Cold Renal Perfusion During Simulation of Juxtarenal Aortic Aneurysm Repair Reduces Systemic Oxidative Stress and Sigmoid Damage in Rats.

OBJECTIVES: Juxtarenal aortic surgery induces renal ischaemia reperfusion, which contributes to systemic inflammatory tissue injury and remote organ damage. Renal cooling during suprarenal cross clamping has been shown to reduce renal damage. It is hypothesised that renal cooling during suprarenal cross clamping also has systemic effects and could decrease damage to other organs, like the sigmoid colon. METHODS: Open juxtarenal aortic aneurysm repair was simulated in 28 male Wistar rats with suprarenal cross clamping for 45 min, followed by 20 min of infrarenal aortic clamping. Four groups were created: sham, no, warm (37 °C saline), and cold (4 °C saline) renal perfusion during suprarenal cross clamping. Primary outcomes were renal damage and sigmoid damage. To assess renal damage, procedure completion serum creatinine rises were measured. Peri-operative microcirculatory flow ratios were determined in the sigmoid using laser Doppler flux. Semi-quantitative immunofluorescence microscopy was used to measure alterations in systemic inflammation parameters, including reactive oxygen species (ROS) production in circulating leukocytes and leukocyte infiltration in the sigmoid. Sigmoid damage was assessed using digestive enzyme (intestinal fatty acid binding protein - I-FABP) leakage, a marker of intestinal integrity. RESULTS: Suprarenal cross clamping caused deterioration of all systemic parameters. Only cold renal perfusion protected against serum creatinine rise: 0.45 mg/dL without renal perfusion, 0.33 mg/dL, and 0.14 mg/dL (p = .009) with warm and cold perfusion, respectively. Microcirculation in the sigmoid was attenuated with warm (p = .002) and cold renal perfusion (p = .002). A smaller increase of ROS production (p = .034) was seen only after cold perfusion, while leukocyte infiltration in the sigmoid colon decreased after warm (p = .006) and cold perfusion (p = .018). Finally, digestive enzyme leakage increased more without (1.5AU) than with warm (1.3AU; p = .007) and cold renal perfusion (1.2AU; p = .002). CONCLUSIONS: Renal ischaemia/reperfusion injury after suprarenal cross clamping decreased microcirculatory flow, increased systemic ROS production, leukocyte infiltration, and I-FABP leakage in the sigmoid colon. Cold renal perfusion was superior to warm perfusion and reduced renal damage and had beneficial systemic effects, reducing sigmoid damage in this experimental study.

Perioperative glutamine supplementation restores disturbed renal arginine synthesis after open aortic surgery: a randomized controlled clinical trial.

Postoperative renal failure is a common complication after open repair of an abdominal aortic aneurysm. The amino acid arginine is formed in the kidneys from its precursor citrulline, and citrulline is formed from glutamine in the intestines. Arginine enhances the function of the immune and cardiovascular systems, which is important for recovery after surgery. We hypothesized that renal arginine production is diminished after ischemia-reperfusion injury caused by clamping of the aorta during open abdominal aortic surgery and that parenteral glutamine supplementation might compensate for this impaired arginine synthesis. This open-label clinical trial randomized patients who underwent clamping of the aorta during open abdominal aortic surgery to receive a perioperative supplement of intravenous alanyl-glutamine (0.5 g·kg(-1)·day(-1); group A, n = 5) or no supplement (group B, n = 5). One day after surgery, stable isotopes and tracer methods were used to analyze the metabolism and conversion of glutamine, citrulline, and arginine. Whole body plasma flux of glutamine, citrulline, and arginine was significantly higher in group A than in group B (glutamine: 391 ± 34 vs. 258 ± 19 µmol·kg(-1)·h(-1), citrulline: 5.7 ± 0.4 vs. 2.8 ± 0.4 µmol·kg(-1)·h(-1), and arginine: 50 ± 4 vs. 26 ± 2 µmol·kg(-1)·h(-1), P < 0.01), as was the synthesis of citrulline from glutamine (4.8 ± 0.7 vs. 1.6 ± 0.3 µmol·kg(-1)·h(-1)), citrulline from arginine (2.3 ± 0.3 vs. 0.96 ± 0.1 µmol·kg(-1)·h(-1)), and arginine from glutamine (7.7 ± 0.4 vs. 2.8 ± 0.2 µmol·kg(-1)·h(-1)), respectively (P < 0.001 for all). In conclusion, the production of citrulline and arginine is severely reduced after clamping during aortic surgery. This study shows that an intravenous supplement of glutamine increases the production of citrulline and arginine and compensates for the inhibitory effect of ischemia-reperfusion injury.

