Carbohydrates and insulin resistance in clinical nutrition: Recommendations from the ESPEN expert group.

Growing evidence underscores the important role of glycemic control in health and recovery from illness. Carbohydrate ingestion in the diet or administration in nutritional support is mandatory, but carbohydrate intake can adversely affect major body organs and tissues if resulting plasma glucose becomes too high, too low, or highly variable. Plasma glucose control is especially important for patients with conditions such as diabetes or metabolic stress resulting from critical illness or surgery. These patients are particularly in need of glycemic management to help lessen glycemic variability and its negative health consequences when nutritional support is administered. Here we report on recent findings and emerging trends in the field based on an ESPEN workshop held in Venice, Italy, 8-9 November 2015. Evidence was discussed on pathophysiology, clinical impact, and nutritional recommendations for carbohydrate utilization and management in nutritional support. The main conclusions were: a) excess glucose and fructose availability may exacerbate metabolic complications in skeletal muscle, adipose tissue, and liver and can result in negative clinical impact; b) low-glycemic index and high-fiber diets, including specialty products for nutritional support, may provide metabolic and clinical benefits in individuals with obesity, insulin resistance, and diabetes; c) in acute conditions such as surgery and critical illness, insulin resistance and elevated circulating glucose levels have a negative impact on patient outcomes and should be prevented through nutritional and/or pharmacological intervention. In such acute settings, efforts should be implemented towards defining optimal plasma glucose targets, avoiding excessive plasma glucose variability, and optimizing glucose control relative to nutritional support.

Pulmonary veno-occlusive disease in myeloproliferative disorder.

The present study reports a case of biopsy-proven pulmonary veno-occlusive disease as a cause of severe pulmonary hypertension in a patient suffering from a chronic myeloproliferative disorder. The pulmonary disease evolved favourably under treatment with defibrotide, a pro-fibrinolytic medication used in hepatic veno-occlusive disease.

Churg Strauss Syndrome masquerading septic shock.

Systemic inflammatory response syndrome (SIRS) can be related to acute inflammatory conditions that can be sometimes missed and inappropriately managed as severe infections. We report a case of Churg Strauss Syndrome (CSS), presenting as septic shock with acute onset of fever and multiple organ failure including pulmonary involvement with severe hypoxemia, hypotension requiring vasoactive support and acute renal failure. Antibiotics were discontinued and intravenous steroids allowed a rapid clinical improvement in close relationship with the fall in circulating eosinophils count.

Nitric oxide-related products and myeloperoxidase in bronchoalveolar lavage fluids from patients with ALI activate NF-kappa B in alveolar cells and monocytes.

An increased production of NO* and peroxynitrite in lungs has been suspected during acute lung injury (ALI) in humans, and recent studies provided evidence for an alveolar production of nitrated compounds. We observed increased concentrations of nitrites/nitrates, nitrated proteins and markers of neutrophil degranulation (myeloperoxidase, elastase and lactoferrine) in the fluids recovered from bronchoalveolar lavage fluids (BALF) of patients with ALI and correlated these changes to the number of neutrophils and the severity of the ALI. We also observed that BALFs stimulated the DNA-binding activity of the nuclear transcription factor kappa B (NF-kappaB) as detected by electrophoretic mobility shift assay in human alveolar cells (A549) and monocytes (THP1). The level of activation of the NF-kappaB-binding activity was correlated to the concentration of nitrated proteins and myeloperoxidase. Furthermore, in vitro studies confirmed that NO*-derived species (peroxynitrite and nitrites) and the neutrophil enzyme myeloperoxidase by themselves increased the activation of NF-kappaB, thereby arguing for an in vivo pathogenetic role of NO*-related products and neutrophil enzymes to human ALI.

Hemodynamic responses to successful weaning from mechanical ventilation after cardiovascular surgery.

