Effects of Nutritional Interventions on Nutritional and Functional Outcomes in Geriatric Rehabilitation Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: It has been recognized that nutritional interventions play a role in improving the nutritional and functional status of older persons. This systematic review summarizes the evidence on nutritional and functional outcomes of nutritional interventions alone or in combination with physical exercise in geriatric rehabilitation patients. DESIGN: Eight electronic databases were searched until July 1, 2019 to identify nutritional intervention studies in patients aged ≥60 years who were admitted to geriatric rehabilitation. A meta-analysis was performed to quantify intervention effects on serum albumin, muscle mass, and hand grip strength (HGS). RESULTS: A total of 1962 studies were screened and 13 included in the systematic review. Studies were heterogeneous in interventions (4 nutritional interventions, 6 physical exercise + nutritional intervention, 1 timing of protein provision, 1 exercise + dietary advice, 1 nutrition-related nursing care) and outcomes. Among the 9 interventions that tested oral nutritional supplements (ONS) with protein, with or without exercise, 7 studies reported protein intake and 6 showed increased protein intakes, 2 of 5 studies showed increased albumin levels, and 5 of 9 reported an improvement in functional outcomes (BI, Functional Independence Measure, mobility). Meta-analyses showed no significant intervention effects on albumin [standardized mean difference (SMD) 0.45, 95% confidence interval (CI) -0.14, 1.04 (4 studies)], muscle mass [mean difference (MD) 2.14 kg, 95% CI -2.17, 6.45 (3 studies)], and HGS [SMD -0.04, 95% CI -0.55, 0.63 (3 studies)], but was based on a very limited number of studies. CONCLUSIONS AND IMPLICATIONS: Only a limited number of studies with heterogeneous nutritional interventions and outcomes were available in the geriatric rehabilitation population. Studies that included ONS improved nutritional outcomes, especially protein intake and albumin levels. Functional outcomes improved in the majority of reporting studies. This indicates benefits of protein supplementation, with or without exercise, in this population. Future well-designed and well-powered clinical trials are needed to clarify existing controversial aspects.

Effect of Sit-to-Stand Exercises Combined With Protein-Rich Oral Supplementation in Older Persons: The Older Person's Exercise and Nutrition Study.

OBJECTIVES: Nursing home (NH) residents are often undernourished and physically inactive, which contributes to sarcopenia and frailty. The Older Person's Exercise and Nutrition Study aimed to investigate the effects of sit-to-stand exercises (STS) integrated into daily care, combined with a protein-rich oral nutritional supplement (ONS), on physical function, nutritional status, body composition, health-related quality of life, and resource use. DESIGN: Residents in 8 NHs were randomized by NH units into an intervention group (IG) or a control group (CG) (n = 60/group). The IG was a combination of STS (4 times/day) and ONS (2 bottles/day providing 600 kcal and 36 g protein) for 12 weeks. SETTING AND PARTICIPANTS: The participants resided in NH units (dementia and somatic care), were ≥75 years of age, and able to rise from a seated position. METHODS: The 30-second Chair Stand Test was the primary outcome. Secondary outcomes were balance, walking speed, dependence in activities of daily living, nutritional status and body composition, health-related quality of life, and resource use. RESULTS: Altogether, 102 residents (age 86 ± 5 years, 62% female) completed the study. No improvement in the physical function assessments was observed in the IG, whereas body weight increased significantly (2.05 ± 3.5 kg, P = .013) vs the CG. Twenty-one (of 52) participants with high adherence to the intervention (ie, at least 40% compliance to the combined intervention) increased their fat free mass (2.12 kg (0.13, 4.26 interquartile range), P = .007 vs CG). Logistic regression analyses indicated that the odds ratio for maintained/improved 30-second Chair Stand Test was 3.5 (confidence interval 1.1, 10.9, P = .034) among the participants with high adherence compared with the CG. CONCLUSIONS/IMPLICATIONS: Twelve-week intervention of daily STS combined with ONS in NH residents did not improve physical function, but increased body weight. Subgroup analyses indicated that high adherence to the combined intervention was associated with maintained or improved physical function and a gain of fat free mass.

Differential effects of leucine and leucine-enriched whey protein on skeletal muscle protein synthesis in aged mice.