Local delivery of CpG-B and GM-CSF induces concerted activation of effector and regulatory T cells in the human melanoma sentinel lymph node.

Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. In an effort to determine the optimal way to strengthen immune defenses, 28 clinical stage I-II melanoma patients were randomized in a 3-arm Phase II study to receive, prior to excision and sampling of the SLN, i.d. injections of saline or low-dose CpG-B (CpG), alone or combined with GM-CSF (GM), around the melanoma excision site. We previously described the combined administration of these DC-targeting agents to result in activation and recruitment of potentially cross-presenting BDCA3(+) DCs to the SLN. In this report we describe the effects on effector and regulatory T and NK cell subsets. Local low-dose CpG administration resulted in lower CD4/CD8 ratios, Th1 skewing, increased frequencies of melanoma-specific CD8(+) T cells and possible recruitment of effector NK cells, irrespective of GM co-administration. These immune-potentiating effects were counterbalanced by increased IL-10 production by T cells and significantly higher levels of FoxP3 and CTLA4 in regulatory T cells (Tregs) with correspondingly higher suppressive activity in the SLN. Notably, CpG ± GM-administered patients showed significantly lower numbers of SLN metastases (saline: 4/9, CpG + GM: 1/9, CpG: 0/10, p = 0.04). These findings indicate that i.d. delivery of low-dose CpG ± GM potentially arms the SLN of early-stage melanoma patients against metastatic spread, but that antitumor efficacy may be further boosted by counteracting the collateral activation of Tregs.

Jejunal Casein Feeding Is Followed by More Rapid Protein Digestion and Amino Acid Absorption When Compared with Gastric Feeding in Healthy Young Men.

BACKGROUND: Dietary protein is required to attenuate the loss of muscle mass and to support recovery during a period of hospitalization. Jejunal feeding is preferred over gastric feeding in patients who are intolerant of gastric feeding. However, the impact of gastric vs. jejunal feeding on postprandial dietary protein digestion and absorption kinetics in vivo in humans remains largely unexplored. OBJECTIVE: We compared the impact of gastric vs. jejunal feeding on subsequent dietary protein digestion and amino acid (AA) absorption in vivo in healthy young men. METHODS: In a randomized crossover study design, 11 healthy young men (aged 21 ± 2 y) were administered 25 g specifically produced intrinsically l-[1-(13)C]phenylalanine-labeled intact casein via a nasogastric and a nasojejunal tube placed ~30 cm distal to the ligament of Treitz. Protein was provided in a 240-mL solution administered over a 65-min period in both feeding regimens. Blood samples were collected during the 7-h postprandial period to assess the increase in plasma AA concentrations and dietary protein-derived plasma l-[1-(13)C]phenylalanine enrichment. RESULTS: Jejunal feeding compared with gastric feeding resulted in higher peak plasma phenylalanine, leucine, total essential AA (EAA), and total AA concentrations (all P < 0.05). This was attributed to a more rapid release of dietary protein-derived AAs into the circulation, as evidenced by a higher peak plasma l-[1-(13)C]phenylalanine enrichment concentration (2.9 ± 0.2 vs. 2.2 ± 0.2 mole percent excess; P < 0.05). The total postprandial plasma AA incremental area under the curve and time to peak did not differ after jejunal vs. gastric feeding. Plasma insulin concentrations increased to a greater extent after jejunal feeding when compared with gastric feeding (275 ± 38 vs. 178 ± 38 pmol/L; P < 0.05). CONCLUSIONS: Jejunal feeding of intact casein is followed by more rapid protein digestion and AA absorption when compared with gastric feeding in healthy young men. The greater postprandial increase in circulating EAA concentrations may allow a more robust increase in muscle protein synthesis rate after jejunal vs. gastric casein feeding. This trial was registered at trialregister.nl as NTR2801.

