The impact of a modified carbohydrate formula, and its constituents, on glycaemic control and inflammatory markers: A nested mechanistic sub-study.

BACKGROUND: Hyperglycaemia occurs frequently in the critically ill. Dietary intake of advanced glycation end-products (AGEs), specifically Nε-(carboxymethyl)lysine (CML), may exacerbate hyperglycaemia through perturbation of insulin sensitivity. The present study aimed to determine whether the use of nutritional formulae, with varying AGE loads, affects the amount of insulin administered and inflammation. METHODS: Exclusively tube fed patients (n = 35) were randomised to receive Nutrison Protein Plus Multifibre®, Diason® or Glucerna Select®. Insulin administration was standardised according to protocol based on blood glucose (<10 mmol L-1 ). Samples were obtained at randomisation and 48 h later. AGEs in nutritional formula, plasma and urine were measured using mass spectrometry. Plasma inflammatory markers were measured using an enzyme-linked immunosorbent assay and multiplex bead-based assays. RESULTS: AGE concentrations of CML in nutritional formulae were greatest with delivery of Nutrison Protein Plus® (mean [SD]; 6335 pmol mol-1 [2436]) compared to Diason® (4836 pmol mol-1 [1849]) and Glucerna Select® (4493 pmol mol-1 [1829 pmol mol-1 ]) despite patients receiving similar amounts of energy (median [interquartile range]; 12 MJ [8.2-13.7 MJ], 11.5 MJ [8.3-14.5 MJ], 11.5 MJ [8.3-14.5 MJ]). More insulin was administered with Nutrison Protein Plus® (2.47 units h-1 [95% confidence interval (CI) = 1.57-3.37 units h-1 ]) compared to Diason® (1.06 units h-1 [95% CI = 0.24-1.89 units h-1 ]) or Glucerna Select® (1.11 units h-1 [95% CI = 0.25-1.97 units h-1 ]; p = 0.04). Blood glucose concentrations were similar. There were associations between greater insulin administration and reductions in circulating interleukin-6 (r = -0.46, p < 0.01), tumour necrosis factor-α (r = -0.44, p < 0.05), high sensitivity C-reactive protein (r = -0.42, p < 0.05) and soluble receptor for advanced glycation end-products (r = -0.45, p < 0.01) concentrations. CONCLUSIONS: The administration of greater AGE load in nutritional formula potentially increases the amount of insulin required to maintain blood glucose within a normal range during critical illness. There was an inverse relationship between exogenous insulin and plasma inflammatory markers.

The effect of a low carbohydrate formula on glycaemia in critically ill enterally-fed adult patients with hyperglycaemia: A blinded randomised feasibility trial.

BACKGROUND: Enteral nutrition is a source of carbohydrate that may exacerbate hyperglycaemia. Its treatment, insulin, potentially exacerbates glycaemic variability. METHODS: This was a prospective, parallel group, blinded, randomised feasibility trial. Patients were eligible if 18 years or over when admitted to the intensive care unit and receiving enteral nutrition (EN) exclusively with two consecutive blood glucose > 10 mmol/L. A standardized glucose management protocol determined administration of insulin. Key outcome measures were insulin administered and glycaemic variability (coefficient of variation) over the first 48 h. RESULTS: 41 patients were randomized to either standard EN (14.1 g/100 mL carbohydrate; n = 20) or intervention EN (7.4 g/100 mL carbohydrate; n = 21). Overall 59% were male, mean (±SD) age of 62.3 years ± 10.4, APACHE II score of 16.5 ± 7.8 and a median (IQR) Body Mass Index 29.0 kg/m2 (25.2-35.5). Most patients (73%) were mechanically ventilated. Approximately half (51%) were identified as having diabetes prior to ICU admission. Patients in the intervention arm received less insulin over the 48 h study period than those in the control group (mean insulin units over study period (95% CI) 45.0 (24.4-68.7) vs. 107 (56.1-157.9) units; p = 0.02) and had lower mean glycaemic variability (12.6 vs. 15.9%, p = 0.01). There was a small difference in the mean percentage of energy requirements met (intervention: 72.9 vs. control: 79.1%; p = 0.4) or protein delivered (78.2 vs. 85.4%; p = 0.3). CONCLUSIONS: A low carbohydrate formula was associated with reduced insulin use and glycaemic variability in enterally-fed critically ill patients with hyperglycaemia. Further large trials are required to determine the impact of this formula on clinical outcomes. Registered under Australian and New Zealand Clinical Trials Registry, ANZCTR number: 12614000166673.

