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.

Statistical analysis plan for the replacing protein via enteral nutrition in a stepwise approach in critically ill patients (REPLENISH) randomized clinical trial.

BACKGROUND: The optimal amount and timing of protein intake in critically ill patients are unknown. REPLENISH (Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial evaluates whether supplemental enteral protein added to standard enteral nutrition to achieve a high amount of enteral protein given from ICU day five until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve a moderate amount of enteral protein would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. METHODS: In this multicenter randomized trial, critically ill patients will be randomized to receive supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition to achieve a high amount of enteral protein (range of 2-2.4 g/kg/day) or no supplemental enteral protein to achieve a moderate amount of enteral protein (0.8-1.2 g/kg/day). The primary outcome is 90-day all-cause mortality; other outcomes include functional and health-related quality-of-life assessments at 90 days. The study sample size of 2502 patients will have 80% power to detect a 5% absolute risk reduction in 90-day mortality from 30 to 25%. Consistent with international guidelines, this statistical analysis plan specifies the methods for evaluating primary and secondary outcomes and subgroups. Applying this statistical analysis plan to the REPLENISH trial will facilitate unbiased analyses of clinical data. CONCLUSION: Ethics approval was obtained from the institutional review board, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia (RC19/414/R). Approvals were also obtained from the institutional review boards of each participating institution. Our findings will be disseminated in an international peer-reviewed journal and presented at relevant conferences and meetings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04475666 . Registered on July 17, 2020.

Malglycemia in the critical care setting. Part III: Temporal patterns, relative potencies, and hospital mortality.

INTRODUCTION: The relationship between critical care mortality and combined impact of malglycemia remains undefined. METHODS: We assessed the risk-adjusted relationship (n = 4790) between hospital mortality with malglycemia, defined as hypergycemia (hours Glycemic Ratio ≥ 1.1, where GR is quotient of mean ICU blood glucose (BG) and estimated average BG), absolute hypoglycemia (hours BG < 70 mg/dL) and relative hypoglycemia (excursions GR < 0.7 in those with HbA1c ≥ 8%). RESULTS: Each malglycemia was independently associated with mortality - hyperglycemia (OR 1.0020/h, 95%CI 1.0009-1.0031, p = 0.0004), absolute hypoglycemia (OR 1.0616/h, 95%CI 1.0190-1.1061, p = 0.0043), and relative hypoglycemia (OR 1.2813/excursion, 95%CI 1.0704-1.5338, p = 0.0069). Absolute (7.4%) and relative hypoglycemia (6.7%) exposure dominated the first 24 h, decreasing thereafter. While hyperglycemia had lower risk association with mortality, it was persistently present across the length-of-stay (68-76% incidence daily), making it the dominant form of malglycemia. Relative contributions in the first five days from hyperglycemia, absolute hypoglycemia and relative hypoglycemia were 60%, 21% and 19% respectively. CONCLUSIONS: Absolute and relative hypoglycemia occurred largely in the first 24 h. Relative to all hypoglycemia, the associated mortality from the seemingly less potent but consistently more prevalent hyperglycemia steadily accumulated with increasing length-of-stay. This has important implications for interpretation of study results.

Society of Critical Care Medicine Guidelines on Glycemic Control for Critically Ill Children and Adults 2024.