Adaptations of Arginine's Intestinal-Renal Axis in Cachectic Tumor-Bearing Rats.

Malignancies induce disposal of arginine, an important substrate for the immune system. To sustain immune function, the tumor-bearing host accelerates arginine's intestinal-renal axis by glutamine mobilization from skeletal muscle and this may promote cachexia. Glutamine supplementation stimulates argi-nine production in healthy subjects. Arginine's intestinal-renal axis and the effect of glutamine supplementation in cancer cach-exia have not been investigated. This study evaluated the long-term adaptations of the interorgan pathway for arginine production following the onset of cachexia and the metabolic effect of glutamine supplementation in the cachectic state. Fischer-344 rats were randomly divided into a tumor-bearing group (n = 12), control group (n = 7) and tumor-bearing group receiving a glutamine-enriched diet (n = 9). Amino acid fluxes and net fractional extractions across intestine, kidneys, and liver were studied. Compared to controls, the portal-drained viscera of tumor-bearing rats took up significantly more glutamine and released significantly less citrulline. Renal metabolism was unchanged in the cachectic tumor-bearing rats compared with controls. Glutamine supplementation had no effects on intestinal and renal adaptations. In conclusion, in the cachectic state, an increase in intestinal glutamine uptake is not accompanied by an increase in renal arginine production. The adaptations found in the cachectic, tumor-bearing rat do not depend on glutamine availability.

The Arginine/ADMA Ratio Is Related to the Prevention of Atherosclerotic Plaques in Hypercholesterolemic Rabbits When Giving a Combined Therapy with Atorvastatine and Arginine.

UNLABELLED: Supplementation with arginine in combination with atorvastatin is more efficient in reducing the size of an atherosclerotic plaque than treatment with a statin or arginine alone in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits. We evaluated the mechanism behind this feature by exploring the role of the arginine/asymmetric dimethylarginine (ADMA) ratio, which is the substrate and inhibitor of nitric oxide synthase (NOS) and thereby nitric oxide (NO), respectively. METHODS: Rabbits were fed either an arginine diet (group A, n = 9), standard rabbit chow plus atorvastatin (group S, n = 8), standard rabbit chow plus an arginine diet with atorvastatin (group SA, n = 8) or standard rabbit chow (group C, n = 9) as control. Blood was sampled and the aorta was harvested for topographic and histological analysis. Plasma levels of arginine, ADMA, cholesterol and nitric oxide were determined and the arginine/ADMA ratio was calculated. RESULTS: The decrease in ADMA levels over time was significantly correlated to fewer aortic lesions in the distal aorta and total aorta. The arginine/ADMA ratio was correlated to cholesterol levels and decrease in cholesterol levels over time in the SA group. A lower arginine/ADMA ratio was significantly correlated to lower NO levels in the S and C group. DISCUSSION: A balance between arginine and ADMA is an important indicator in the prevention of the development of atherosclerotic plaques.

Effect of oral taurine on morbidity and mortality in elderly hip fracture patients: a randomized trial.

Hip fracture patients represent a large part of the elderly surgical population and face severe postoperative morbidity and excessive mortality compared to adult surgical hip fracture patients. Low antioxidant status and taurine deficiency is common in the elderly, and may negatively affect postoperative outcome. We hypothesized that taurine, an antioxidant, could improve clinical outcome in the elderly hip fracture patient. A double blind randomized, placebo controlled, clinical trial was conducted on elderly hip fracture patients. Supplementation started after admission and before surgery up to the sixth postoperative day. Markers of oxidative status were measured during hospitalization, and postoperative outcome was monitored for one year after surgery. Taurine supplementation did not improve in-hospital morbidity, medical comorbidities during the first year, or mortality during the first year. Taurine supplementation lowered postoperative oxidative stress, as shown by lower urinary 8-hydroxy-2-deoxyguanosine levels (Generalized estimating equations (GEE) analysis average difference over time; regression coefficient (Beta): -0.54; 95% CI: -1.08--0.01; p = 0.04), blunted plasma malondialdehyde response (Beta: 1.58; 95% CI: 0.00-3.15; p = 0.05) and a trend towards lower lactate to pyruvate ratio (Beta: -1.10; 95% CI: -2.33-0.12; p = 0.08). We concluded that peri-operative taurine supplementation attenuated postoperative oxidative stress in elderly hip fracture patients, but did not improve postoperative morbidity and mortality.

