A 4-week exercise and protein program improves muscle mass and physical functioning in older adults - A pilot study.

BACKGROUND: Prehabilitation might attenuate common surgery-induced losses in muscle mass and physical performance. Beneficial effects of physical exercise with protein supplementation have been reported in older adults, but typically after an intervention of at least 12 weeks. The time-window for pre-surgery training is often limited to around 30 days, and it is not known if it is possible to achieve comparable results in such a short time window. OBJECTIVES: The aim of this study was to pilot-test the effectiveness of a controlled four-week combined exercise and protein supplementation program on skeletal muscle-related outcomes in a Dutch older adult population. DESIGN: This study was a one-armed pilot trial. PARTICIPANTS: Seventeen older men and women, aged 55-75y, not scheduled for surgery. INTERVENTION: A 4-week intervention program consisting of a twice-weekly supervised resistance and high-intensity aerobic exercise training of 75 min, combined with daily protein supplementation (2 doses of 15.5 g/day at breakfast and lunch). MEASUREMENT: After two and four weeks, isometric quadriceps maximal voluntary contraction (MVC) was assessed via Biodex and quadriceps cross-sectional area (CSA) via magnetic resonance imaging. Other outcome measures were handgrip strength, chair rise time and maximal aerobic capacity (VO2-max), as assessed from a submaximal exercise test. RESULTS: Compliance to the supervised training sessions (99.3%) and the protein supplementation (97%) was very high. The 4-week exercise and protein program led to an increase in quadriceps CSA of 2.3 ± 0.7 cm2 (P = 0.008) in the dominant leg and 3.2 ± 0.7 cm2 (P < 0.001) in the non-dominant leg. Isometric quadriceps MVC increased in the dominant leg (Δ14 ± 4 Nm, P = 0.001) and in the non-dominant leg (Δ17 ± 5 Nm, P = 0.003). Chair rise test time improved with -3.8 ± 0.5 s (P < 0.0001), and VO2-max improved with 3.3 ± 1.1 ml/min/kg (P = 0.014). We observed no changes in body weight and handgrip strength. CONCLUSION: A 4-week exercise and protein intervention led to improvements in muscle-related outcomes in older adults with low levels of physical activity.

The Influence of Muscle Weakness on the Association Between Obesity and Inpatient Recovery From Total Hip Arthroplasty.

BACKGROUND: There is ongoing discussion about whether preoperative obesity is negatively associated with inpatient outcomes of total hip arthroplasty (THA). The aim was to investigate the interaction between obesity and muscle strength and the association with postoperative inpatient recovery after THA. METHODS: Preoperative obesity (body mass index [BMI] >30 kg/m2) and muscle weakness (hand grip strength <20 kg for woman and <30 kg for men) were measured about 6 weeks before THA. Patients with a BMI <18.5 kg/m2 were excluded. Outcomes were delayed inpatient recovery of activities (>2 days to reach independence of walking) and prolonged length of hospital stay (LOS, >4 days and/or discharge to extended rehabilitation). Univariate and multivariable regression analyses with the independent variables muscle weakness and obesity, and the interaction between obesity and muscle weakness, were performed and corrected for possible confounders. RESULTS: Two hundred and ninety-seven patients were included, 54 (18%) of whom were obese and 21 (7%) who also had muscle weakness. Obesity was not significantly associated with prolonged LOS (odds ratio [OR] 1.36, 95% confidence interval [CI] 0.75-2.47) or prolonged recovery of activities (OR 1.77, 95% CI 0.98-3.22), but the combination of obesity and weakness was significantly associated with prolonged LOS (OR 3.59, 95% CI 1.09-11.89) and prolonged recovery of activities (OR 6.21, 95% CI 1.64-23.65). CONCLUSION: Obesity is associated with inpatient recovery after THA only in patients with muscle weakness. The results of this study suggest that we should measure muscle strength in addition to BMI (or body composition) to identify patients at risk of prolonged LOS.

Taurine Concentrations Decrease in Critically Ill Patients With Shock Given Enteral Nutrition.

