Impact of withholding early parenteral nutrition on 2-year mortality and functional outcome in critically ill adults.

PURPOSE: In critically ill adults, withholding parenteral nutrition until 1 week after intensive care admission (Late-PN) facilitated recovery as compared with early supplementation of insufficient enteral nutrition with parenteral nutrition (Early-PN). However, the impact on long-term mortality and functional outcome, in relation to the estimated nutritional risk, remains unclear. METHODS: In this prospective follow-up study of the multicenter EPaNIC randomized controlled trial, we investigated the impact of Late-PN on 2-year mortality (N = 4640) and physical functioning, assessed by the 36-Item Short Form Health Survey (SF-36; in 3292 survivors, responding 819 [738-1058] days post-randomization). To account for missing data, we repeated the analyses in two imputed models. To identify potential heterogeneity of treatment effects, we investigated the impact of Late-PN in different nutritional risk subgroups as defined by Nutritional Risk Screening-2002-score, modified NUTrition Risk in the Critically Ill-score, and age (above/below 70 years), and we evaluated whether there was statistically significant interaction between classification to a nutritional risk subgroup and the effect of the randomized intervention. Secondary outcomes were SF-36-derived physical and mental component scores (PCS & MCS). RESULTS: Two-year mortality (20.5% in Late-PN, 19.8% in Early-PN; P = 0.54) and physical functioning (70 [40-90] in both study-arms; P = 0.99) were similar in both groups, also after imputation of missing physical functioning data. Likewise, Late-PN had no impact on 2-year mortality and physical functioning in any nutritional risk subgroup. PCS and MCS were similar in both groups. CONCLUSION: Late-PN did not alter 2-year survival and physical functioning in adult critically ill patients, independent of anticipated nutritional risk.

Prospective multicenter study to describe the prevalence, outcomes, and management of phosphate disorders in intensive care patients: Study protocol for part B of the international GUTPHOS study.

BACKGROUND: Aberrations in blood phosphate (Pi) levels, whether presenting as hypo- or hyperphosphatemia, appear to be associated with clinical complications and adverse outcomes in patients admitted to an intensive care unit (ICU). However, the prevalence of Pi disorders and the association with subsequent factors and organ failures leading to death in ICU patients are poorly described. Despite endeavors to understand the etiology and treatment of low Pi levels from systematic reviews and meta-analyses, the literature lacks comprehensive guidance for managing hypophosphatemia. Hyperphosphatemia, on the other hand, appears to be associated with higher mortality among critically ill patients, yet its prevalence among ICU patients, particularly following phosphate repletion, remains unknown. The present study aims to investigate the prevalence of Pi abnormalities upon ICU admission and their incidence during the first week of ICU stay, the factors associated with Pi alterations, and the effect of phosphate repletion on the normalization of Pi levels, and its associations with clinical outcomes. METHODS: This multicentre, prospective, non-interventional cohort study will include at least 1000 consecutive adult ICU patients (≥18 years) as part B of the GUTPHOS study. Sites are eligible if an anticipated minimal inclusion of 50 eligible patients during eight weeks from January 2024 until June 2024 and daily phosphate measurements during the first seven days of ICU stay are expected. All consecutive adult patients admitted to a participating ICU during the recruitment period, lasting up to eight weeks, or up to 120 patients if enrollment reaches that limit earlier, will be included. Study parameters include study site characteristics, patient demographics, daily assessment of Pi levels, Pi-related treatment, feeding details, renal replacement therapy details, the incidence of refeeding-associated hypophosphatemia and administered medication (during the first seven calendar days of ICU stay). There will be a follow-up period of a maximum of 90 days to document 28- and 90-day all-cause mortality as the primary outcome. Multiple logistic regression will be used to assess independent associations with mortality in addition to Receiver Operating Characteristics curves to identify cut-off Pi values associated with mortality and overcorrection. Linear mixed models will be conducted to assess Pi treatment effects. Subgroup analyses will be performed based on Pi abnormalities observed during ICU admission, categorized as normo-, hypo-, hyper-, or mixed, along with its severity (mild, moderate, or severe). DISCUSSION: The GUTPHOS study will be the first multicentre, prospective observational cohort study to investigate the prevalence, management practices, and consequent outcomes associated with Pi abnormalities during the first week of ICU admission. Its results may bridge the current evidence gap in repletion protocols while establishing the groundwork for a subsequent randomized controlled trial. CLINICAL TRIAL REGISTRY: NCT05909722.

