Nutrition support, carbohydrate feeding and insulin sensitivity in the critically ill patient: a complex relationship.

PURPOSE OF REVIEW: This review aims to summarize recent studies that highlight the complex relationship between nutrition, carbohydrate, insulin provision and glycaemic control in the critically ill patient population. RECENT FINDINGS: Results of observational studies concur to support early hypoglycaemia and persisting hyperglycaemia as life-threatening events. In contrast, interventional studies indicate that early macronutrient restriction appears to reduce the benefits related to insulin therapy. This restriction is however associated with improved outcomes in itself. The potential role of modified enteral solutions as an adjunctive treatment to attenuate hyperglycaemia warrants further research. The selection of a therapeutic modality may also differ according to the characteristics of the setting, such as the nurse-to-patient ratio, the type and accuracy of meters, including near-continuous glucose monitoring and the availability of computer-guided protocols. SUMMARY: There appears to be significant interplay between nutrition, including carbohydrate provision, blood glucose control and clinical outcomes. Individualized care is probably needed to define the optimal glucose target and nutritional intervention. This can differ according to the preexistence of chronic hyperglycaemia, the timing from the onset of critical illness and the clinical condition itself.

Nutritional therapy in critically ill patients with diabetes.

PURPOSE OF REVIEW: There has been a significant increase in nutrition therapy related studies within the critical care cohort in recent years. Management of patients with both diabetes and stress hyperglycaemia through targeted nutrition interventions is no exception. The aim of this review is to outline current available diabetes specific nutrition formula, its impact on gastric emptying and subsequently glycaemic control as well as explore recent literature on the efficacy of utilizing nutrition support to optimize glycaemic control in critically ill patients. RECENT FINDINGS: Studies explored within this review were similar in terms of outcomes measures, focusing primarily on insulin use and glycaemic control. Although there were promising results in terms of the impact of diabetes-specific nutrition formula on these outcome measures, there were no significant associations with clinical outcomes. SUMMARY: The use of diabetes-specific formulae in critically ill patients with pre-existing diabetes and stress hyperglycaemia can be considered a logical approach to minimize the risks associated with high doses of insulin. Additional research is required to address the effects of these formulae on the dysglycaemia, nursing workload, safety of glycaemic control and cost-effectiveness.

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.

Nutrition management for critically and acutely unwell hospitalised patients with coronavirus disease 2019 (COVID-19) in Australia and New Zealand.

Coronavirus disease 2019 (COVID-19) results from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical features and subsequent medical treatment, combined with the impact of a global pandemic, require specific nutritional therapy in hospitalised adults. This document aims to provide Australian and New Zealand clinicians with guidance on managing critically and acutely unwell adult patients hospitalised with COVID-19. These recommendations were developed using expert consensus, incorporating the documented clinical signs and metabolic processes associated with COVID-19, the literature from other respiratory illnesses, in particular acute respiratory distress syndrome, and published guidelines for medical management of COVID-19 and general nutrition and intensive care. Patients hospitalised with COVID-19 are likely to have preexisting comorbidities, and the ensuing inflammatory response may result in increased metabolic demands, protein catabolism, and poor glycaemic control. Common medical interventions, including deep sedation, early mechanical ventilation, fluid restriction, and management in the prone position, may exacerbate gastrointestinal dysfunction and affect nutritional intake. Nutrition care should be tailored to pandemic capacity, with early gastric feeding commenced using an algorithm to provide nutrition for the first 5-7 days in lower-nutritional-risk patients and individualised care for high-nutritional-risk patients where capacity allows. Indirect calorimetry should be avoided owing to potential aerosole exposure and therefore infection risk to healthcare providers. Use of a volume-controlled, higher-protein enteral formula and gastric residual volume monitoring should be initiated. Careful monitoring, particularly after intensive care unit stay, is required to ensure appropriate nutrition delivery to prevent muscle deconditioning and aid recovery. The infectious nature of SARS-CoV-2 and the expected high volume of patient admissions will require contingency planning to optimise staffing resources including upskilling, ensure adequate nutrition supplies, facilitate remote consultations, and optimise food service management. These guidelines provide recommendations on how to manage the aforementioned aspects when providing nutrition support to patients during the SARS-CoV-2 pandemic.

Epidemiology of Hypophosphatemia in Critical Illness: A Multicentre, Retrospective Cohort Study.