BACKGROUND & AIMS: It has been suggested that anabolic resistance, or a blunted protein synthetic response to anabolic stimuli, contributes to the failure of muscle mass maintenance in older adults. The amino acid leucine is one of the most prominent food-related anabolic stimuli. However, data on muscle protein synthesis (MPS) after administration of a single bolus of leucine in aged populations is lacking and long-term single leucine supplementation has not been shown to increase muscle mass. This study aimed to determine the MPS response to the administration of a single bolus of leucine or to leucine combined with whey protein, in aged mice. METHODS: Overnight fasted C57/BL6RJ mice at 25-mo of age received an oral gavage with leucine or whey-protein enriched with leucine (0.75 g/kg bodyweight total leucine in both) or 0.5 mL water (fasted control). Subsequently, mice were s.c. injected with puromycin (0.04 µmol/g bw at t = 30, 45 or 60 min) and were sacrificed 30 min thereafter. Amino acid concentrations were determined in plasma and right muscle tibialis anterior (TA). Left TA was used to analyse MPS by SUnSET method and phosphorylation rate of Akt, 4E-BP1 and p70S6k by western blot. RESULTS: In aged mice, leucine administration failed to increase MPS, despite a 6-fold increase in plasma leucine and elevated muscle free leucine levels (P < 0.05). In contrast, leucine-enriched whey protein significantly stimulated MPS in aged mice at 60 min after gavage (P < 0.05). Muscle free EAA, NEAA and the phosphorylation rate of Akt, 4E-BP1 and p70S6k increased significantly (P < 0.05), only after administration of leucine-enriched whey protein. CONCLUSIONS: MPS is stimulated in aged mice by leucine-enriched whey protein but not by leucine administration only. Administration of other amino acids may be required for leucine administration to stimulate muscle protein synthesis in aged mice.

Both basal and post-prandial muscle protein synthesis rates, following the ingestion of a leucine-enriched whey protein supplement, are not impaired in sarcopenic older males.

BACKGROUND: Studying the muscle protein synthetic response to food intake in elderly is important, as it aids the development of interventions to combat sarcopenia. Although sarcopenic elderly are the target group for many of these nutritional interventions, no studies have assessed basal or post-prandial muscle protein synthesis rates in this population. OBJECTIVE: To assess the basal and post-prandial muscle protein synthesis rates between healthy and sarcopenic older men. DESIGN: A total of 15 healthy (69 ± 1 y) and 15 sarcopenic (81 ± 1 y) older men ingested a leucine-enriched whey protein nutritional supplement containing 21 g of protein, 9 g of carbohydrate, and 3 g of fat. Stable isotope methodology combined with frequent collection of blood and muscle samples was applied to assess basal and post-prandial muscle protein fractional synthetic rates. Handgrip strength, muscle mass, and gait speed were assessed to identify sarcopenia, according to international criteria. RESULTS: Basal mixed muscle protein fractional synthetic rates (FSR) averaged 0.040 ± 0.005 and 0.032 ± 0.003%/h (mean ± SEM) in the sarcopenic and healthy group, respectively (P = 0.14). Following protein ingestion, FSR increased significantly to 0.055 ± 0.004 and 0.053 ± 0.004%/h in the post-prandial period in the sarcopenic (P = 0.003) and healthy groups (P < 0.001), respectively, with no differences between groups (P = 0.45). Furthermore, no differences were observed between groups in muscle protein synthesis rates during the early (0.058 ± 0.007 vs 0.060 ± 0.008%/h, sarcopenic vs healthy, respectively) and late (0.052 ± 0.004 vs 0.048 ± 0.003%/h) stages of the post-prandial period (P = 0.93 and P = 0.34, respectively). CONCLUSIONS: Basal muscle protein synthesis rates are not lower in sarcopenic older men compared to healthy older men. The ingestion of 21 g of a leucine-enriched whey protein effectively increases muscle protein synthesis rates in both sarcopenic and healthy older men. Public trial registry number: NTR3047.

Differences in Nutrient Intake and Biochemical Nutrient Status Between Sarcopenic and Nonsarcopenic Older Adults-Results From the Maastricht Sarcopenia Study.