BACKGROUND: Nutrition studies in the intensive care unit (ICU) have shown that adequate enteral nutrition (EN) support has clinical benefits. However, the course of amino acid concentrations in plasma has never been investigated in patients admitted with shock receiving EN. We hypothesized that plasma concentrations, when deficit, increase during EN and that persistent deficiency is associated with poor outcome. METHODS: In 33 septic or cardiogenic shock patients receiving EN, plasma amino acid concentrations were measured during 5 days. Changes in amino acid concentrations, correlations with clinical outcome variables, and regression analyses were studied. RESULTS: On ICU admission, several plasma concentrations were deficient. Plasma concentrations of almost all amino acids increased. In contrast, taurine decreased by >50%, from 47.6 µmol/L on admission to 20.0 µmol/L at day 1, and remained low at day 5. Taurine (admission) correlated with time on mechanical ventilation (R = -0.42, P = .015). Taurine decrease within 24 hours correlated with Acute Physiology and Chronic Health Evaluation II predicted mortality (R = 0.43, P = .017) and Sequential Organ Failure Assessment score (R = 0.36, P = .05). Regression analyses confirmed correlations. CONCLUSIONS: Several amino acids were deficient in plasma on ICU admission but increased during EN. Taurine concentrations declined and were associated with longer periods of mechanical ventilation and ICU support. Fast taurine decline correlated with severity of organ failure. These findings support the role of taurine during ischemia, reperfusion, and inflammation. Taurine may be an essential candidate to enrich nutrition support for critically ill patients, although more research is required.

Nutrition before and during Surgery and the Inflammatory Response of the Heart: A Randomized Controlled Trial.

Major surgery induces a long fasting time and provokes an inflammatory response which increases the risk of infections. Nutrition given before and during surgery can avoid fasting and has been shown to increase the arginine/asymmetric dimetlhylarginine ratio, a marker of nitric oxide availability, in cardiac tissue and increased concentrations of branched chain amino acids in blood plasma. However, the effect of this new nutritional strategy on organ inflammatory response is unknown. Therefore, we studied the effect of nutrition before and during cardiac surgery on myocardial inflammatory response. In this trial, 32 patients were randomised between enteral, parenteral, and no nutrition supplementation (control) from 2 days before, during, up to 2 days after coronary artery bypass grafting. Both solutions included proteins or amino acids, glucose, vitamins, and minerals. Myocardial atrial tissue was sampled before and after revascularization and was analysed immunohistochemically, subdivided into cardiomyocytic, fatty, and fibrotic areas. Inflammatory cells, especially leukocytes, were present in cardiac tissue in all study groups. No significant differences were found in the myocardial inflammatory response between the enteral, parenteral, and control groups. In conclusion, nutrition given before and during surgery neither stimulates nor diminishes the myocardial inflammatory response in patients undergoing coronary artery bypass grafting. The trial was registered in Netherlands Trial Register (NTR): NTR2183.

Nutrition before, during, and after surgery increases the arginine:asymmetric dimethylarginine ratio and relates to improved myocardial glucose metabolism: a randomized controlled trial.

BACKGROUND: Nitric oxide (NO) is essential for the optimal perfusion of the heart and its vasculature. NO may be insufficient in surgical patients because its precursor arginine is decreased, and the inhibitor of NO synthesis asymmetric dimethylarginine (ADMA) is increased. Besides arginine, the presence of other amino acids essential for the proper metabolism of cardiac cells may be decreased too. Supplementation of these amino acids with enteral and parenteral nutrition before, during, and after surgery may augment the myocardial and plasma arginine:ADMA ratio and availability of amino acids. Myocardial glucose metabolism and nutritional conditioning may result in a reduction of cardiac injury and support rapid recovery after major surgery. OBJECTIVE: We investigated the effect of nutrition before, during, and after surgery on amino acids and the myocardial arginine:ADMA ratio and its relation to myocardial glucose metabolism. DESIGN: In this trial, 33 patients who were undergoing off-pump coronary artery bypass grafting (CABG) were randomly assigned between enteral, parenteral, or no nutrition (control) from 2 d before, during, and until 2 d after surgery. Both enteral and parenteral solutions were prepared with commercially available products and included proteins or amino acids, glucose, vitamins, and minerals. Concentrations of amino acids including ADMA were analyzed in myocardial tissue and plasma samples. ¹8F-fluorodeoxyglucose positron emission tomography was performed before and after surgery to assess myocardial glucose metabolism. RESULTS: The myocardial arginine:ADMA ratio increased during surgery and was significantly higher in the enteral and parenteral groups than in the control group [median (IQR): 115.0 (98.0-142.2) (P = 0.012), 116.9 (100.3-135.3) (P = 0.004), and 93.3 (82.7-101.1), respectively]. Furthermore, the change in the preoperative to postoperative plasma arginine:ADMA ratio correlated with the change in myocardial glucose metabolism in positron emission tomography (r = 0.427, P = 0.033). CONCLUSION: Enteral or parenteral nutrition before, during, and after CABG may positively influence myocardial glucose metabolism by increasing the plasma and myocardial arginine:ADMA ratio.