Asymmetric dimethylarginine and critical illness.

PURPOSE OF REVIEW: Asymmetric dimethylarginine (ADMA) is an analog of arginine and functions as an endogenous inhibitor of the nitric oxide synthase, which forms nitric oxide. Nitric oxide is crucial for perfusion of vital organs and is an important signaling agent in the development of critical illness. The role of ADMA in the pathophysiological mechanisms underlying critical illness is widely studied in the last decades, and recently it has become clear that ADMA should not be overlooked by clinicians working at the ICU. The aim of this review is to describe new insights into the role of ADMA in critical illness and its clinical relevance. RECENT FINDINGS: High levels of ADMA are found in critically ill patients, because of higher levels of protein methylation, increased rate of protein turnover, decreased activity of dimethylamine dimethylaminohydrolase, and impaired renal and hepatic clearance capacity. These high levels are an independent risk factor for cardiac dysfunction, organ failure, and ICU mortality. The arginine : ADMA ratio in particular is of clinical importance and the restoration of this ratio is expedient to restore several functions that are disturbed during critical illness. SUMMARY: Elevated ADMA levels occur in critically ill patients, which is detrimental for morbidity and mortality. The arginine : ADMA ratio should be restored to maintain nitric oxide production and therewith improve the clinical outcome of the patient.

Characterization of four conventional dendritic cell subsets in human skin-draining lymph nodes in relation to T-cell activation.

To increase (tumor) vaccine efficacy, there is an urgent need for phenotypic and functional characterization of human dendritic cell (DC) subsets residing in lymphoid tissues. In this study we identified and functionally tested 4 human conventional DC (cDC) subsets within skin-draining sentinel lymph nodes (SLNs) from early-stage melanoma patients. These SLNs were all tumor negative and were removed on average 44 days after excision of the primary melanoma. As such, they were considered representative of steady-state conditions. On comparison with skin-migrated cDC, 2 CD1a(+) subsets were identified as most likely skin-derived CD11c(int) Langerhans cells (LC) with intracellular langerin and E-cadherin expression or as CD11c(hi) dermal DCs with variable expression of langerin. Two other CD1a(-) LN-residing cDC subsets were characterized as CD14(-)BDCA3(hi)CD103(-) and CD14(+)BDCA3(lo)CD103(+), respectively. Whereas the CD1a(+) skin-derived subsets displayed greater levels of phenotypic maturation, they were associated with lower levels of inflammatory cytokine release and were inferior in terms of allogeneic T-cell priming and IFNγ induction. Thus, despite their higher maturation state, skin-derived cDCs (and LCs in particular) proved inferior T-cell activators compared with the CD1a(-) cDC subsets residing in melanoma-draining LNs. These observations should be considered in the design of DC-targeting immunotherapies.

Pre-cachexia and cachexia at diagnosis of stage III non-small-cell lung carcinoma: an exploratory study comparing two consensus-based frameworks.