BACKGROUND: There is growing evidence of a relationship between nutrients and muscle mass, strength, and physical performance. Although nutrition is seen as an important pillar of treating sarcopenia, data on the nutritional intake of sarcopenic older adults are limited. OBJECTIVE: To investigate potential nutritional gaps in the sarcopenic population, the present study compared nutrient intake and biochemical nutrient status between sarcopenic and nonsarcopenic older adults. DESIGN: The Maastricht Sarcopenia Study included 227 community-dwelling older adults (≥65 years) from Maastricht, 53 of whom were sarcopenic based on the European Working Group on Sarcopenia in Older People algorithm. Habitual dietary intake was assessed with a food frequency questionnaire and data on dietary supplement use were collected. In addition, serum 25-hydroxyvitamin D, magnesium and α-tocopherol/cholesterol, plasma homocysteine and red blood cell n-3, and n-6 fatty acids profiles were assessed. Nutrient intake and biochemical nutrient status of the sarcopenic groups were compared with those of the nonsarcopenic groups. The robustness of these results was tested with a multiple regression analysis, taking into account between-group differences in characteristics. RESULTS: Sarcopenic older adults had a 10%-18% lower intake of 5 nutrients (n-3 fatty acids, vitamin B6, folic acid, vitamin E, magnesium) compared with nonsarcopenic older adults (P < .05). When taking into account dietary supplement intake, a 19% difference remained for n-3 fatty acids intake (P = .005). For the 2 biochemical status markers, linoleic acid and homocysteine, a 7% and 27% difference was observed, respectively (P < .05). The higher homocysteine level confirmed the observed lower vitamin B intake in the sarcopenic group. Observed differences in eicosapentaenoic acid and 25-hydroxyvitamin D between the groups were related to differences in age and living situation. CONCLUSIONS: Sarcopenic older adults differed in certain nutritional intakes and biochemical nutrient status compared with nonsarcopenic older adults. Dietary supplement intake reduced the gap for some of these nutrients. Targeted nutritional intervention may therefore improve the nutritional intake and biochemical status of sarcopenic older adults.

Protein type and caloric density of protein supplements modulate postprandial amino acid profile through changes in gastrointestinal behaviour: A randomized trial.

BACKGROUND & AIMS: The requirement of leucine and essential amino acids (EAA) to stimulate muscle protein synthesis increases with age. To target muscle anabolism it is suggested that higher postprandial blood levels of leucine and EAA are needed in older people. The aim was to evaluate the impact of oral nutritional supplements with distinct protein source and energy density, resembling mixed meals, on serum amino acid profiles and on gastrointestinal behaviour. METHODS: Four iso-nitrogenous protein (21 g) supplements were studied containing leucine-enriched whey protein with 150/320 kcal (W150/W320) or casein protein with 150/320 kcal (C150/C320); all products contained carbohydrates (10 or 32 g) and fat (3 or 12 g). Postprandial serum AA profiles were evaluated in twelve healthy, older subjects who participated in a randomized, controlled, single blind, cross-over study. Gastrointestinal behaviour was studied in vitro by looking at gastric coagulation and cumulative intestinal protein digestion over time. RESULTS: The peak serum leucine concentration was twofold higher for W150 vs. C150 (521 ± 15 vs. 260 ± 15 µmol/L, p < 0.001), higher for W320 vs. C320 (406 ± 15 vs. 228 ± 15 µmol/L, p < 0.001), and higher for low-caloric vs. high-caloric products (p < 0.001 for pooled analyses; p < 0.001 for interaction protein source*caloric density). Similar effects were observed for the peak concentrations of EAA and total AA (TAA). In vitro gastric coagulation was observed only for the casein protein supplements. Intestinal digestion for 90 min resulted in higher levels of free TAA, EAA, and leucine for W150 vs. C150, for W150 vs. W320, and for C150 vs. C320 (p < 0.0125). CONCLUSIONS: A low caloric leucine-enriched whey protein nutritional supplement provides a higher rise in serum levels of TAA, EAA and leucine compared to casein protein or high caloric products in healthy, elderly subjects. These differences appear to be mediated in part by the gastrointestinal behaviour of these products. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02013466.

Micronutrient intakes and potential inadequacies of community-dwelling older adults: a systematic review.

Micronutrient deficiencies and low dietary intakes among community-dwelling older adults are associated with functional decline, frailty and difficulties with independent living. As such, studies that seek to understand the types and magnitude of potential dietary inadequacies might be beneficial for guiding future interventions. We carried out a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Observational cohort and longitudinal studies presenting the habitual dietary intakes of older adults (≥65 years) were included. Sex-specific mean (and standard deviation) habitual micronutrient intakes were extracted from each article to calculate the percentage of older people who were at risk for inadequate micronutrient intakes using the estimated average requirement (EAR) cut-point method. The percentage at risk for inadequate micronutrient intakes from habitual dietary intakes was calculated for twenty micronutrients. A total of thirty-seven articles were included in the pooled systematic analysis. Of the twenty nutrients analysed, six were considered a possible public health concern: vitamin D, thiamin, riboflavin, Ca, Mg and Se. The extent to which these apparent inadequacies are relevant depends on dynamic factors, including absorption and utilisation, vitamin and mineral supplement use, dietary assessment methods and the selection of the reference value. In light of these considerations, the present review provides insight into the type and magnitude of vitamin and mineral inadequacies.