RATIONALE: Maintaining glycemic control of critically ill patients may impact outcomes such as survival, infection, and neuromuscular recovery, but there is equipoise on the target blood levels, monitoring frequency, and methods. OBJECTIVES: The purpose was to update the 2012 Society of Critical Care Medicine and American College of Critical Care Medicine (ACCM) guidelines with a new systematic review of the literature and provide actionable guidance for clinicians. PANEL DESIGN: The total multiprofessional task force of 22, consisting of clinicians and patient/family advocates, and a methodologist applied the processes described in the ACCM guidelines standard operating procedure manual to develop evidence-based recommendations in alignment with the Grading of Recommendations Assessment, Development, and Evaluation Approach (GRADE) methodology. Conflict of interest policies were strictly followed in all phases of the guidelines, including panel selection and voting. METHODS: We conducted a systematic review for each Population, Intervention, Comparator, and Outcomes question related to glycemic management in critically ill children (≥ 42 wk old adjusted gestational age to 18 yr old) and adults, including triggers for initiation of insulin therapy, route of administration, monitoring frequency, role of an explicit decision support tool for protocol maintenance, and methodology for glucose testing. We identified the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the GRADE approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak or as a good practice statement. In addition, "In our practice" statements were included when the available evidence was insufficient to support a recommendation, but the panel felt that describing their practice patterns may be appropriate. Additional topics were identified for future research. RESULTS: This guideline is an update of the guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. It is intended for adult and pediatric practitioners to reassess current practices and direct research into areas with inadequate literature. The panel issued seven statements related to glycemic control in unselected adults (two good practice statements, four conditional recommendations, one research statement) and seven statements for pediatric patients (two good practice statements, one strong recommendation, one conditional recommendation, two "In our practice" statements, and one research statement), with additional detail on specific subset populations where available. CONCLUSIONS: The guidelines panel achieved consensus for adults and children regarding a preference for an insulin infusion for the acute management of hyperglycemia with titration guided by an explicit clinical decision support tool and frequent (≤ 1 hr) monitoring intervals during glycemic instability to minimize hypoglycemia and against targeting intensive glucose levels. These recommendations are intended for consideration within the framework of the patient's existing clinical status. Further research is required to evaluate the role of individualized glycemic targets, continuous glucose monitoring systems, explicit decision support tools, and standardized glycemic control metrics.

Malglycemia in the critical care setting. Part II: Relative and absolute hypoglycemia.

INTRODUCTION: The relationship between critical care mortality and hypoglycemia, both relative (>30% below average preadmission glycemia) and absolute (blood glucose (BG) <70 mg/dL (<10 mmol/L)) requires further definition. METHODS: We assessed the risk-adjusted relationship between hospital mortality with relative hypoglycemia using the Glycemic Ratio (GR), and with absolute hypoglycemia using BG in a retrospective cohort investigation (n = 4790). RESULTS: Relative hypoglycemia excursions below GR 0.7 with a of 24-h non-exposure period between excursions in those with HbA1c ≥ 8% were independently associated with mortality (n = 373, OR 2.49, 95% CI 1.54-4.04, p = 0.0002) but not those with HbA1c < 8% (n = 4417, OR 0.98 95% CI 0.89-1.08, p = 0.70). Hours below GR 0.7 (1.0037, 0.9995-1.0080, 0.0846) or minimum GR (0.0896, 0.0030-2.6600, 0.1632) were not independently associated with outcome. Absolute hypoglycemia occurred across the HbA1c spectrum in a U-shaped pattern. There was no difference in mortality associated with exposure to BG < 70 mg/dL for HbA1c ≥ 6.5% vs <6.5% (29.7% vs 24.3%, p = 0.77). Hours below 70 mg/dL demonstrated strongest association with outcome, while minimum BG, and excursions below 70 mg/dL were also independently associated. CONCLUSIONS: Relative hypoglycemia represented by excursions below GR 0.7 in those with HbA1c ≥ 8% occurred commonly and was independently associated with mortality. Absolute hypoglycemia had similar association with mortality regardless of HbA1c.

Intensive glucose control in critically ill adults: a protocol for a systematic review and individual patient data meta-analysis / Controle intensivo da glicose em adultos em estado grave: um protocolo de revisão sistemática e metanálise de dados individuais de pacientes