Glycaemic variability and its association with enteral and parenteral nutrition in critically ill ventilated patients.

BACKGROUND & AIMS: Extremes of dysglycaemia as well as glycaemic variability are associated with excess mortality in critically ill patients. Glycaemic variability is an increasingly important measure of glucose control in the intensive care unit (ICU) due to this association; however, there is limited data pertaining to the relationship between exogenous glucose from nutrition and glycaemic variability and clinical outcomes. The primary aim of this study was to determine if glycaemic variability is associated with an increase in mortality. Secondary objectives were to investigate any factors affecting glycaemic variability, and to characterise the role nutrition, particularly carbohydrate, plays as a contributing factor to glycaemic variability and other clinical outcomes (duration of ventilation and ICU length of stay). METHODS: Data on patients in a combined medical/surgical tertiary Australian Intensive Care Unit (ICU), ventilated for >24 h and exclusively fed by artificial nutrition support was extracted from a clinical database of prospectively collected information over an 18 month period. Glycaemic variability was defined as the coefficient of variation (GV; standard deviation/mean of blood glucose levels x 100). Statistical analysis was performed using logistic regression, zero-truncated negative binomial and linear regression as appropriate to the distribution of the outcome variable using R software. RESULTS: Data on up to 759 subjects was available. The average age of the study cohort was 56.9 years with a mean (standard deviation) APACHE III score of 72 (28). 66% of the study subjects were male. Glycaemic variability was associated with an increase in mortality (odds ratio 1.02; 95% CI: 1.00-1.04, p = 0.03). Factors associated with glycaemic variability included Acute Physiology and Chronic Health Evaluation III score (0.09, 0.06-0.11, p < 0.001), being male (-1.67, -2.97 to -0.38), p = 0.01) and mean units of insulin per day (0.08, 0.06-0.09, p < 0.001). There was no effect of any nutritional factor on glycaemic variability. Further exploratory analyses though showed that for those patients who required insulin during ICU admission, increased insulin dose was associated with increasing carbohydrate (incidence rate ratio (IRR) 1.003, 1.001-1.005, p = 0.001). Mean daily carbohydrate provision (grams) was associated with an increase in ventilation hours (IRR, 95% CI: 1.009, 1.008-1.009, p < 0.001) and length of intensive care unit stay (IRR, 95% CI: 1.007, 1.006-1.008, p < 0.001). CONCLUSION: This study confirms that GV was associated with excess mortality. Furthermore, administration of increasing doses of insulin was associated with increased GV. Increased carbohydrate intake was associated with an increased insulin requirement, as well as increased duration of mechanical ventilation and ICU length of stay. These findings provide important context for further prospective trials investigating the effect of carbohydrate provision in mechanically ventilated critically ill patients requiring artificial nutritional support.

Diabetes-Specific Formulae Versus Standard Formulae as Enteral Nutrition to Treat Hyperglycemia in Critically Ill Patients: Protocol for a Randomized Controlled Feasibility Trial.