Cardiac surgery-specific screening tool identifies preoperative undernutrition in cardiac surgery.

BACKGROUND: Loss of body tissue resulting in undernutrition can be caused by reduced food intake, altered metabolism, ageing, and physical inactivity. The predominant cause of undernutrition before cardiac operations is unknown. First, we explored the association of reduced food intake and inactivity with undernutrition in patients before elective cardiac operations. Second, we assessed if adding these reversible, cause-based items to the nutritional screening process improved diagnostic accuracy. METHODS: A prospective observational study was performed. Undernutrition was defined by low fat-free mass index (LFFMI) measured by bioelectrical impedance spectroscopy and/or unintended weight loss (UWL). Reduced food intake was defined as the patient having a decreased appetite over the previous month. Patients admitted to hospital preoperatively were assumed to be less physically active than patients awaiting cardiac operations at home. Using these data, we developed a new tool and compared this with an existing cardiac surgery-specific tool (Cardiac Surgery-Specific Malnutrition Universal Screening Tool [CSSM]). RESULTS: A total of 325 patients who underwent open cardiac operations were included. Reduced food intake and inactivity were associated with undernutrition (odds ratio [OR], 4.2; 95% confidence interval [CI], 2.1-8.5 and OR, 2.0; 95% CI, 1.0-4.0). Reduced food intake and inactivity were integrated with body mass index (BMI) and UWL into a new scoring system: the Cardiac Surgery-Specific Undernutrition Screening Tool (CSSUST). Sensitivity in identification of undernourished patients was considerably higher with the CSSUST (90%) than with the CSSM (71%) (receiver operating characteristic [ROC] curve-based area under the curve [AUC], 0.79; 95% CI, 0.73-0.86 and ROC AUC, 0.71; 95% CI, 0.63-0.80). CONCLUSIONS: Results suggest that reduced food intake and inactivity partly explain undernutrition before cardiac operations. Our new cause-based CSSUST, which includes reduced food intake and inactivity, is superior to existing tools in identifying undernutrition in patients undergoing cardiac operations.

The bioelectrical impedance phase angle as an indicator of undernutrition and adverse clinical outcome in cardiac surgical patients.

BACKGROUND & AIMS: In cardiac surgical patients, undernutrition increases the risk of adverse clinical outcome. We investigated whether the bioelectrical impedance phase angle is an indicator of undernutrition and clinical outcome in cardiac surgery. METHODS: In 325 cardiac surgical patients, we prospectively analyzed the associations between a preoperative low phase angle, measured by bioelectrical impedance spectroscopy, and well-established indicators of undernutrition such as body mass index (kg/m(2)), unintended weight loss, and fat free mass index (kg/m(2)), and muscle strength (handgrip strength (kg)), immune function (C-reactive protein and albumin), and adverse clinical outcomes. RESULTS: A low phase angle (<5.38°) was present in 29.8% (n = 96) of the patients, and was associated with low body mass index (p < 0.001), low fat free mass index (p < 0.001), and less handgrip strength (p = 0.063), but not with unintended weight loss or immune function. Furthermore, a preoperative low phase angle was associated with a prolonged intensive care unit and hospital stay (adj. hazard ratio: 0.68; 95%CI: 0.49-0.94; p = 0.020 and adj. hazard ratio: 0.74; 95%CI: 0.55-0.99; p = 0.048, respectively). CONCLUSIONS: A preoperative low bioelectrical impedance phase angle is associated with undernutrition, and increases the risk of adverse clinical outcome after cardiac surgery. The phase angle might help to identify undernourished cardiac surgical 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.