Despite the development of consensus-based frameworks to define cancer cachexia, the validity and usefulness of these frameworks are relatively unknown. The aim of the present study was to study the presence of pre-cachexia and cachexia in patients with stage III nonsmall-cell lung carcinoma (NSCLC) by using a cancer-specific framework and a general framework for cachexia, and to explore the prognostic value of pre-cachexia and cachexia. In forty patients at diagnosis of stage III NSCLC, weight loss, fat-free mass, handgrip strength, anorexia and serum biochemistry, assessed before the first chemotherapy, were used to define 'cancer cachexia' or 'cachexia'. The cancer-specific framework also classified for pre-cachexia and refractory cachexia. Additionally, quality of life was assessed by the European Organisation for Research and Treatment of Cancer­Quality of Life Questionnaire C30. Groups were compared using independent t tests, ANOVA, Kaplan­Meier and Cox survival analyses. Based on the cancer-specific framework, pre-cachexia was present in nine patients (23%) and cancer cachexia was present in seven patients (18%). Cancer cachexia was associated with a reduced quality of life (P = 0.03) and shorter survival (hazard ratio (HR) = 2.9; P = 0.04). When using the general framework, cachexia was present in eleven patients (28%), and was associated with a reduced quality of life (P = 0.08) and shorter survival (HR = 4.4; P = 0.001). In conclusion, pre-cachexia and cachexia are prevalent in this small population of patients at diagnosis of stage III NSCLC. For both frameworks, cachexia appears to be associated with a reduced quality of life and shorter survival. Further studies are warranted to more extensively explore the validity and prognostic value of these new frameworks in cancer patients.

Role of the human erythrocyte in generation and storage of asymmetric dimethylarginine.

Proteolytic activity in whole blood may lead to release of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). We investigated the role of the human erythrocyte in storage and generation of ADMA in healthy controls (n = 36) and critically ill patients (n = 38). Both free and total (sum of free and protein-incorporated) ADMA were measured. Upon incubation of intact erythrocytes with extracellular ADMA (0 to 40 µmol/l), equilibrium between intra- and extracellular ADMA was reached within 3 h. Compared with controls, patients had significantly higher basal concentrations of ADMA in plasma (0.88 ± 0.75 vs. 0.41 ± 0.07 µmol/l) and erythrocytes (1.28 ± 0.55 vs. 0.57 ± 0.14 µmol/l). Intracellular and plasma ADMA were significantly correlated in the patient group only (r = 0.834). Upon lysis, followed by incubation at 37°C for 2 h, free ADMA increased sevenfold (to 8.60 ± 3.61 µmol/l in patients and 3.90 ± 0.78 µmol/l in controls). In lysates of controls, free ADMA increased further to 9.85 ± 1.35 µmol/l after 18 h. Total ADMA was 15.43 ± 2.44 µmol/l and did not change during incubation. The increase of free ADMA during incubation corresponded to substantial release of ADMA from the erythrocytic protein-incorporated pool (21.9 ± 4.6% at 2 h and 60.8 ± 7.6% at 18 h). ADMA was released from proteins other than hemoglobin, which only occurred after complete lysis and was blocked by combined inhibition of proteasomal and protease activity. Neither intact nor lysed erythrocytes mediated degradation of free ADMA. We conclude that intact erythrocytes play an important role in storage of ADMA, whereas upon erythrocyte lysis large amounts of free ADMA are generated by proteolysis of methylated proteins, which may affect plasma levels in hemolysis-associated diseases.

Imbalance of arginine and asymmetric dimethylarginine is associated with markers of circulatory failure, organ failure and mortality in shock patients.

In shock, organ perfusion is of vital importance because organ oxygenation is at risk. NO, the main endothelial-derived vasodilator, is crucial for organ perfusion and coronary patency. The availability of NO might depend on the balance between a substrate (arginine) and an inhibitor (asymmetric dimethylarginine; ADMA) of NO synthase. Therefore, we investigated the relationship of arginine, ADMA and their ratio with circulatory markers, disease severity, organ failure and mortality in shock patients. In forty-four patients with shock (cardiogenic n 17, septic n 27), we prospectively measured plasma arginine and ADMA at intensive care unit admission, Acute Physiology and Chronic Health Evaluation (APACHE) II-(predicted mortality) and Sequential Organ Failure Assessment (SOFA) score, and circulatory markers to investigate their relationship. Arginine concentration was decreased (34·6 (SD 17·9) µmol/l) while ADMA concentration was within the normal range (0·46 (SD 0·18) µmol/l), resulting in a decrease in the arginine:ADMA ratio. The ratio correlated with several circulatory markers (cardiac index, disseminated intravascular coagulation, bicarbonate, lactate and pH), APACHE II and SOFA score, creatine kinase and glucose. The arginine:ADMA ratio showed an association (OR 0·976, 95 % CI 0·963, 0·997, P = 0·025) and a diagnostic accuracy (area under the curve 0·721, 95 % CI 0·560, 0·882, P = 0·016) for hospital mortality, whereas the arginine or ADMA concentration alone or APACHE II-predicted mortality failed to do so. In conclusion, in shock patients, the imbalance of arginine and ADMA is related to circulatory failure, organ failure and disease severity, and predicts mortality. We propose a pathophysiological mechanism in shock: the imbalance of arginine and ADMA contributes to endothelial and cardiac dysfunction resulting in poor organ perfusion and organ failure, thereby increasing the risk of death.

