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.

Cardiovascular status of childhood cancer survivors exposed and unexposed to cardiotoxic therapy.

PURPOSE: To determine whether cardiovascular abnormalities in childhood cancer survivors are restricted to patients exposed to cardiotoxic anthracyclines and cardiac irradiation and how risk factors for atherosclerotic disease and systemic inflammation contribute to global cardiovascular status. METHODS: We assessed echocardiographic characteristics and atherosclerotic disease risk in 201 survivors of childhood cancer with and without exposure to cardiotoxic treatments at a median of 11 years after diagnosis (range, 3 to 32 years) and in 76 sibling controls. RESULTS: The 156 exposed survivors had below normal left ventricular (LV) mass, wall thickness, contractility, and fractional shortening and above normal LV afterload. The 45 unexposed survivors also had below normal LV mass overall, and females had below normal LV wall thickness. Exposed and unexposed survivors, compared with siblings, had higher levels of N-terminal pro-brain natriuretic peptide (81.7 and 69.0 pg/mL, respectively, v 39.4 pg/mL), higher mean fasting serum levels of non-high-density lipoprotein cholesterol (126.5 and 121.1 mg/dL, respectively, v 109.8 mg/dL), higher insulin levels (10.4 and 10.5 µU/mL, respectively, v 8.2 µU/mL), and higher levels of high-sensitivity C-reactive protein (2.7 and 3.1 mg/L, respectively, v 0.9 mg/L; P < .001 for all comparisons). Age-adjusted, predicted-to-ideal 30-year risk of myocardial infarction, stroke, or coronary death was also higher for exposed and unexposed survivors compared with siblings (2.16 and 2.12, respectively, v 1.70; P < .01 for both comparisons). CONCLUSION: Childhood cancer survivors not receiving cardiotoxic treatments nevertheless have cardiovascular abnormalities, systemic inflammation, and an increased risk of atherosclerotic disease. Survivorship guidelines should address cardiovascular concerns, including the risk of atherosclerotic disease and systemic inflammation, in exposed and unexposed survivors.

Aggregating traditional cardiovascular disease risk factors to assess the cardiometabolic health of childhood cancer survivors: an analysis from the Cardiac Risk Factors in Childhood Cancer Survivors Study.

BACKGROUND: Childhood cancer survivors are at increased risk of cardiovascular disease (CVD), which may be associated with traditional CVD risk factors. We used CVD risk aggregation instruments to describe survivor cardiometabolic health and compared their results with sibling controls. METHODS: Traditional CVD risk factors measured in 110 survivors and 31 sibling controls between 15 and 39 years old were aggregated using Pathobiological Determinants of Atherosclerosis in Youth (PDAY) scores and the Framingham Risk Calculator (FRC) and expressed as ratios. The PDAY odds ratio represents the increased odds of currently having an advanced coronary artery lesion, and the FRC risk ratio represents the increased risk of having a myocardial infarction, stroke, or coronary death in the next 30 years. Ratios are relative to an individual of similar age and sex without CVD risk factors. RESULTS: The median PDAY odds ratio for survivors was 2.2 (interquartile range 1.3-3.3), with 17% >4. The median FRC risk ratio was 1.7 (interquartile range 1.0-2.0), with 12% >4. Survivors and siblings had similar mean PDAY odds ratios (2.33 vs 2.29, P = .86) and FRC risk ratios (1.72 vs 1.53, P = .24). Cancer type and treatments were not associated with cardiometabolic health. There was a suggested association for physical inactivity with PDAY odds ratios (r = 0.17, P = .10) and FRC risk ratios (r = 0.19, P = .12). CONCLUSIONS: Cardiometabolic health is poor in childhood cancer survivors but not different than that of their siblings, highlighting the importance of managing traditional CVD risk factors and considering novel exposures in survivors.

Characteristics and determinants of adiposity in pediatric cancer survivors.

BACKGROUND: Adiposity and the diseases associated with it, including cardiovascular disease, are emerging long-term complications of pediatric cancer survivors. Direct evaluations of adiposity and comparisons to contemporary controls that can differentiate recent trends in obesity from cancer-related treatments and sequelae are limited. METHODS: We evaluated demographic, treatment, lifestyle, and endocrine factors at the time of dual-energy X-ray absorptiometry testing in 170 non-Hispanic white survivors and 71 sibling controls, and compared three measures of adiposity [body mass index (BMI), total body fat, and trunk fat]. For the survivors alone, we determined factors independently associated with BMI and body fat. RESULTS: Survivors were at 12 years since diagnosis; 58% had leukemia or lymphoma. BMI did not differ between groups. Among males, body fat was greater in survivors than in controls (25.8% versus 20.7%; P = 0.007), as was trunk fat (26.7% versus 21.3%; P = 0.008). Total or trunk fat did not differ among females. Cholesterol, triglycerides, low-density lipoprotein cholesterol, and television viewing hours were higher among male survivors than in controls. Independent factors associated with higher BMI and total and trunk fat included any cranial radiation and television viewing hours, whereas prior treatment with cyclophosphamide was associated with lower BMI and body fat measures. CONCLUSIONS: Compared with siblings, male survivors have greater body fat and metabolic risks. Cranial irradiation and television hours are important risk factors for adiposity in pediatric cancer survivors. IMPACT: Pediatric cancer survivors should be carefully monitored for cardiovascular risk factors and sedentary lifestyles.

Changes in lung function measured by spirometry and the forced oscillation technique in cystic fibrosis patients undergoing treatment for respiratory tract exacerbation.

Objective measures of lung function are critical for the treatment and study of lung diseases such as cystic fibrosis (CF). Spirometry is the most widely used and accepted method of pulmonary function testing in CF, but not all patients can perform the maneuvers required to obtain valid results from spirometry. The forced oscillation technique (FOT) requires less cooperation than spirometry. The goals of this study were to determine if FOT could detect changes in lung function in CF patients receiving inpatient treatment of respiratory tract exacerbations (RTEs), and to gather preliminary data on the magnitude of these changes and the variability of FOT data in such patients. We performed a retrospective chart review of CF patients admitted to the hospital for RTEs. We identified 14 patients who had both spirometry and FOT performed at the beginning and end of their treatment course. Their mean age was 15.9 years (range, 8-18). The mean forced expiratory volume in 1 sec (FEV1) on admission was 62.57% predicted. FEV1 increased by 27.1 +/- 33.15% (mean +/- SD, P = 0.008). The absolute value of reactance at 5 Hz (X5) decreased by 22.3 +/- 25.1% (P = 0.005), while resistance at 5 Hz decreased by 11.6 +/- 17.3% (P = 0.025). There was a significant relationship between changes in FEV1 and X5 (P = 0.003, r2 = 0.54). Our study demonstrates that FOT can detect significant changes in lung function in CF patients receiving treatment for RTEs. We speculate that FOT can serve as an alternative method to measure lung function in CF patients unable to perform spirometry, such as young children.