ABSTRACT Objective: The optimal target for blood glucose concentration in critically ill patients is unclear. We will perform a systematic review and meta-analysis with aggregated and individual patient data from randomized controlled trials, comparing intensive glucose control with liberal glucose control in critically ill adults. Data sources: MEDLINE®, Embase, the Cochrane Central Register of Clinical Trials, and clinical trials registries (World Health Organization, clinical trials.gov). The authors of eligible trials will be invited to provide individual patient data. Published trial-level data from eligible trials that are not at high risk of bias will be included in an aggregated data meta-analysis if individual patient data are not available. Methods: Inclusion criteria: randomized controlled trials that recruited adult patients, targeting a blood glucose of ≤ 120mg/dL (≤ 6.6mmol/L) compared to a higher blood glucose concentration target using intravenous insulin in both groups. Excluded studies: those with an upper limit blood glucose target in the intervention group of > 120mg/dL (> 6.6mmol/L), or where intensive glucose control was only performed in the intraoperative period, and those where loss to follow-up exceeded 10% by hospital discharge. Primary endpoint: In-hospital mortality during index hospital admission. Secondary endpoints: mortality and survival at other timepoints, duration of invasive mechanical ventilation, vasoactive agents, and renal replacement therapy. A random effect Bayesian meta-analysis and hierarchical Bayesian models for individual patient data will be used. Discussion: This systematic review with aggregate and individual patient data will address the clinical question, 'what is the best blood glucose target for critically ill patients overall?' Protocol version 0.4 - 06/26/2023 PROSPERO registration: CRD42021278869

RESUMO Objetivo: Não está claro qual é a meta ideal de concentração de glicose no sangue em pacientes em estado grave. Realizaremos uma revisão sistemática e uma metanálise com dados agregados e de pacientes individuais de estudos controlados e randomizados, comparando o controle intensivo da glicose com o controle liberal da glicose em adultos em estado grave. Fontes de dados: MEDLINE®, Embase, Cochrane Central Register of Clinical Trials e registros de ensaios clínicos (Organização Mundial da Saúde, clinical trials.gov). Os autores dos estudos qualificados serão convidados a fornecer dados individuais de pacientes. Os dados publicados em nível de ensaio qualificado que não apresentem alto risco de viés serão incluídos em uma metanálise de dados agregados se os dados individuais de pacientes não estiverem disponíveis. Métodos: Critérios de inclusão: ensaios clínicos controlados e randomizados que recrutaram pacientes adultos, com meta de glicemia ≤ 120mg/dL (≤ 6,6mmol/L) comparada a uma meta de concentração de glicemia mais alta com insulina intravenosa em ambos os grupos. Estudos excluídos: aqueles com meta de glicemia no limite superior no grupo de intervenção > 120mg/dL (> 6,6mmol/L), ou em que o controle intensivo de glicose foi realizado apenas no período intraoperatório, e aqueles em que a perda de seguimento excedeu 10% até a alta hospitalar. Desfecho primário: Mortalidade intra-hospitalar durante a admissão hospitalar. Desfechos secundários: Mortalidade e sobrevida em outros momentos, duração da ventilação mecânica invasiva, agentes vasoativos e terapia de substituição renal. Utilizaremos metanálise bayesiana de efeito randômico e modelos bayesianos hierárquicos para dados individuais de pacientes. Discussão: Essa revisão sistemática com dados agregados e de pacientes individuais abordará a questão clínica: Qual é a melhor meta de glicose no sangue de pacientes graves em geral? Protocolo versão 0.4 - 26/06/2023 Registro PROSPERO: CRD42021278869

Replacing protein via enteral nutrition in a stepwise approach in critically ill patients: the REPLENISH randomized clinical trial protocol.

BACKGROUND: Protein intake is recommended in critically ill patients to mitigate the negative effects of critical illness-induced catabolism and muscle wasting. However, the optimal dose of enteral protein remains unknown. We hypothesize that supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition formula to achieve high amount of enteral protein (range 2-2.4 g/kg/day) given from ICU day 5 until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve moderate amount enteral protein (0.8-1.2 g/kg/day) would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. METHODS: The REPLENISH (Replacing Protein Via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial is an open-label, multicenter randomized clinical trial. Patients will be randomized to the supplemental protein group or the control group. Patients in both groups will receive the primary enteral formula as per the treating team, which includes a maximum protein 1.2 g/kg/day. The supplemental protein group will receive, in addition, supplemental protein at 1.2 g/kg/day starting the fifth ICU day. The control group will receive the primary formula without supplemental protein. The primary outcome is 90-day all-cause mortality. Other outcomes include functional and quality of life assessments at 90 days. The trial will enroll 2502 patients. DISCUSSION: The study has been initiated in September 2021. Interim analysis is planned at one third and two thirds of the target sample size. The study is expected to be completed by the end of 2025. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04475666 . Registered on July 17, 2020.