Hypothermic renal perfusion during aortic surgery reduces the presence of lipocalin-2 and preserves renal extraction of dimethylarginines in rats.

Cold perfusion through the renal arteries during renal ischemia has been suggested to diminish postoperative renal damage after juxtarenal aortic aneurysm repair. As the kidneys play a key role in dimethylarginine metabolism, which in turn is associated with renal hemodynamics, we hypothesized that the protective effect of cold perfusion is associated with a preserved renal extraction of dimethylarginines. Renal ischemia was induced in three groups of anesthetized Wistar rats (n = 7/group), which underwent suprarenal aortic clamping (45 min) with no perfusion (group 1), renal perfusion with 37°C saline (group 2), or renal perfusion with 4°C saline (group 3), respectively, followed by 90 min of renal reperfusion in all groups. The sham group had no clamping. In group 3 (renal ischemia with cold perfusion), postoperative serum creatinine levels as well as the presence of luminal lipocalin-2 and its associated brush-border damage were lower compared with groups 1 and 2 (P < 0.05). Also, renal extraction of asymmetrical (ADMA) and symmetrical (SDMA) dimethylarginine as well as the arginine/ADMA ratio, which defines the bioavailability of nitric oxide, remained intact in group 3 only (P < 0.04). The arginine/ADMA ratio correlated with cortical flow, lipocalin-2, and creatinine rises. Warm and cold renal perfusion (groups 2 and 3) during ischemia were similarly effective in lowering protein nitrosylation levels, renal leukocyte accumulation, neutrophil gelatinase-associated lipocalin (NGAL) expression in distal tubules, and urine NGAL (P < 0.05). These data support the use of cold renal perfusion during renal ischemia in situations where renal ischemia is inevitable, as it reduces tubular damage and preserves renal extraction of dimethylarginines. Renal perfusion with saline per se during renal ischemia is effective in diminishing renal leukocyte accumulation and oxidative stress.

Infrarenal aortic-clamping after renal ischaemia aggravates acute renal failure.

BACKGROUND: Renal failure is a frequent complication of juxtarenal abdominal aortic aneurysm (JAA)-repair. During this operation, suprarenal aortic-clamping is followed by infrarenal aortic-clamping (below renal arteries) to restore renal flow, while performing the distal anastomosis. We hypothesized that infrarenal aortic-clamping, despite restoring renal perfusion provokes additional renal damage. MATERIALS AND METHODS: We studied three groups of rats. After 45min of suprarenal aortic-clamping, group 1 had renal reperfusion for 90min without aortic-clamps (n=7). In group 2, 45min of suprarenal aortic-clamping with a distal clamp on the aortic-bifurcation was followed by 20min of infrarenal aortic-clamping. Renal reperfusion was continued for 70min without aortic-clamps (i.e. 90 min of renal reperfusion; n=8). The sham-group had no clamps (n=7). We measured renal haemodynamics, functional parameters and tissue damage. RESULTS: On suprarenal aortic-clamp removal, renal artery flow, cortical flow and arterial pressures were higher in group 2 than in group 1. We detected increased tubular brush border damage, luminal lipocalin-2 and 30-60% higher renal protein nitrosylation in group 2 when compared to group 1 (P<0·05). Group 2 showed more release of asymmetrical dimethylarginine (ADMA) from the kidneys in the renal vein, therefore indicating diminished clearing capacity (P<0·001). Arginine/ADMA-ratio, which defines the bio-availability of nitric oxide, tended to be lower in group 2 and correlated with renal flow. Furthermore, there were no significant differences found in creatinine levels and renal leucocyte accumulation between group 1 and 2. CONCLUSIONS: Additional infrarenal aortic-clamping leads to increased renal damage and oxidative stress, despite adequate perfusion of kidneys after suprarenal aortic-clamping. This study indicates that the clamping sequence used in JAA-repair causes more than simple renal I/R-injury.