Arginine infusion in patients with septic shock increases nitric oxide production without haemodynamic instability.

Arginine deficiency in sepsis may impair nitric oxide (NO) production for local perfusion and add to the catabolic state. In contrast, excessive NO production has been related to global haemodynamic instability. Therefore, the aim of the present study was to investigate the dose-response effect of intravenous arginine supplementation in post-absorptive patients with septic shock on arginine-NO and protein metabolism and on global and regional haemodynamics. Eight critically ill patients with a diagnosis of septic shock participated in this short-term (8 h) dose-response study. L-Arginine-HCl was continuously infused [intravenously (IV)] in three stepwise-increasing doses (33, 66 and 99 µmol·kg-1·h-1). Whole-body arginine-NO and protein metabolism were measured using stable isotope techniques, and baseline values were compared with healthy controls. Global and regional haemodynamic parameters were continuously recorded during the study. Upon infusion, plasma arginine increased from 48±7 to 189±23 µmol·l-1 (means±S.D.; P<0.0001). This coincided with increased de novo arginine (P<0.0001) and increased NO production (P<0.05). Sepsis patients demonstrated elevated protein breakdown at baseline (P<0.001 compared with healthy controls), whereas protein breakdown and synthesis both decreased during arginine infusion (P<0.0001). Mean arterial and pulmonary pressure and gastric mucosal-arterial partial pressure of carbon dioxide difference (Pr-aCO2) gap did not alter during arginine infusion (P>0.05), whereas stroke volume (SV) increased (P<0.05) and arterial lactate decreased (P<0.05). In conclusion, a 4-fold increase in plasma arginine with intravenous arginine infusion in sepsis stimulates de novo arginine and NO production and reduces whole-body protein breakdown. These potential beneficial metabolic effects occurred without negative alterations in haemodynamic parameters, although improvement in regional perfusion could not be demonstrated in the eight patients with septic shock who were studied.

Postprandial muscle protein synthesis is higher after a high whey protein, leucine-enriched supplement than after a dairy-like product in healthy older people: a randomized controlled trial.

BACKGROUND: Decreased ability of muscles to respond to anabolic stimuli is part of the underlying mechanism for muscle loss with aging. Previous studies suggest that substantial amounts of essential amino acids (EAA), whey protein and leucine are beneficial for stimulation of acute muscle protein synthesis in older adults. However, these studies supplied only proteins, and no bolus studies have been done with dairy products or supplements that contained also fat and carbohydrates besides proteins. The aim of this study was to evaluate whether a specifically designed nutritional supplement in older adults stimulates muscle protein synthesis acutely to a greater extent than a conventional dairy product. Moreover, the combined effect with resistance exercise was studied by using a unilateral resistance exercise protocol. METHODS: Utilizing a randomized, controlled, double blind study design, healthy older adults received a single bolus of a high whey protein, leucine-enriched supplement (EXP: 20 g whey protein, 3g total leucine, 150 kcal; n = 9) or an iso-caloric milk protein control ( CONTROL: 6g milk protein; n = 10), immediately after unilateral resistance exercise. Postprandial mixed muscle protein fractional synthesis rate (FSR) was measured over 4h using a tracer infusion protocol with L-[ring-¹³C6]-phenylalanine and regular blood and muscle sampling. RESULTS: FSR was significantly higher overall after EXP (0.0780 ± 0.0070%/h) vs CONTROL (0.0574 ± 0.0066%/h (EMM ± SE)) (p = 0.049). No interaction between treatment and exercise was observed (p = 0.519). Higher postprandial concentrations of EAA and leucine are possible mediating factors for the FSR response, while plasma insulin increase did not dictate the FSR response. Moreover, when the protein intake from the supplements was expressed per kg leg lean mass (LLM), a significant correlation was observed with resting postprandial FSR (r = 0.48, P = 0.038). CONCLUSIONS: Ingestion of a high whey protein, leucine-enriched supplement resulted in a larger overall postprandial muscle protein synthesis rate in healthy older subjects compared with a conventional dairy product. This acute effect is promising for long-term effects on parameters of muscle mass, strength and function in sarcopenic older people, which requires further study. TRIAL REGISTRATION: This trial is registered in the Dutch Trial Register under number NTR1823.