ESPEN practical and partially revised guideline: Clinical nutrition in the intensive care unit.

Following the new ESPEN Standard Operating Procedures, the previous 2019 guideline to provide best medical nutritional therapy to critically ill patients has been shortened and partially revised. Following this update, we propose this publication as a practical guideline based on the published scientific guideline, but shortened and illustrated by flow charts. The main goal of this practical guideline is to increase understanding and allow the practitioner to implement the Nutrition in the ICU guidelines. All the items discussed in the previous guidelines are included as well as special conditions.

Malglycemia in the critical care setting. Part I: Defining hyperglycemia in the critical care setting using the glycemic ratio.

INTRODUCTION: Stress-induced hyperglycemia (SIH) is conventionally represented by Blood Glucose (BG) although recent evidence indicates the Glycemic Ratio (GR, quotient of mean BG and estimated preadmission BG) is a superior prognostic marker. We assessed the association between in-hospital mortality and SIH, using BG and GR in an adult medical-surgical ICU. METHODS: We included patients with hemoglobin A1c (HbA1c) and minimum four BGs in a retrospective cohort investigation (n = 4790). RESULTS: A critical SIH threshold of GR 1.1 was identified. Mortality increased with increasing exposure to GR ≥ 1.1 (r2 = 0.94, p = 0.0007). Duration of exposure to BG ≥ 180 mg/dL demonstrated a less robust association with mortality (r2 = 0.75, p = 0.059). In risk-adjusted analyses, hours GR ≥ 1.1 (OR 1.0014, 95%CI (1.0003-1.0026), p = 0.0161) and hours BG ≥ 180 mg/dL (OR 1.0080, 95%CI (1.0034-1.0126), p = 0.0006) were associated with mortality. In the cohort with no exposure to hypoglycemia however, only hours GR ≥ 1.1 was associated with mortality (OR 1.0027, 95%CI (1.0012-1.0043), p = 0.0007), not BG ≥ 180 mg/dL (OR 1.0031, 95%CI (0.9949-1.0114), p = 0.50) and this relationship remained intact for those who never experienced BG outside the 70-180 mg/dL range (n = 2494). CONCLUSIONS: Clinically significant SIH commenced above GR 1.1. Mortality was associated with hours of exposure to GR ≥ 1.1 which was a superior marker of SIH compared to BG.

Potential nutritional and pharmacological treatment of glycocalyx alterations during sepsis.

During sepsis, a combination of pathophysiological insults disrupts the glycocalyx. The thickness of the glycocalyx is correlated with parameters of disease severity, making it a potential new and independent target for therapeutic strategies in sepsis. The aim of this review was to examine potential beneficial effects of nutritional and pharmacological measures on glycocalyx alterations during sepsis and their timing.

Nutritional rehabilitation after acute illness among older patients: A systematic review and meta-analysis.

BACKGROUND & AIMS: Acute illness can lead to disability and reduced quality of life in older patients. The aim of this systematic review was to evaluate the effect of nutritional rehabilitation provided during and after hospitalisation for an acute event on functional status, muscle mass, discharge destination and quality of life of older patients. METHODS: The protocol for this systematic review was registered in PROSPERO (CRD42021264971). Articles were searched using Scopus, Medline, Google Scholar and Clinical. TRIALS: gov. For studies included in the meta-analysis, Hedges'g standardized mean difference effect size was calculated and transformed in odds ratios. RESULTS: We identified 7383 articles, of which 45 publications (41 trials, n = 8538 participants, mean age 80.35 ± 7.01 years.) were eligible for the systematic review. Patients were hospitalized for acute medical diseases (n = 6925) and fractures (n = 1063). The interventions included supplementation with a fixed amount of oral nutritional supplements (ONS, n = 17 trials), individualized diet plan (n = 3), combination of physical exercise with nutrition therapy (n = 14 trials), combination of anabolic agents with nutrition therapy (n = 5 trials). Overall nutritional rehabilitation improved functional status (Odds ratio 1.63 [1.15; 2.3], p = 0.003) and muscle mass (Odds ratio 2.61 [1.22; 5.5], p = 0.01), but not the quality of life or the discharge destination. CONCLUSION: Nutritional rehabilitation was found to improve functional status and muscle mass. There is a need for larger studies involving older hospitalized patients.