Prospective multicenter study to validate the gastrointestinal dysfunction score (GIDS) in intensive care patients: Study protocol for Part A of the international GUTPHOS study.

BACKGROUND: While gastrointestinal (GI) dysfunction is commonly encountered among critically ill patients, a uniform prospectively validated scoring system is lacking. The present study aims to validate the recently developed Gastrointestinal Dysfunction Score (GIDS) in a multicenter, prospective cohort of consecutive adult patients admitted to intensive care units (ICU). METHODS: GUTPHOS is a prospective, multicenter, non-interventional cohort study in which at least 1400 consecutive adult patients (age ≥18 years) admitted to the ICU will be monitored daily for abdominal signs and symptoms of GI dysfunction. The previously developed GIDS constructed from these signs and symptoms will be tested in relation to mortality and duration of ICU dependency and parenteral nutrition (PN) dependency. Between January and June 2024, each participating clinical site will include 50-120 consecutive patients over an eight-week period. Study data will be collected in three phases: baseline data upon ICU admission, daily observations throughout a maximum of 7 days in ICU or until discharge, and a follow-up period of 90 days. The primary outcomes are 28- and 90-day all-cause mortality. Secondary outcomes include ICU and hospital mortality, ICU and hospital length of stay, days alive and free of ICU by day 28 and day 90, days alive and free of hospital by day 28 and day 90, and days alive and free of organ support and PN dependency by day 28. DISCUSSION: The GUTPHOS study will be the first worldwide, multicenter, prospective, observational cohort study to validate the GIDS in adult patients admitted to ICUs against 28- and 90-day mortality. The availability of a validated tool will allow its use in interventional studies that are currently hindered by the lack of a validated measurement tool for GI dysfunction. CLINICAL TRIAL REGISTRY: NCT05909722.

LLL 44 - Module 3: Micronutrients in Chronic disease.

Micronutrients (MN), i.e. trace elements and vitamins, are essential organic molecules, which are required in the diet in relatively small amounts in any form of nutrition (oral, enteral, parenteral). The probability of MN depletion or deficiencies should be considered in all chronic illnesses, especially in those that can interfere with intake, digestion, or intestinal absorption. Low socio-economic status and food deprivation are recognized as the most prevalent reasons for MN deficiencies world-wide. Elderly multimorbid patients with multimodal therapy, as well as patients with long-lasting menu restrictions, are at high risk for both disease related malnutrition as well as multiple MN deficiencies, needing careful specific follow-up. The importance of monitoring MN blood levels along with CRP is essential for optimal care. Drug interactions are also highlighted. In patients with chronic conditions depending on medical nutrition therapy, the provision of adequate dietary reference intakes (DRI) of MN doses and monitoring of their adequacy belongs to standard of care.

LLL 44-1 Micronutrients in clinical nutrition: Trace elements.

BACKGROUND: Trace elements are an essential component of metabolism and medical nutrition therapy, with key roles in metabolic pathways, antioxidation, and immunity, which the present course aims at summarizing. RESULTS: Medical nutrition therapy includes the provision of all essential trace elements. The clinical essential issues are summarized for Copper, Iron, Selenium, Zinc, Iodine, Chromium, Molybdenum, and Manganese: the optimal analytical techniques are presented. The delivery of all these elements occurs nearly automatically when the patient is fed with enteral nutrition, but always requires separate prescription in case of parenteral nutrition. Isolated deficiencies may occur, and some patients have increased requirements, therefore a regular monitoring is required. The clinicians should always consider the impact of inflammation on blood levels, mostly lowering them even in absence of deficiency. CONCLUSION: This text summarises the most relevant clinical manifestations of trace element depletion and deficiency, the difficulties in assessing status, and makes practical recommendations for provision for enteral and parenteral nutrition.