Weaning from mechanical ventilation is usually associated with an increase in oxygen consumption (VO2), which may stress the cardiovascular system. We studied relative changes in the cardiac index and oxygen extraction ratio (EO2) during successful weaning in patients after cardiac surgery (n = 52), cardiac transplantation (n = 17), or abdominal aortic surgery (n = 11). Cardiac index was determined by the thermodilution technique and arterial and mixed venous blood gases were obtained before and 30 min after the start of weaning through a T-piece. The cardiovascular changes were evaluated in 42 patients in whom VO2 (calculated by Fick's equation) increased by more than 10%. Cardiac index increased more after abdominal aortic surgery (from 3.27 +/- 0.77 to 4.44 +/- 0.581 min(-1) m(-2), p < 0.01) than after cardiac surgery (from 2.53 +/- 0.59 to 2.87 +/- 0.46 1 min(-1) m(-2), p < 0.01) or cardiac transplantation (from 2.99 +/- 0.64 to 3.33 +/- 0.741 min(-1) m(-2), p < 0.05). EO2 remained stable in patients after aortic surgery (from 25.9 +/- 7.1 to 25.2 +/- 5.6 %, NS) but increased slightly after cardiac surgery (from 33.3 +/- 6.1 to 37.3 +/- 6.4%, NS) and significantly after cardiac transplantation (from 25.8 +/- 4.1 to 28.2 +/- 4.0%, p < 0.05). Hence the cardiovascular response to weaning from mechanical ventilation may vary according to the type of surgery.

Enteral feeding with a solution enriched with antioxidant vitamins A, C, and E enhances the resistance to oxidative stress.

OBJECTIVE: To assess whether dietary supplementation with the antioxidant vitamins A, C, and E enhances parameters of oxidative stress and influences the course of critically ill patients. DESIGN: Prospective, randomized, double-blinded, placebo-controlled study. SETTING: Department of medicosurgical intensive care of an academic hospital. PATIENTS: Fifty-one patients expected to require at least 7 days of enteral feeding. Thirty-seven of these patients (age, 57 +/- 7 yrs; Simplified Acute Physiology Score II, 33 +/- 6 points) completed the study. INTERVENTIONS: Twenty patients were randomized to receive the formula supplemented with vitamins A (67 microg/dL), C (13.3 mg/ dL), and E (4.94 mg/dL), and 17 patients received an isocaloric and isonitrogenous control solution. MEASUREMENTS AND MAIN RESULTS: Plasma levels of antioxidant vitamins, lipid peroxidation (estimated by the malonyldialdehyde assay), and low-density lipoprotein (LDL), and erythrocyte resistance to experimental oxidative stress were determined on samples drawn two consecutive days before the initiation of feeding and at the end of the 7-day period. Clinical outcome measures included documented infection and intensive care unit and 28-day survival. Administration of the supplemented solution increased significantly the concentration of plasma beta-carotene (from 0.2 +/- 0.0 microg/mL to 0.6 +/- 0.1 microg/mL; p < 0.01) and plasma and LDL-bound alpha-tocopherol (from 6.0 +/- 0.4 microg/mL and 2.9 +/- 0.9 microg/mL to 9.7 +/- 0.5 microg/mL and 4.3 +/- 1.2 microg/mL, respectively; p < 0.05), and improved LDL resistance to oxidative stress by 21 +/- 4% (p < 0.05). No such change was observed in the control group. There was no significant difference in clinical outcome between the two groups. CONCLUSIONS: Supplemental antioxidant vitamins added to enteral feeding solutions are well absorbed. Dietary supplementation with vitamins A, C, and E is associated with an improvement in antioxidant defenses, as assessed by ex vivo tests.

Isoflavone-mediated inhibition of tyrosine kinase: a novel antiinflammatory approach.

Tyrosine kinase (TK)-mediated phosphorylation regulates signal transduction pathways resulting in the expression of a variety of inflammatory genes. Inhibition of TK activity in vivo has been shown to increase survival in a lethal model of murine endotoxemia, suggesting a novel therapeutic approach to inflammation and circulatory shock. We examined the role of TK activity on the expression of the inducible nitric oxide (NO) synthase (iNOS). Under resting conditions, iNOS is not expressed in human cells. In response to various proinflammatory stimuli, however, iNOS expression is upregulated, resulting in high-output NO synthesis. iNOS-derived NO plays a critical role as a cytotoxic effector species and has been implicated in the pathogenesis of many clinical inflammatory conditions, including inflammatory bowel disease, arthritis, transplant rejection, diabetes, and sepsis. We examined the signaling pathways governing iNOS expression in monolayers of DLD-1 cells, a human epithelial cell line derived from an intestinal adenocarcinoma. Induction of iNOS transcription in interferon-gamma-primed cells by treatment with lipopolysaccharide, Salmonella sp., or interleukin-1beta was potently inhibited by pretreatment with genistein, an isoflavone derived from the soy species genistin. Other isoflavones, such as genistin, daidzein, and daidzin, were not inhibitory. TK inhibition by genistein had no effect on the expression or nuclear translocation of the transcription factors interferon regulatory factor-1 and nuclear factor-KB, respectively, both of which have been implicated in transcriptional regulation of the human iNOS gene. Nuclear run-on analysis demonstrated that the effect of genistein on iNOS messenger RNA expression was not at the level of transcription, suggesting that posttranscriptional regulation of iNOS messenger RNA might be TK dependent. Isoflavones, such as genistein, are useful tools to dissect regulatory pathways in vitro and in vivo and may have potential use as novel antiinflammatory therapeutic agents.