Arginine de novo and nitric oxide production in disease states.

Arginine is derived from dietary protein intake, body protein breakdown, or endogenous de novo arginine production. The latter may be linked to the availability of citrulline, which is the immediate precursor of arginine and limiting factor for de novo arginine production. Arginine metabolism is highly compartmentalized due to the expression of the enzymes involved in arginine metabolism in various organs. A small fraction of arginine enters the NO synthase (NOS) pathway. Tetrahydrobiopterin (BH4) is an essential and rate-limiting cofactor for the production of NO. Depletion of BH4 in oxidative-stressed endothelial cells can result in so-called NOS3 "uncoupling," resulting in production of superoxide instead of NO. Moreover, distribution of arginine between intracellular transporters and arginine-converting enzymes, as well as between the arginine-converting and arginine-synthesizing enzymes, determines the metabolic fate of arginine. Alternatively, NO can be derived from conversion of nitrite. Reduced arginine availability stemming from reduced de novo production and elevated arginase activity have been reported in various conditions of acute and chronic stress, which are often characterized by increased NOS2 and reduced NOS3 activity. Cardiovascular and pulmonary disorders such as atherosclerosis, diabetes, hypercholesterolemia, ischemic heart disease, and hypertension are characterized by NOS3 uncoupling. Therapeutic applications to influence (de novo) arginine and NO metabolism aim at increasing substrate availability or at influencing the metabolic fate of specific pathways related to NO bioavailability and prevention of NOS3 uncoupling. These include supplementation of arginine or citrulline, provision of NO donors including inhaled NO and nitrite (sources), NOS3 modulating agents, or the targeting of endogenous NOS inhibitors like asymmetric dimethylarginine.

Increased protein-energy intake promotes anabolism in critically ill infants with viral bronchiolitis: a double-blind randomised controlled trial.

OBJECTIVE: The preservation of nutritional status and growth is an important aim in critically ill infants, but difficult to achieve due to the metabolic stress response and inadequate nutritional intake, leading to negative protein balance. This study investigated whether increasing protein and energy intakes can promote anabolism. The primary outcome was whole body protein balance, and the secondary outcome was first pass splanchnic phenylalanine extraction (SPE(Phe)). DESIGN: This was a double-blind randomised controlled trial. Infants (n=18) admitted to the paediatric intensive care unit with respiratory failure due to viral bronchiolitis were randomised to continuous enteral feeding with protein and energy enriched formula (PE-formula) (n=8; 3.1 ± 0.3 g protein/kg/24 h, 119 ± 25 kcal/kg/24 h) or standard formula (S-formula) (n=10; 1.7 ± 0.2 g protein/kg/24 h, 84 ± 15 kcal/kg/24 h; equivalent to recommended intakes for healthy infants <6 months). A combined intravenous-enteral phenylalanine stable isotope protocol was used on day 5 after admission to determine whole body protein metabolism and SPE(Phe). RESULTS: Protein balance was significantly higher with PE-formula than with S-formula (PE-formula: 0.73 ± 0.5 vs S-formula: 0.02 ± 0.6 g/kg/24 h) resulting from significantly increased protein synthesis (PE-formula: 9.6 ± 4.4, S-formula: 5.2 ± 2.3 g/kg/24 h), despite significantly increased protein breakdown (PE-formula: 8.9 ± 4.3, S-formula: 5.2 ± 2.6 g/kg/24 h). SPE(Phe) was not statistically different between the two groups (PE-formula: 39.8 ± 18.3%, S-formula: 52.4 ± 13.6%). CONCLUSIONS: Increasing protein and energy intakes promotes protein anabolism in critically ill infants in the first days after admission. Since this is an important target of nutritional support, increased protein and energy intakes should be preferred above standard intakes in these infants. Dutch Trial Register number: NTR 515.

Effects of L-arginine pretreatment on nitric oxide metabolism and hepatosplanchnic perfusion during porcine endotoxemia.