BACKGROUND: During critical illness, hyperglycemia is prevalent and is associated with adverse outcomes. While treating hyperglycemia with insulin reduces morbidity and mortality, it increases glycemic variability and hypoglycemia risk, both of which have been associated with an increase in mortality. Therefore, other interventions which improve glycemic control, without these complications should be explored. Nutrition forms part of standard care, but the carbohydrate load of these formulations has the potential to exacerbate hyperglycemia. Specific diabetic-formulae with a lesser proportion of carbohydrate are available, and these formulae are postulated to limit glycemic excursions and reduce patients' requirements for exogenous insulin. OBJECTIVE: The primary outcome of this prospective, blinded, single center, randomized controlled trial is to determine whether a diabetes-specific formula reduces exogenous insulin administration. Key secondary outcomes include the feasibility of study processes as well as glycemic variability. METHODS: Critically ill patients will be eligible if insulin is administered whilst receiving exclusively liquid enteral nutrition. Participants will be randomized to receive a control formula, or a diabetes-specific, low glycemic index, low in carbohydrate study formula. Additionally, a third group of patients will receive a second diabetes-specific, low glycemic index study formula, as part of a sub-study to evaluate its effect on biomarkers. This intervention group (n=12) will form part of recruitment to a nested cohort study with blood and urine samples collected at randomization and 48 hours later for the first 12 participants in each group with a secondary objective of exploring the metabolic implications of a change in nutrition formula. Data on relevant medication and infusions, nutrition provision and glucose control will be collected to a maximum of 48 hours post randomization. Baseline patient characteristics and anthropometric measures will be recorded. A 28-day phone follow-up will explore weight and appetite changes as well as blood glucose control pre and post intensive care unit (ICU) discharge. RESULTS: Recruitment commenced in February 2015 with an estimated completion date for data collection by May 2018. Results are expected to be available late 2018. CONCLUSIONS: This feasibility study of the effect of diabetes-specific formulae on the administration of insulin in critically ill patients and will inform the design of a larger, multi-center trial. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ANZCTR):12614000166673; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12614000166673 (Archived by WebCite at http://www.webcitation.org/6xs0phrVu).

Dietary Sodium Modifies Serum Uric Acid Concentrations in Humans.

BACKGROUND: Subjects with hypertension are frequently obese or insulin resistant, both conditions in which hyperuricemia is common. Obese and insulin-resistant subjects are also known to have blood pressure that is more sensitive to changes in dietary sodium intake. Whether hyperuricemia is a resulting consequence, moderating or contributing factor to the development of hypertension has not been fully evaluated and very few studies have reported interactions between sodium intake and serum uric acid. METHODS: We performed further analysis of our randomized controlled clinical trials (Australian New Zealand Clinical Trials Registry #12609000161224 and #12609000292279) designed to assess the effects of modifying sodium intake on concentrations of serum markers, including uric acid. Uric acid and other variables (including blood pressure, renin, and aldosterone) were measured at baseline and 4 weeks following the commencement of low (60 mmol/day), moderate (150 mmol/day), and high (200-250 mmol/day) dietary sodium intake. RESULTS: The median aldosterone-to-renin ratio was 1.90 [pg/ml]/[pg/ml] (range 0.10-11.04). Serum uric acid fell significantly in both the moderate and high interventions compared to the low sodium intervention. This pattern of response occurred when all subjects were analyzed, and when normotensive or hypertensive subjects were analyzed alone. CONCLUSIONS: Although previously reported in hypertensive subjects, these data provide evidence in normotensive subjects of an interaction between dietary sodium intake and serum uric acid. As this interaction is present in the absence of hypertension, it is possible it could play a role in hypertension development, and will need to be considered in future trials of dietary sodium intake. CLINICAL TRIALS REGISTRATION: The trials were registered with the Australian and New Zealand Clinical Trials Registry as ACTRN12609000161224 and ACTRN1260.

The effect of dietary sodium modification on blood pressure in adults with systolic blood pressure less than 140 mmHg: a systematic review.