Role of dimethylarginine dimethylaminohydrolase activity in regulation of tissue and plasma concentrations of asymmetric dimethylarginine in an animal model of prolonged critical illness.

High plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are associated with adverse outcome in critically ill patients. Asymmetric dimethylarginine is released within cells during proteolysis of methylated proteins and is either degraded by dimethylarginine dimethylaminohydrolase (DDAH) or exported to the circulation via cationic amino acid transporters. We aimed to establish the role of DDAH activity in the regulation of tissue and plasma concentrations of ADMA. In 33 critically ill rabbits, we measured DDAH activity in kidney, liver, heart, and skeletal muscle and related these values to concentrations of ADMA in these tissues and in the circulation. Both DDAH activity and ADMA concentration were highest in kidney and lowest in skeletal muscle, with intermediate values for liver and heart. Whereas ADMA content was significantly correlated between tissues (r = 0.40-0.78), DDAH activity was not. Significant inverse associations between DDAH activity and ADMA content were only observed in heart and liver. Plasma ADMA was significantly associated with ADMA in the liver (r = 0.41), but not in the other tissues. In a multivariable regression model, DDAH activities in muscle, kidney, and liver, but not in heart, were negatively associated with plasma ADMA concentration, together explaining approximately 50% of its variation. In critical illness, plasma ADMA poorly reflects intracellular ADMA. Furthermore, tissue DDAH activity is a stronger predictor of plasma ADMA than of intracellular ADMA, indicating that, compared with DDAH activity, generation of ADMA and cationic amino acid transporter-mediated exchange may be more important regulators of intracellular ADMA.

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.

Rationale and design of a proof-of-concept trial investigating the effect of uninterrupted perioperative (par)enteral nutrition on amino acid profile, cardiomyocytes structure, and cardiac perfusion and metabolism of patients undergoing coronary artery bypass grafting.

BACKGROUND: Malnutrition is very common in patients undergoing cardiac surgery. Malnutrition can change myocardial substrate utilization which can induce adverse effects on myocardial metabolism and function. We aim to investigate the hypothesis that there is a disturbed amino acids profile in the cardiac surgical patient which can be normalized by (par)enteral nutrition before, during and after surgery, subsequently improving cardiomyocyte structure, cardiac perfusion and glucose metabolism. METHODS/DESIGN: This randomized controlled intervention study investigates the effect of uninterrupted perioperative (par)enteral nutrition on cardiac function in 48 patients undergoing coronary artery bypass grafting. Patients are given enteral nutrition (n = 16) or parenteral nutrition (n = 16), at least two days before, during, and two days after coronary artery bypass grafting, or are treated according to the standard guidelines (control) (n = 16). We will illustrate the effect of (par)enteral nutrition on differences in concentrations of amino acids and asymmetric dimethylarginine and in activity of dimethylarginine dimethylaminohydrolase and arginase in cardiac tissue and blood plasma. In addition, cardiomyocyte structure by histological, immuno-histochemical and ultrastructural analysis will be compared between the (par)enteral and control group. Furthermore, differences in cardiac perfusion and global left ventricular function and glucose metabolism, and their changes after coronary artery bypass grafting are evaluated by electrocardiography-gated myocardial perfusion scintigraphy and ¹8F-fluorodeoxy-glucose positron emission tomography respectively. Finally, fat free mass is measured before and after intervention with bioelectrical impedance spectrometry in order to evaluate nutritional status. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2183.

The role of asymmetric dimethylarginine and arginine in the failing heart and its vasculature.

Nitric oxide (NO) is formed from arginine by the enzyme nitric oxide synthase (NOS). Asymmetric dimethylarginine (ADMA) can inhibit NO production by competing with arginine for NOS binding. Therefore, the net amount of NO might be indicated by the arginine/ADMA ratio. In turn, arginine can be metabolized by the enzyme arginase, and ADMA by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). While ADMA has been implicated as a cardiovascular risk factor, arginine supplementation has been indicated as a treatment in cardiac diseases. This review discusses the roles of ADMA and arginine in the failing heart and its vasculature. Furthermore, it proposes nutritional therapies to improve NO availability.