INTRODUCTION: Hypophosphatemia is common in critically ill patients. We have described the epidemiology of hypophosphatemia in patients admitted to the Intensive Care Units. METHODS: A multicentre, retrospective cohort study of 12 ICUs in Queensland, Australia from January 1st, 2015, to December 31st, 2021. Exclusions included readmissions, renal replacement therapy, end-stage renal disease, and palliative intent admissions and transfers from other ICUs. Patients were classified into four groups based on the severity of the first episode of low serum phosphate (PO4): "None" (PO4: ≥ 0.81 mmol/L, ``Mild" (PO4: ≥ 0.50 & < 0.81 mmol/L) "Moderate" (PO4: ≥ 0.30 & < 0.50 mmol/L) and "Severe" (PO4: < 0.30 mmol/L). A mixed-effect logistic regression model, including hospital as a random effect, was developed to examine factors associated with 90-day case fatality. RESULTS: Of the 89,776 patients admitted, 68,699 patients were included in this study, with 23,485 (34.2%) having hypophosphatemia with onset mostly on Day 2 of ICU admission and correcting to normal 3 days after hypophosphatemia was identified. There was substantial variation among participating ICUs in phosphate replacement; the threshold, and the route by which it was replaced. Day-90 case fatality increased with severity of hypophosphatemia (None: 3,974 (8.8%), Mild: 2,306 (11%), Moderate: 377 (14%); Severe: 108 (21%) (p < 0.001)). Multivariable regression analysis showed that compared to those without hypophosphatemia, patients with moderate (odds ratio (OR) 1.24; 95% confidence intervals (CI) 1.07-1.44; p = 0.004) or severe (OR 1.49; 95% CI 1.13-1.97; p = 0.005) hypophosphatemia had increased risk of 90-day case fatality. CONCLUSION: Hypophosphatemia was common, and mostly occurred on day 2 with early correction of serum phosphate. Phosphate replacement practices were variable among ICUs. Moderate and severe hypophosphatemia was associated with increased 90-day case fatality.

Association between elevated lactate and clinical outcomes in adults with diabetic ketoacidosis.

PURPOSE: To assess the occurrence of hyperlactatemia among patients admitted to the intensive care unit (ICU) with diabetic ketoacidosis (DKA), and effect on in-hospital mortality. MATERIALS AND METHODS: A retrospective, multicentre, cohort study of adult patients admitted to ICU with a primary diagnosis of DKA in Australia and New Zealand, utilising a pre-existing dataset. The primary exposure variable was lactate, dichotomised into normolactatemia (lactate <2.0 mmol/L) and hyperlactatemia (lactate ≥ 2.0 mmol/L) groups. The primary outcome was in-hospital mortality. Secondary outcomes included ICU and hospital length of stay (LOS), requirement for ventilation, renal replacement therapy (RRT) and inotropes. RESULTS: The final dataset included 9061 patients. Hyperlactatemia was associated with in-hospital mortality (Odds Ratio [OR] 1.785 (95% CI 1.122-2.841, p = 0.014), hospital LOS (Geometric mean ratio [GMR] 1.063, 95% CI 1.025-1.103, p = 0.001), ICU LOS (GMR 1.057, 95% CI 1.026-1.09. p < 0.001), RRT (OR 2.198, 95% CI 1.449-3.334, p < 0.001) and inotropes (OR 1.578, 95% CI 1.311-1.899, p < 0.001). These associations persisted in Type 2 but not Type 1 diabetics. CONCLUSIONS: Hyperlactatemia in patients admitted to ICU with DKA is associated with higher mortality, longer hospital and ICU LOS, and higher rates of mechanical ventilation, RRT and inotropes.

Nutrition management for critically and acutely unwell hospitalised patients with coronavirus disease 2019 (COVID-19) in Australia and New Zealand.

Coronavirus disease 2019 (COVID-19) results from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical features and subsequent medical treatment, combined with the impact of a global pandemic, require specific nutritional therapy in hospitalised adults. This document aims to provide Australian and New Zealand clinicians with guidance on managing critically and acutely unwell adult patients hospitalised with COVID-19. These recommendations were developed using expert consensus, incorporating the documented clinical signs and metabolic processes associated with COVID-19, the literature from other respiratory illnesses, in particular acute respiratory distress syndrome, and published guidelines for medical management of COVID-19 and general nutrition and intensive care. Patients hospitalised with COVID-19 are likely to have preexisting comorbidities, and the ensuing inflammatory response may result in increased metabolic demands, protein catabolism, and poor glycaemic control. Common medical interventions, including deep sedation, early mechanical ventilation, fluid restriction, and management in the prone position, may exacerbate gastrointestinal dysfunction and affect nutritional intake. Nutrition care should be tailored to pandemic capacity, with early gastric feeding commenced using an algorithm to provide nutrition for the first 5-7 days in lower-nutritional-risk patients and individualised care for high-nutritional-risk patients where capacity allows. Indirect calorimetry should be avoided owing to potential aerosol exposure and therefore infection risk to healthcare providers. Use of a volume-controlled, higher-protein enteral formula and gastric residual volume monitoring should be initiated. Careful monitoring, particularly after intensive care unit stay, is required to ensure appropriate nutrition delivery to prevent muscle deconditioning and aid recovery. The infectious nature of SARS-CoV-2 and the expected high volume of patient admissions will require contingency planning to optimise staffing resources including upskilling, ensure adequate nutrition supplies, facilitate remote consultations, and optimise food service management. These guidelines provide recommendations on how to manage the aforementioned aspects when providing nutrition support to patients during the SARS-CoV-2 pandemic.

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.

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.

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).