Association between early nutrition support and 28-day mortality in critically ill patients: the FRANS prospective nutrition cohort study.

BACKGROUND: Current guidelines suggest the introduction of early nutrition support within the first 48 h of admission to the intensive care unit (ICU) for patients who cannot eat. In that context, we aimed to describe nutrition practices in the ICU and study the association between the introduction of early nutrition support (< 48 h) in the ICU and patient mortality at day 28 (D28) using data from a multicentre prospective cohort. METHODS: The 'French-Speaking ICU Nutritional Survey' (FRANS) study was conducted in 26 ICUs in France and Belgium over 3 months in 2015. Adult patients with a predicted ICU length of stay > 3 days were consecutively included and followed for 10 days. Their mortality was assessed at D28. We investigated the association between early nutrition (< 48 h) and mortality at D28 using univariate and multivariate propensity-score-weighted logistic regression analyses. RESULTS: During the study period, 1206 patients were included. Early nutrition support was administered to 718 patients (59.5%), with 504 patients receiving enteral nutrition and 214 parenteral nutrition. Early nutrition was more frequently prescribed in the presence of multiple organ failure and less frequently in overweight and obese patients. Early nutrition was significantly associated with D28 mortality in the univariate analysis (crude odds ratio (OR) 1.69, 95% confidence interval (CI) 1.23-2.34) and propensity-weighted multivariate analysis (adjusted OR (aOR) 1.05, 95% CI 1.00-1.10). In subgroup analyses, this association was stronger in patients ≤ 65 years and with SOFA scores ≤ 8. Compared with no early nutrition, a significant association was found of D28 mortality with early enteral (aOR 1.06, 95% CI 1.01-1.11) but not early parenteral nutrition (aOR 1.04, 95% CI 0.98-1.11). CONCLUSIONS: In this prospective cohort study, early nutrition support in the ICU was significantly associated with increased mortality at D28, particularly in younger patients with less severe disease. Compared to no early nutrition, only early enteral nutrition appeared to be associated with increased mortality. Such findings are in contrast with current guidelines on the provision of early nutrition support in the ICU and may challenge our current practices, particularly concerning patients at low nutrition risk. Trial registration ClinicalTrials.gov Identifier: NCT02599948. Retrospectively registered on November 5th 2015.

Toward nutrition improving outcome of critically ill patients: How to interpret recent feeding RCTs?

Although numerous observational studies associated underfeeding with poor outcome, recent randomized controlled trials (RCTs) have shown that early full nutritional support does not benefit critically ill patients and may induce dose-dependent harm. Some researchers have suggested that the absence of benefit in RCTs may be attributed to overrepresentation of patients deemed at low nutritional risk, or to a too low amino acid versus non-protein energy dose in the nutritional formula. However, these hypotheses have not been confirmed by strong evidence. RCTs have not revealed any subgroup benefiting from early full nutritional support, nor benefit from increased amino acid doses or from indirect calorimetry-based energy dosing targeted at 100% of energy expenditure. Mechanistic studies attributed the absence of benefit of early feeding to anabolic resistance and futile catabolism of extra provided amino acids, and to feeding-induced suppression of recovery-enhancing pathways such as autophagy and ketogenesis, which opened perspectives for fasting-mimicking diets and ketone supplementation. Yet, the presence or absence of an anabolic response to feeding cannot be predicted or monitored and likely differs over time and among patients. In the absence of such monitor, the value of indirect calorimetry seems obscure, especially in the acute phase of illness. Until now, large feeding RCTs have focused on interventions that were initiated in the first week of critical illness. There are no large RCTs that investigated the impact of different feeding strategies initiated after the acute phase and continued after discharge from the intensive care unit in patients recovering from critical illness.

The need for biomarkers to determine response to enteral nutrition during and after critical illness: an update.