BACKGROUND: Sepsis is accompanied by an increased need for and a decreased supply of arginine, reflecting a condition of arginine deficiency. OBJECTIVE: The objective was to evaluate the effects of l-arginine pretreatment on arginine-nitric oxide (NO) production and hepatosplanchnic perfusion during subsequent endotoxemia. DESIGN: In a randomized controlled trial, pigs (20-25 kg) received 3 µg . kg(-1) . min(-1) lipopolysaccharide (LPS; 5 endotoxin units/ng) intravenously and saline resuscitation. l-Arginine (n = 8; 5.3 µmol . kg(-1) . min(-1)) or saline (n = 8) was infused starting 12 h before LPS infusion and continued for 24 h after the endotoxin infusion ended. Whole-body appearance rates, portal-drained viscera (PDV), and liver fluxes of arginine, citrulline, NO, and arginine de novo synthesis were measured by using stable-isotope infusion of [(15)N(2)]arginine and [(13)C-(2)H(2)]citrulline. Hepatosplanchnic perfusion was assessed by using a primed continuous infusion of para-aminohippuric acid and jejunal intramucosal partial pressure of carbon dioxide and was related to systemic hemodynamics. RESULTS: Arginine supplementation before LPS increased whole-body NO production in the PDV but not in the liver. Furthermore, it increased blood flow in the portal vein but not in the aorta and hepatic artery. During endotoxin infusion, arginine pretreatment was associated with an increased whole-body arginine appearance and NO production in the gut. Additional effects included a preserved mean arterial pressure, the prevention of an increase in pulmonary arterial pressure, an attenuated metabolic acidosis, and an attenuated increase in the intramucosal partial pressure of carbon dioxide. CONCLUSION: Arginine treatment starting before endotoxemia appears to be beneficial because it improves hepatosplanchnic perfusion and oxygenation during prolonged endotoxemia, probably through an enhancement in NO synthesis, without causing deleterious systemic side effects.

Regulation of nitric oxide production in health and disease.

PURPOSE OF REVIEW: The purpose of this review is to highlight recent publications examining nitric oxide production in health and disease and its association with clinical nutrition and alterations in metabolism. RECENT FINDINGS: The role of the cofactor tetrahydrobiopterin in nitric oxide production and its relation with arginine availability is indicated as an important explanation for the arginine paradox. This offers potential for nitric oxide regulation by dietary factors such as arginine or its precursors and vitamin C. Because diets with a high saturated fat content induce high plasma fatty acid levels, endothelial nitric oxide production is often impaired due to a reduction in nitric oxide synthase 3 phosphorylation. Increasing the arginine availability by arginine therapy or arginase inhibition was, therefore, proposed as a potential therapy to treat hypertension. Recent studies in septic patients and transgenic mice models found that inadequate de-novo arginine production from citrulline reduces nitric oxide production. Citrulline supplementation may, therefore, be a novel therapeutic approach in conditions of arginine deficiency. SUMMARY: Both lack and excess of nitric oxide production in diseases can have various important implications in which dietary factors can play a modulating role. Future research is needed to expand our understanding of the regulation and adequate measurement of nitric oxide production at the organ level and by the different nitric oxide synthase isoforms, also in relation to clinical nutrition.

Exogenous arginine in sepsis.

Sepsis is a severe condition in critically ill patients and is considered an arginine deficiency state. The rationale for arginine deficiency in sepsis is mainly based on the reduced arginine levels in sepsis that are associated with the specific changes in arginine metabolism related to endothelial dysfunction, severe catabolism, and worse outcome. Exogenous arginine supplementation in sepsis shows controversial results with only limited data in humans and variable results in animal models of sepsis. Since in these studies the severity of sepsis varies but also the route, timing, and dose of arginine, it is difficult to draw a definitive conclusion for sepsis in general without considering the influence of these factors. Enhanced nitric oxide production in sepsis is related to suggested detrimental effects on hemodynamic instability and enhanced oxidative stress. Potential mechanisms for beneficial effects of exogenous arginine in sepsis include enhanced (protein) metabolism, improved microcirculation and organ function, effects on immune function and antibacterial effects, improved gut function, and an antioxidant role of arginine. We recently performed a study indicating that arginine can be given to septic patients without major effects on hemodynamics, suggesting that more studies can be conducted on the effects of arginine supplementation in septic patients.

Biomarkers of arginine and lysine excess.