Open surgical repair of ruptured juxtarenal aortic aneurysms with and without renal cooling: observations regarding morbidity and mortality.

OBJECTIVES: Little is known about the outcome of ruptured juxtarenal aortic aneurysm (RJAA) repair. Surgical treatment of RJAAs requires suprarenal aortic cross-clamping, which causes additional renal ischemia-reperfusion injury on top of the pre-existing hypovolemic shock syndrome. As endovascular alternatives rarely exist in this situation, open repair continues to be the gold standard. We analyzed our results of open RJAA repair during an 11-year period. DESIGN: Retrospective observational study. MATERIALS AND METHODS: Between July 1997 and December 2008, all consecutive patients with RJAAs were included in the study. Part of these patients received cold perfusion of the kidneys during suprarenal aortic cross-clamping. Perioperative variables, morbidity, and 30-day or in-hospital mortality were assessed. Renal insufficiency was defined as an acute rise of >or=0.5 mg/dL in serum creatinine level. Multiple organ failure (MOF) was scored using the sequential organ failure assessment score (SOFA score). RESULTS: A total of 29 consecutive patients with an RJAA, confirmed by computed tomography-scanning, presented to our hospital. In eight patients, the operation was aborted before the start of aortic repair, because no blood pressure could be regained in spite of maximal resuscitation measures. They were excluded from further analysis. Of the remaining 21 patients, 10 died during hospital stay. Renal insufficiency occurred in 11 out of 21 of the patients. Eleven out of 21 patients developed MOF postoperatively. In a subgroup of patients who received renal cooling during suprarenal aortic clamping, the 30-day or in-hospital mortality was two of 10 vs eight of 11 in patients who did not receive renal cooling (P = .03); renal insufficiency occurred in one out of 10 patients in the subgroup with renal cooling vs 10 out of 11 without renal cooling (P < .001) and MOF in two of 10 vs nine of 11, respectively (P = .009). CONCLUSIONS: Open surgical repair of RJAAs is still associated with high mortality and morbidity. To our knowledge, this is the first report of cold perfusion of the kidneys during RJAA repair. Although numbers are small, a beneficial effect of renal cooling on the outcome of RJAA repair is suggested, warranting further research with this technique.

Oral nutritional supplements containing (n-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), (n-3) fatty acids from fish oil, have immune-modulating effects and may improve nutritional status in cancer. The objective of this study was to investigate the effects of an oral nutritional supplement containing (n-3) fatty acids on nutritional status and inflammatory markers in patients with non-small cell lung cancer (NSCLC) undergoing multimodality treatment. In a double-blind experiment, 40 patients with stage III NSCLC were randomly assigned to receive 2 cans/d of a protein- and energy-dense oral nutritional supplement containing (n-3) fatty acids (2.0 g EPA + 0.9 g DHA/d) or an isocaloric control supplement. EPA in plasma phospholipids, energy intake, resting energy expenditure (REE), body weight, fat free mass (FFM), mid-upper arm circumference (MUAC), and inflammatory markers were assessed. Effects of intervention were analyzed by generalized estimating equations and expressed as regression coefficients (B). The intervention group (I) had a better weight maintenance than the control (C) group after 2 and 4 wk (B = 1.3 and 1.7 kg, respectively; P < 0.05), a better FFM maintenance after 3 and 5 wk (B = 1.5 and 1.9 kg, respectively; P < 0.05), a reduced REE (B = -16.7% of predicted; P = 0.01) after 3 wk, and a trend for a greater MUAC (B = 9.1; P = 0.06) and lower interleukin-6 production (B = -27.9; P = 0.08) after 5 wk. After 4 wk, the I group had a higher energy and protein intake than the C group (B = 2456 kJ/24 h, P = 0.03 and B = 25.0 g, P = 0.01, respectively). In conclusion, a protein- and energy-dense oral nutritional supplement containing (n-3) fatty acids beneficially affects nutritional status during multimodality treatment in patients with NSCLC.

