors. The associations between SAM or SAH and hospital mortality were no longer significant after adjusting for renal dysfunction. CONCLUSIONS: Methionine metabolite concentrations are abnormal in sepsis and linked with clinical outcomes. Further study is required to determine whether these abnormalities have pathophysiologic significance.

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.

Effect of gender on cardiovascular risk stratification with ECG gated SPECT left ventricular volume indices and ejection fraction.

BACKGROUND: Optimal gender-specific risk prediction using ECG-gated SPECT left ventricular (LV) volumes and ejection fraction (EF) remains undefined despite reported gender differences in baseline LV function. METHODS: ECG-gated SPECT studies of 891 consecutively referred patients (43% women) were evaluated for LV end-systolic and diastolic volume indices (ESVI, EDVI) and EF. Effects of gender on prediction of hard cardiac events (HCE) and the combined endpoint of all-cause mortality or non-fatal infarction (ACMMI) were evaluated. RESULTS: Women had smaller ESVI (37 vs 55 mL/m(2)), EDVI (78 vs 99 mL/m(2)), and higher LVEF (56 vs 47%, P < 0.0001 for each) with equivalent rates of HCE (6.1%) and ACMMI (11.8%). HCE risk started at smaller ESVI and EDVI in women compared to men (P < or = 0.05 for each). In women, ESVI 37 mL/m(2) provided maximum HCE prediction compared to 53 mL/m(2) in men. A 1 mL/m(2) increase in ESVI was associated with a 2.9% increased HCE risk in women (P < 0.0001) and a 0.9% increased ACMMI risk in men (P = 0.03). Women with ESVI > 35 mL/m(2) had HCE HR 12.0 compared to women with ESVI < 23 mL/m(2). CONCLUSION: LV volume indices and LVEF predict subsequent morbid clinical events in men and women. In women, risk of subsequent events started at smaller LV volume indices compared to men despite similar risk profiles.

Older adults with intellectual disability in residential care centers in Israel: health status and service utilization.

To determine their health status, we studied 2,282 Israeli adults with intellectual disability who were at least 40 years of age and lived in residential care. Results showed that age is a significant factor in health status. The frequency of different disease categories (e.g., cardiovascular disease, cancer, and sensory impairments) increased significantly with age for both genders. Cardiovascular disease in this population was less prevalent when compared to the general population, suggesting that underdiagnosis of some diseases or conditions may be prevalent in this population. The patterns of organ-system morbidity with increasing age were similar to those in other studies conducted in several countries, suggesting that health status and outcomes could be independent of cultural factors.