Arginine supplementation is used in several disease states. In arginine-deficient states, supplementation is a logical choice of therapy. However, the definition of an arginine-deficient state is complex. For example, plasma arginine levels could be within normal range but intracellular arginine levels could be reduced because of membrane transport problems. Lysine competes with arginine for transport into the cell. In these situations, arginine supplementation of higher than required levels is proposed. Arginine has several important functions in metabolism as it is a precursor of metabolically active components such as nitric oxide (NO), ornithine, creatine, and polyamines. Supplementing arginine in excess could potentially overstimulate metabolism via enhanced production of NO. NO is a reactive component that, via production of radicals, will inactivate proteins. NO is also a powerful vasodilator, which could lead to severe hemodynamic instability. A good marker for excess supplementation of arginine or lysine could be an increased or reduced production rate of NO. However, NO production is difficult to measure because NO is a very labile component and is rapidly oxidized in blood. Stable isotope-labeled arginine and citrulline are used to trace the arginine-NO route. During supplementation of arginine in septic pigs or patients in septic shock, NO production, measured with stable isotope technology, is enhanced.

The role of arginine in infection and sepsis.

Sepsis is a systemic response to an infection, with high morbidity and mortality rates. Metabolic changes during infection and sepsis could be related to changes in metabolism of the amino acid L-arginine. In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery because both endogenous de novo arginine production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine via the arginase and nitric oxide pathways. As a result, lowered plasma arginine levels are usually found. Arginine may therefore be considered as an essential amino acid in sepsis, and supplementation could be beneficial in sepsis by improving microcirculation and protein anabolism. L-Arginine supplementation in a hyperdynamic pig model of sepsis prohibits the increase in pulmonary arterial blood pressure, improves muscle and liver protein metabolism, and restores the intestinal motility pattern. Arguments raised against arginine supplementation are mainly pointed at stimulating nitric oxide (NO) production, with concerns about toxicity of increased NO and hemodynamic instability with refractory hypotension. NO synthase inhibition, however, increased mortality. Arginine supplementation in septic patients has transient effects on hemodynamics when supplied as a bolus but seems without hemodynamic side effects when supplied continuously. In conclusion, arginine could have an essential role in infection and sepsis.

Sepsis: an arginine deficiency state?

OBJECTIVE: Sepsis is a major health problem considering its significant morbidity and mortality rate. The amino acid L-arginine has recently received substantial attention in relation to human sepsis. However, knowledge of arginine metabolism during sepsis is limited. Therefore, we reviewed the current knowledge about arginine metabolism in sepsis. DATA SOURCE: This review summarizes the literature on arginine metabolism both in general and in relation to sepsis. Moreover, arginine-related therapies are reviewed and discussed, which includes therapies of both nitric oxide (NO) and arginine administration and therapies directed toward inhibition of NO. DATA: In sepsis, protein breakdown is increased, which is a key process to maintain arginine delivery, because both endogenous de novo production from citrulline and food intake are reduced. Arginine catabolism, on the other hand, is markedly increased by enhanced use of arginine in the arginase and NO pathways. As a result, lowered plasma arginine levels are usually found. Clinical symptoms of sepsis that are related to changes in arginine metabolism are mainly related to hemodynamic alterations and diminished microcirculation. NO administration and arginine supplementation as a monotherapy demonstrated beneficial effects, whereas nonselective NO synthase inhibition seemed not to be beneficial, and selective NO synthase 2 inhibition was not beneficial overall. CONCLUSIONS: Because sepsis has all the characteristics of an arginine-deficiency state, we hypothesise that arginine supplementation is a logical option in the treatment of sepsis. This is supported by substantial experimental and clinical data on NO donors and NO inhibitors. However, further evidence is required to prove our hypothesis.

Pros and cons of L-arginine supplementation in disease.

The amino acid arginine and one of its metabolites NO have gathered broad attention in the last decade. Although arginine is regarded as a conditionally essential amino acid in disease, L-arginine supplementation in severe illness has not found its way into clinical practice. This might be due to the invalid interpretation of results from studies with immune-enhancing diets containing L-arginine amongst other pharmaconutrients. However, not much attention is given to research using L-arginine as a monotherapy and the possibility of the alternative hypothesis: that L-arginine supplementation is beneficial in disease. The present review will discuss data from studies in healthy and diseased animals and patients with monotherapy of L-arginine to come to an objective overview of positive and negative aspects of L-arginine supplementation in disease with special emphasis on sepsis, cancer, liver failure and wound healing.