Effects of nitric oxide on blood flow distribution and O2 extraction capabilities during endotoxic shock.

The effects of the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) and the NO donor 3-morpholinosydnonimine (SIN-1) were tested in 18 endotoxic dogs. L-NMMA infusion (10 mg . kg-1 . h-1) increased arterial and pulmonary artery pressures and systemic and pulmonary vascular resistances but decreased cardiac index, left ventricular stroke work index, and blood flow to the hepatic, portal, mesenteric, and renal beds. SIN-1 infusion (2 microg . kg-1 . min-1) increased cardiac index; left ventricular stroke work index; and hepatic, portal, and mesenteric blood flow. It did not significantly influence arterial and pulmonary artery pressures but decreased renal blood flow. The critical O2 delivery was similar in the L-NMMA group and in the control group (13.3 +/- 1.6 vs. 12.8 +/- 3.3 ml . kg-1 . min-1) but lower in the SIN-1 group (9.1 +/- 1.8 ml . kg-1 . min-1, both P < 0.05). The critical O2 extraction ratio was also higher in the SIN-1 group than in the other groups (58.7 +/- 10.6 vs. 42.2 +/- 7.6% in controls, P < 0.05; 43.0 +/- 15.5% in L-NMMA group, P = not significant). We conclude that NO is not implicated in the alterations in O2 extraction capabilities observed early after endotoxin administration.

Intravenous nicardipine in the treatment of postoperative arterial hypertension.

BACKGROUND: Calcium entry blockers are commonly used in the management of postoperative hypertension. The hemodynamic and blood gas effects of nicardipine, a dihydropyridine derivative available intravenously, were studied in patients after abdominal aortic surgery. METHODS: Sixteen patients (66 +/- 8 years) who developed arterial hypertension (mean arterial pressure, > 90 mmHg) after abdominal aortic aneurysm reconstruction were studied. Fourteen patients had already been treated with a sodium nitroprusside infusion, the doses of which were maintained constant (mean dose: 1.42 +/- 1.04 micrograms/kg/min). Hemodynamic and blood gas data were collected at baseline, 15 minutes, and 45 minutes after a slow bolus administration of 3 to 5 mg of nicardipine. RESULTS: After the nicardipine administration, mean arterial pressure decreased from 101 +/- 11 to 83 +/- 11 mmHg (p < 0.001), and the cardiac index acutely increased from 3.96 +/- 0.74 to 4.57 +/- 0.83 L/min/m2 (p < 0.05). Systemic vascular resistance significantly decreased. There were no significant changes in heart rate, stroke volume, cardiac filling pressures, pulmonary artery pressures, pulmonary vascular resistance, left ventricular stroke work, or right ventricular stroke work. One patient developed acute pulmonary edema, associated with a dramatic increase in cardiac filling pressures, and electrocardiographic signs of myocardial ischemia. Nicardipine administration was also associated with an acute reduction in Pao2 from 85.0 +/- 12.1 mmHg to 70.3 +/- 9.2 mmHg (p < 0.001), associated with an increase in venous admixture from 21.7% +/- 3.2% to 28.0% +/- 5.2% (p < 0.01). Oxygen delivery increased moderately and oxygen extraction decreased, but oxygen consumption was unchanged. CONCLUSION: This study confirms the excellent efficacy of nicardipine in the management of postoperative hypertension, but underlines the risk of poor cardiac tolerance in patients after major surgery. Although oxygen delivery to the cells is usually well preserved, nicardipine can also significantly after blood oxygenation by increasing ventilation/perfusion mismatch.

Effects of nitric oxide donor SIN-1 on oxygen availability and regional blood flow during endotoxic shock.