Antioxidant-enriched enteral nutrition and immuno-inflammatory response after major gastrointestinal tract surgery.

Major surgery induces an immuno-inflammatory response accompanied by oxidative stress that may impair cellular function and delay recovery. The objective of the study was to investigate the effect of an enteral supplement, containing glutamine and antioxidants, on circulating levels of immuno-inflammatory markers after major gastrointestinal tract surgery. Patients (n 21) undergoing major gastrointestinal tract surgery were randomised in a single-centre, open-label study. The effects on circulating levels of immuno-inflammatory markers were determined on the day before surgery and on days 1, 3, 5 and 7 after surgery. Major gastrointestinal surgery increased IL-6, TNF receptor 55/60 (TNF-R55) and C-reactive protein (CRP). Surgery reduced human leucocyte antigen-DR (HLA-DR) expression on monocytes. CRP decrease was more pronounced in the first 7 d in the treatment group compared with the control group. In the treatment group, from the moment Module AOX was administered on day 1 after surgery, TNF receptor 75/80 (TNF-R75) level decreased until the third post-operative day and then stabilised, whereas in the control group the TNF-R75 level continued to increase. The results of the present pilot study suggest that enteral nutrition enriched with glutamine and antioxidants possibly moderates the immuno-inflammatory response (CRP, TNF-R75) after surgery.

Low arginine/asymmetric dimethylarginine ratio deteriorates systemic hemodynamics and organ blood flow in a rat model.

OBJECTIVE: Both arginine and asymmetric dimethylarginine (ADMA) play a crucial role in the arginine-nitric oxide pathway. Low arginine and high ADMA levels can be found in critically ill patients after major surgery. The aim of this study was to evaluate the effects of low arginine plasma concentrations in combination with high ADMA plasma concentrations on hemodynamics and organ blood flow. DESIGN: Randomized, placebo-controlled animal laboratory investigation. SUBJECTS: Male Wistar rats (n = 21), anesthetized. INTERVENTIONS: Rats were randomly assigned to three groups: a control group, an ADMA group, or an arginase (ASE)/ADMA group. In the control group, rats received (at t = 0) an intravenous (IV) infusion of 1.5 mL 0.9% NaCl during a 20-minute period. After 60 minutes (t = 60), rats received an IV bolus of 1.0 mL 0.9% NaCl. In the ADMA group, rats received an IV infusion of 1.5 mL 0.9% NaCl during a 20-minute period and at t = 60 an IV bolus of 1.0 mL ADMA (20 mg/kg). In the ASE/ADMA group, rats received an IV infusion of 1.5 mL ASE (3200 IU) solution during a 20-minute period and at t = 60 an IV bolus of 1.0 mL ADMA (20 mg/kg). MEASUREMENTS AND MAIN RESULTS: Infusion of ADMA (20 mg/kg) and ASE (3200 IU) resulted in increased plasma ADMA levels and decreased arginine levels. During the whole experiment, systemic hemodynamics (heart rate, mean arterial pressure [MAP], and cardiac output) were measured. In addition, organ blood flow was measured at t = 90 and t = 180 minutes, using fluorescent microspheres. Compared with the control group, MAP and systemic vascular resistance were increased after infusion of ADMA. Infusion of ASE in combination with ADMA significantly deteriorated systemic hemodynamics (MAP, cardiac output, stroke volume, and systemic vascular resistance) and organ blood flow through the kidney and spleen. In addition, an initial decrease in arterial flow, followed by a later major increase, and panlobular apoptosis and necrosis of the liver was observed. CONCLUSIONS: The current study shows that low arginine plasma levels in combination with high ADMA plasma levels deteriorates systemic hemodynamics and reduces blood flow through the kidney and spleen and liver. These data suggest that a diminished nitric oxide production may be involved in the onset of organ failure.