LLL 44 - 2 - Micronutrients in clinical nutrition: Vitamins.

Vitamins are essential organic molecules, which are required in the diet in relatively small amounts in any form of nutrition (oral, enteral, parenteral). Despite the small amounts that are required, the vitamins are essential both for maintenance of health, growth, and treatment of disease. After reminding about the principal function of all the vitamins, their needs and the clinical consequences of their deficit, the text present some common clinical problems: the impact of inflammation on the assessment of status. The reasons and diseases which cause increased requirements are presented, with the indications to monitoring of blood levels which remain the classical way to assess status in clinical settings. The text summarises the most relevant clinical manifestations of vitamins depletion and deficiency, the difficulties in assessing status, and makes recommendations for provision for medical nutrition therapy.

LLL 44-4 : Micronutrients in acute disease and critical illness.

Micronutrients (MN), i.e. trace elements and vitamins, are essential components of the diet in relatively small amounts in any form of nutrition, with special needs in critically ill patients. Critical illness is characterised by the presence of inflammation and oxidative stress. MNs are tightly involved in antioxidant and immune defences. In addition, some conditions, and treatments result in large losses of biological fluids containing MNs: therefore, acute renal injury requiring renal replacement therapy, acute intestinal failure, and major burns and trauma are at high risk of acute depletion of body stores, and of deficiency. MN requirements are increased above standard DRI. Blood level interpretation is complicated by inflammation: some biomarkers assist the status determination. Due to the acute challenges of critical illness, it of utmost importance to cover the needs to maintain the organism's endogenous immune and antioxidant defences, and capacity to repair tissues. Practical strategies are proposed.

Diagnosis and Management of Esophageal Fistulas After Lung Transplantation: A Case Series.

Background: Lung transplantations are highly complex procedures, often conducted in frail patients. Through the addition of immunosuppressants, healing can be compromised, primarily leading to the development of bronchopleural fistulas. Although esophageal fistulas (EFs) after lung transplantation remain rare, they are associated with significant morbidity. We aimed to investigate the clinical presentation, diagnostic approaches, and treatment strategies of EF after lung transplantation. Methods: All patients who developed EF after lung transplantation at the University Hospitals Leuven between January 2019 and March 2022 were retrospectively reviewed and the clinical presentations, diagnostic approaches, and treatment strategies were summarized. Results: Among 212 lung transplantation patients, 5 patients (2.4%) developed EF. Three patients were male and median age was 39 y (range, 34-63). Intraoperative circulatory support was required in 3 patients, with 2 needing continued support postoperatively. Bipolar energy devices were consistently used for mediastinal hemostasis. All EFs were right-sided. Median time to diagnosis was 28 d (range, 12-48) and 80% of EFs presented as recurrent respiratory infections or empyema. Diagnosis was made through computed tomography (n = 3) or esophagogastroscopy (n = 2). Surgical repair with muscle flap covering achieved an 80% success rate. All patients achieved complete resolution, with only 1 patient experiencing a fatal outcome during a complicated EF-related recovery. Conclusion: Although EF after lung transplantation remains rare, vigilance is crucial, particularly in cases of right-sided intrathoracic infection. Moreover, caution must be exercised when applying thermal energy in the mediastinal area to prevent EF development and mitigate the risk of major morbidity. Timely diagnosis and surgical intervention can yield favorable outcomes.

ESPEN practical short micronutrient guideline.