BACKGROUND: An excessive release of nitric oxide (NO) has been incriminated in the circulatory disturbances of septic shock. OBJECTIVE: To study the effects of an NO donor, 3-morpholinosydnonimine (SIN-1), an oxygen availability and regional blood flow during endotoxic shock to see if a beneficial effect of NO synthase inhibitors in septic shock could be conclusively demonstrated. MATERIALS AND METHODS: In 14 anesthetized and mechanically ventilated dogs, global invasive hemodynamic monitoring was completed and ultrasonic flow probes were placed around the superior mesenteric, left renal, and left femoral arteries for simultaneous measurements of regional blood flow. All dogs received Escherichia coli endotoxin, 2 mg/kg. A control group (n = 7) was administered saline at 20 mL/kg per hour, and a SIN-1 group (n = 7) was given a combination of saline with SIN-1 at successive doses of 1, 2, and 4 micrograms/kg per minute. RESULTS: Neither systemic nor pulmonary arterial pressures were influenced by SIN-1. Cardiac index, stroke index, and left ventricular stroke work index did increase at low to moderate doses of SIN-1 but tended to decrease at the highest dose. Systemic and pulmonary vascular resistances decreased. Fractional blood flow increased in the mesenteric bed at all doses used, was not influenced in the renal bed, but decreased in the femoral bed at the highest dose. Oxygen-derived variables were similar in the 2 groups. Blood lactate and plasma concentrations of tumor necrosis factor were not significantly influenced. At the end of the SIN-1 infusion, the administration of 5 mg/kg of methylene blue increased arterial pressure, pulmonary arterial pressure, and systemic and pulmonary vascular resistances but decreased cardiac index and regional blood flow. CONCLUSIONS: The administration of low to moderate doses of the NO donor SIN-1 can significantly increase cardiac index and superior mesenteric blood flow without deleterious effects on arterial pressure in this model of endotoxic shock. These findings support the hypothesis that NO is essential to maintain organ blood flow even during endotoxic shock.

Is endotoxin-induced hypotension related to nitric oxide formation?

Nitric oxide (NO), an endothelium-derived relaxing factor (EDRF), is released by different types of cells under the influence of endotoxin and various cytokines: a causative role of endothelium-derived NO in the endotoxin-induced hypotension has thus been suggested. To test the hypothesis that NO may be involved in the acute hypotension following endotoxin challenge, we administered a competitive inhibitor of NO synthase, L-N-monomethylarginine (L-NMMA) to anesthetized dogs in the presence and absence of endotoxin. Dogs were randomly allocated to three groups. Group 1 (n = 3) was given Escherichia coli endotoxin (3 mg/kg, i.v.), group 2 (n = 3) was given L-NMMA (5 mg/kg, i.v. bolus) 15 min after endotoxin and group 3 (n = 3) was given L-NMMA only. One additional dog was given L-arginine (100 mg/kg, i.v. bolus) after L-NMMA and endotoxin to reverse the inhibition of NO synthase. In each animal, saline was infused intravenously throughout the experiment to restore and maintain pulmonary artery occluded pressure at baseline level. After L-NMMA, the increases in mean arterial pressure were similar in group 2 (from 55 +/- 18 to 75 +/- 15 mm Hg, p < 0.01) and in group 3 (from 107 +/- 27 to 128 +/- 24 mm Hg, p < 0.01). Systemic vascular resistance increased from 2,994 +/- 72 to 3,658 +/- 673 dyn.s.cm-5 (p < 0.01) in group 3. Group 1 had lower plasma lactate levels than group 2 (3.5 +/- 2.3 +/- vs. 2.0 +/- 1.6 mEq/l, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-6 administration has no acute hemodynamic or hematologic effect in the dog.

To investigate the possible hemodynamic effects of interleukin-6 (IL-6), a single dose of 15 mcg/kg of recombinant IL-6 isolated from Escherichia coli was injected intravenously in six pentobarbital-anesthetized dogs. After 30 min, saline infusion was performed to maintain the pulmonary artery balloon-occluded pressure at baseline level. The animals were observed for up to 5 hours. No other hemodynamic alteration was observed than a gradual decline in cardiac output attributed to anesthesia. Hematologic variables, blood glucose, and total serum proteins were also constant. IL-6 levels were markedly elevated in the blood, but no tumor necrosis factor activity was detected. Thus a primary role for IL-6 in the early cardiovascular alterations associated with septic shock seems unlikely.