BACKGROUND: Modifying dietary sodium intake is a cornerstone of diet advice for lowering blood pressure (BP) under the assumption that it is protective against cardiovascular disease. Previous meta-analyses of normotensive participants have not excluded all studies that recruited participants with systolic blood pressure (SBP) > 140 mmHg, which greatly hinders generalization to the wider normotensive population. OBJECTIVES: The objective of this review was to identify the effectiveness of reducing or increasing sodium intake on BP in normotensive participants with SBP ≤ 140 mmHg. INCLUSION CRITERIA TYPES OF PARTICIPANTS: This review considered studies on adult participants (≥18 years) with SBP ≤ 140 mmHg. Studies on pregnant women or patients prescribed antihypertensive or vasoactive medications were excluded. TYPES OF INTERVENTIONS: Interventions that quantitatively evaluated dietary sodium intake for equal to or greater than four weeks duration were considered. Only studies that included two study arms comprising different levels of sodium intake were included. TYPES OF OUTCOMES: Studies that reported SBP, diastolic blood pressure (DBP), pulse wave velocity (PWV), pulse wave analysis or flow mediated dilatation were considered. TYPES OF STUDIES: Experimental study designs including randomized controlled trials and non-randomized controlled trials were considered. SEARCH STRATEGY: An initial search strategy was conducted on databases MEDLINE and CINAHL before an extensive search of all relevant published and gray literature databases, and clinical trial registries were searched. METHODOLOGICAL QUALITY: Potential papers were assessed for methodological validity using the standardized critical appraisal instrument from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI). DATA EXTRACTION: Quantitative data were extracted from papers using the standardized data extraction tool from JBI-MAStARI. DATA SYNTHESIS: Quantitative data were pooled in statistical meta-analysis. Effect sizes were expressed as weighted mean differences and 95% confidence intervals. Meta-analysis was conducted using a random-effect model, and heterogeneity assessed statistically using the standard Chi-square test and the I index. A priori sub-group analysis was undertaken on studies achieving ≥40 mmol versus <40 mmol in urinary sodium excretion and post hoc on studies with a mean body mass index (BMI) ≥ 30 versus less than 30. RESULTS: Five trials were included with a total of 1214 participants. The overall reduction in SBP was -0.71 mmHg (95% CI: -2.62, 1.20, P = 0.47) and DBP -0.57 mmHg (95% CI: -1.26, 0.12, P = 0.10). There was no significant change in PWV following reduction of dietary sodium over a four to six-week period. Sub-group analysis did not find a significant effect of urinary sodium excretion or BMI on outcomes; however, a trend toward a greater reduction in BP was observed in those with a higher BMI (MD -2.41, 95% CI -5.72, +0.91, P = 0.16). CONCLUSION: Blood pressure in normotensive participants was not significantly affected by sodium modification and was controlled to within 1% of baseline values. Reducing dietary sodium in normotensive participants may still be of importance for cardiovascular risk management; however, good quality interventional research is limited.

Positive association of tomato consumption with serum urate: support for tomato consumption as an anecdotal trigger of gout flares.

BACKGROUND: Gout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels. METHODS: Two thousand fifty one New Zealanders (of Maori, Pacific Island, European or other ancestry) with clinically-ascertained gout were asked about gout trigger foods. European individuals from the Atherosclerosis Risk In Communities (ARIC; n = 7517) Study, Cardiovascular Health Study (CHS; n = 2151) and Framingham Heart Study (FHS; n = 3052) were used to test, in multivariate-adjusted analyses, for association between serum urate and tomato intake. RESULTS: Seventy one percent of people with gout reported having ≥1 gout trigger food. Of these 20% specifically mentioned tomatoes, the 4(th) most commonly reported trigger food. There was association between tomato intake and serum urate levels in the ARIC, CHS and FHS combined cohort (ß = 0.66 µmolL(-1) increase in serum urate per additional serve per week; P = 0.006) - evident in both sexes (men: ß = 0.84 µmolL(-1), P = 0.035; women: ß = 0.59 µmolL (-1), P = 0.041). CONCLUSIONS: While our descriptive and observational data are unable to support the claim that tomato consumption is a trigger of gout attacks, the positive association between tomato consumption and serum urate levels suggests that the self-reporting of tomatoes as a dietary trigger by people with gout has a biological basis.

Overweight and obese adolescent girls: the importance of promoting sensible eating and activity behaviors from the start of the adolescent period.

The adolescent period is associated with changes in eating and activity behaviors in girls. Less reliance on parental provision and choice of food, coupled with a decrease in participation in physical activity and sport, can create an energy imbalance, predisposing to weight gain. Physiological alterations to body composition, reduction in insulin sensitivity, and psychological adjustments may further amplify the risk of becoming overweight and maintaining an unhealthy level of body fat into childbearing years. During pregnancy excess body fat is a risk factor for poor pregnancy outcomes and may predispose an infant to a lifelong heightened risk of being overweight and developing chronic disease. Interventions aimed at preventing the accumulation of body fat in adolescent girls and young women may have far reaching impact and be critically important in reducing intergenerational weight gain. Lifestyle interventions in adolescence have the potential to modify adult obesity risk by switching at-risk individuals from a high to lower obesity risk trajectory. This paper discusses multiple approaches to assist at-risk individuals reduce obesity risk. A key focus is placed on engagement in food preparation and choice, and opportunities for physical activity and sport. Support, education, and opportunity at home and at school, are often associated with the success of lifestyle interventions, and may enable adolescents to make positive choices, and engage in health promoting behaviors during adolescence and childbearing years.