PURPOSE OF REVIEW: Biomarkers proposed to provide prognosis or to determine the response to enteral nutrition have been assessed in a number of experimental and clinical studies which are summarized in the current review. RECENT FINDINGS: There are several pathophysiological mechanisms identified which could provide biomarkers to determine response to enteral nutrition. Several biomarkers have been studied, most of them insufficiently and none of them has made its way to clinical practice. Available studies have mainly assessed a simple association of a biomarker with outcomes, but are less focused on dynamic changes in the biomarker levels. Importantly, studies on pathophysiology and clinical features of gastrointestinal dysfunction, including enteral feeding intolerance, are also needed to explore the mechanisms potentially providing specific biomarkers. Not only an association of the biomarker with any adverse outcome, but also a rationale for repeated assessment to assist in treatment decisions during the course of illness is warranted. SUMMARY: There is no biomarker currently available to reliably provide prognosis or determine the response to enteral nutrition in clinical practice, but identification of such a biomarker would be valuable to assist in clinical decision-making.

Severe vitamin D deficiency in patients admitted to the emergency department with severe sepsis is associated with an increased 90-day mortality.

BACKGROUND: The role of vitamin D in the response to infection has been increasingly acknowledged. However, the influence of severe vitamin D deficiency on the outcome of patients admitted for severe sepsis is unknown. Hence, this study aimed to investigate the association between severe vitamin D deficiency and sepsis-related outcomes in patients presenting to the ED. METHODS: This single centre prospective study included patients presenting to the ED with severe sepsis from April 2014 until December 2017. 25-Hydroxy vitamin D (25(OH)D) was measured in a blood sample drawn within 24 hours of admission to the ED, and severe vitamin D deficiency was defined as 25(OH)D <12 ng/mL. 90-day mortality was compared between patients with and without severe vitamin D deficiency by a multivariable analysis adjusting for confounders and according to a Kaplan-Meier survival analysis. RESULTS: 263 patients were initially screened and 164 patients with severe sepsis were included in this study, 18% of whom had septic shock. Severe vitamin D deficiency was present in 46% of patients. The overall 90-day mortality rate was 26.2% and the median length of stay was 14 days. In a logistic regression accounting for sepsis severity and age-adjusted comorbidities, severe vitamin D deficiency was associated with increased mortality (OR=2.69 (95% CI 1.03 to 7.00), p=0.043), and lower chances of hospital discharge (sub-HR=0.66 (95% CI 0.44 to 0.98)). In the subgroup of patients admitted to the intensive care unit, severe vitamin D deficiency was associated with an increased 28-day adjusted mortality (HR=3.06 (95% CI 1.05 to 8.94), p=0.04) and lower chances of discharge (sub-HR=0.51 (95% CI 0.32 to 0.81)). CONCLUSIONS: Severe vitamin D deficiency at ED admission is associated with higher mortality and longer hospital stay in patients with severe sepsis.

Intensive glucose control in critically ill adults: a protocol for a systematic review and individual patient data meta-analysis.

OBJECTIVE: The optimal target for blood glucose concentration in critically ill patients is unclear. We will perform a systematic review and meta-analysis with aggregated and individual patient data from randomized controlled trials, comparing intensive glucose control with liberal glucose control in critically ill adults. DATA SOURCES: MEDLINE®, Embase, the Cochrane Central Register of Clinical Trials, and clinical trials registries (World Health Organization, clinical trials.gov). The authors of eligible trials will be invited to provide individual patient data. Published trial-level data from eligible trials that are not at high risk of bias will be included in an aggregated data meta-analysis if individual patient data are not available. METHODS: Inclusion criteria: randomized controlled trials that recruited adult patients, targeting a blood glucose of ≤ 120mg/dL (≤ 6.6mmol/L) compared to a higher blood glucose concentration target using intravenous insulin in both groups. Excluded studies: those with an upper limit blood glucose target in the intervention group of > 120mg/dL (> 6.6mmol/L), or where intensive glucose control was only performed in the intraoperative period, and those where loss to follow-up exceeded 10% by hospital discharge. PRIMARY ENDPOINT: In-hospital mortality during index hospital admission. Secondary endpoints: mortality and survival at other timepoints, duration of invasive mechanical ventilation, vasoactive agents, and renal replacement therapy. A random effect Bayesian meta-analysis and hierarchical Bayesian models for individual patient data will be used. DISCUSSION: This systematic review with aggregate and individual patient data will address the clinical question, 'what is the best blood glucose target for critically ill patients overall?'Protocol version 0.4 - 06/26/2023PROSPERO registration:CRD42021278869.