Dietary sodium loading in normotensive healthy volunteers does not increase arterial vascular reactivity or blood pressure.

BACKGROUND: Studies of dietary sodium on vascular function and blood pressure in normotensive volunteers have shown conflicting results. There are very limited data available on the effect of chronic sodium loading from a low-sodium diet to a high-sodium diet on vascular function and blood pressure in normotensive volunteers. OBJECTIVE: To assess the effect of modifying dietary sodium intake on arterial function and surrogate markers of arterial remodelling in normal healthy volunteers. DESIGN: Twenty-three normotensive volunteers met the inclusion criteria. After a 2 week run-in with a low-sodium diet (60 mmol/day), the participants maintained their low-sodium diets and were randomly assigned to receive sequentially one of three interventions for 4 weeks, with a 2 week washout between interventions: sodium-free tomato juice (A), tomato juice containing 90 mmol Na (B) and tomato juice containing 140 mmol Na (C). The outcomes measured were changes in pulse wave velocity (PWV), systolic blood pressure and diastolic blood pressure. RESULTS: There was no difference in PWV between interventions (B-A 0.00 m/s, 95% CI: -0.30, 0.31 m/s; C-A 0.01 m/s, 95% CI: -0.38, 0.40 m/s). There was also no change in pulse wave analysis, systolic or diastolic blood pressure between interventions. There was an appropriate increase in urinary sodium excretion in the added sodium interventions. CONCLUSION: Dietary salt loading did not produce significant increases in PWV and blood pressure in normotensive subjects with systolic blood pressure <130 mmHg. The lack of an observed effect supports Guyton's pressure-natriuresis hypothesis with appropriate renal excretion of the excess sodium load.

Dietary salt loading impairs arterial vascular reactivity.

BACKGROUND: Studies of sodium have shown improvements in vascular function and blood pressure (BP). The effect of chronic sodium loading from a low-sodium diet to a Western diet on vascular function and BP has been less well studied. OBJECTIVE: The objective was to examine the effects of dietary salt intake on vascular function and BP. DESIGN: Thirty-five hypertensive volunteers met the inclusion criteria. After a 2-wk run-in with a low-sodium diet (60 mmol/d), the participants maintained their diets and were randomly assigned to receive sequentially 1 of 3 interventions for 4 wk, with a 2-wk washout between interventions: sodium-free tomato juice (A), tomato juice containing 90 mmol Na (B), and tomato juice containing 140 mmol Na (C). The outcomes were changes in pulse wave velocity (PWV), systolic BP (SBP), and diastolic BP (DBP). RESULTS: The difference in PWV between interventions B and A was 0.39 m/s (95% CI: 0.18, 0.60 m/s; P < or = 0.001) and between C and A was 0.35 m/s (95% CI: 0.13, 0.57 m/s; P < or = 0.01). Differences in SBP and DBP between interventions B and A were 4.4 mm Hg (95% CI: 1.2, 7.8 mm Hg; P < or = 0.01) and 2.4 mm Hg (95% CI: 0.8, 4.1 mm Hg; P < or = 0.001), respectively, and between interventions C and A were 5.6 mm Hg (95% CI: 2.7, 8.4 mm Hg; P < or = 0.01) and 3.3 mm Hg (95% CI: 1.5, 5.0 mm Hg; P < or = 0.001), respectively. Changes in PWV correlated with changes in SBP (r = 0.52) and DBP (r = 0.58). CONCLUSIONS: Dietary salt loading produced significant increases in PWV and BP in hypertensive volunteers. Correlations between BP and PWV suggest that salt loading may have a BP-independent effect on vascular wall function. This further supports the importance of dietary sodium restriction in the management of hypertension. This trial was registered with the Australian and New Zealand Clinical Trials Registry as ACTRN12609000161224.