Case-control Investigation of Previously Undiagnosed Diabetes in the Critically Ill.

Context: The outcome of patients requiring intensive care can be influenced by the presence of previously undiagnosed diabetes (undiagDM). Objective: This work aimed to define the clinical characteristics, glucose control metrics, and outcomes of patients admitted to the intensive care unit (ICU) with undiagDM, and compare these to patients with known DM (DM). Methods: This case-control investigation compared undiagDM (glycated hemoglobin A1c [HbA1c] ≥ 6.5%, no history of diabetes) to patients with DM. Glycemic ratio (GR) was calculated as the quotient of mean ICU blood glucose (BG) and estimated preadmission glycemia, based on HbA1c ([28.7 × HbA1c] - 46.7 mg/dL). GR was analyzed by bands: less than 0.7, 0.7 to less than or equal to 0.9, 0.9 to less than 1.1, and greater than or equal to 1.1. Risk-adjusted mortality was represented by the Observed:Expected mortality ratio (OEMR), calculated as the quotient of observed mortality and mortality predicted by the severity of illness (APACHE IV prediction of mortality). Results: Of 5567 patients 294 (5.3%) were undiagDM. UndiagDM had lower ICU mean BG (P < .0001) and coefficient of variation (P < .0001) but similar rates of hypoglycemia (P = .08). Mortality and risk-adjusted mortality were similar in patients with GR less than 1.1 comparing undiagDM and DM. However, for patients with GR greater than or equal to 1.1, mortality (38.5% vs 10.3% [P = .0072]) and risk-adjusted mortality (OEMR 1.18 vs 0.52 [P < .0001]) were higher in undiagDM than in DM. Conclusion: These data suggest that DM patients may develop tolerance to hyperglycemia that occurs during critical illness, a protective mechanism not observed in undiagDM, for whom hyperglycemia remains strongly associated with higher risk of mortality. These results may shed light on the natural history of diabetes.

Effect of an enteral amino acid blend on muscle and gut functionality in critically ill patients: a proof-of-concept randomized controlled trial.

BACKGROUND: A defining feature of prolonged critical illness is muscle wasting, leading to impaired recovery. Supplementation with a tailored blend of amino acids may bolster the innate gut defence, promote intestinal mucosa repair and limit muscle loss. METHODS: This was a monocentric, randomized, double-blind, placebo-controlled study that included patients with sepsis or acute respiratory distress syndrome. Patients received a specific combination of five amino acids or placebo mixed with enteral feeding for 21 days. Markers of renal function, gut barrier structure and functionality were collected at baseline and 1, 2, 3 and 8 weeks after randomization. Muscle structure and function were assessed through MRI measurements of the anterior quadriceps volume and by twitch airway pressure. Data were compared between groups relative to the baseline. RESULTS: Thirty-five critically ill patients were randomized. The amino acid blend did not impair urine output, blood creatinine levels or creatinine clearance. Plasma citrulline levels increased significantly along the treatment period in the amino acid group (difference in means [95% CI] 5.86 [1.72; 10.00] nmol/mL P = 0.007). Alanine aminotransferase and alkaline phosphatase concentrations were lower in the amino acid group than in the placebo group at one week (ratio of means 0.5 [0.29; 0.86] (P = 0.015) and 0.73 [0.57; 0.94] (P = 0.015), respectively). Twitch airway pressure and volume of the anterior quadriceps were greater in the amino acid group than in the placebo group 3 weeks after randomization (difference in means 10.6 [0.99; 20.20] cmH20 (P = 0.035) and 3.12 [0.5; 5.73] cm3/kg (P = 0.022), respectively). CONCLUSIONS: Amino acid supplementation increased plasma citrulline levels, reduced alanine aminotransferase and alkaline phosphatase levels, and improved twitch airway pressure and anterior quadriceps volume. Trial registration ClinicalTrials.gov, NCT02968836. Registered November 21, 2016.