BACKGROUND: Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. The importance of MNs in common pathologies is recognized by recent research, with deficiencies significantly impacting the outcome. OBJECTIVE: This short version of the guideline aims to provide practical recommendations for clinical practice. METHODS: An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL for the initial guideline. The search focused on physiological data, historical evidence (for papers published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. RESULTS: The limited number of interventional trials prevented meta-analysis and led to a low level of evidence for most recommendations. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90 % of votes. Altogether the guideline proposes 3 general recommendations and specific recommendations for the 26 MNs. Monitoring and management strategies are proposed. CONCLUSION: This short version of the MN guideline should facilitate handling of the MNs in at-risk diseases, whilst offering practical advice on MN provision and monitoring during nutritional support.

Tight Blood-Glucose Control without Early Parenteral Nutrition in the ICU.

BACKGROUND: Randomized, controlled trials have shown both benefit and harm from tight blood-glucose control in patients in the intensive care unit (ICU). Variation in the use of early parenteral nutrition and in insulin-induced severe hypoglycemia might explain this inconsistency. METHODS: We randomly assigned patients, on ICU admission, to liberal glucose control (insulin initiated only when the blood-glucose level was >215 mg per deciliter [>11.9 mmol per liter]) or to tight glucose control (blood-glucose level targeted with the use of the LOGIC-Insulin algorithm at 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]); parenteral nutrition was withheld in both groups for 1 week. Protocol adherence was determined according to glucose metrics. The primary outcome was the length of time that ICU care was needed, calculated on the basis of time to discharge alive from the ICU, with death accounted for as a competing risk; 90-day mortality was the safety outcome. RESULTS: Of 9230 patients who underwent randomization, 4622 were assigned to liberal glucose control and 4608 to tight glucose control. The median morning blood-glucose level was 140 mg per deciliter (interquartile range, 122 to 161) with liberal glucose control and 107 mg per deciliter (interquartile range, 98 to 117) with tight glucose control. Severe hypoglycemia occurred in 31 patients (0.7%) in the liberal-control group and 47 patients (1.0%) in the tight-control group. The length of time that ICU care was needed was similar in the two groups (hazard ratio for earlier discharge alive with tight glucose control, 1.00; 95% confidence interval, 0.96 to 1.04; P = 0.94). Mortality at 90 days was also similar (10.1% with liberal glucose control and 10.5% with tight glucose control, P = 0.51). Analyses of eight prespecified secondary outcomes suggested that the incidence of new infections, the duration of respiratory and hemodynamic support, the time to discharge alive from the hospital, and mortality in the ICU and hospital were similar in the two groups, whereas severe acute kidney injury and cholestatic liver dysfunction appeared less prevalent with tight glucose control. CONCLUSIONS: In critically ill patients who were not receiving early parenteral nutrition, tight glucose control did not affect the length of time that ICU care was needed or mortality. (Funded by the Research Foundation-Flanders and others; TGC-Fast ClinicalTrials.gov number, NCT03665207.).

Skeletal Muscle Myokine Expression in Critical Illness, Association With Outcome and Impact of Therapeutic Interventions.

Context: Muscle expresses and secretes several myokines that bring about benefits in distant organs. Objective: We investigated the impact of critical illness on muscular expression of irisin, kynurenine aminotransferases, and amylase; association with clinical outcome; and impact of interventions that attenuate muscle wasting/weakness. Methods: We studied critically ill patients who participated in 2 randomized controlled trials (EPaNIC/NESCI) and documented time profiles in critically ill mice. Included in the study were 174 intensive care unit (ICU) patients (day 8 ± 1) vs 19 matched controls, and 60 mice subjected to surgery/sepsis vs 60 pair-fed healthy mice. Interventions studied included 7-day neuromuscular electrical stimulation (NMES), and withholding parenteral nutrition (PN) in the first ICU week (late PN) vs early PN. The main outcome measures were FNDC5 (irisin- precursor), KYAT1, KYAT3, and amylase mRNA expression in skeletal muscle. Results: Critically ill patients showed 34% to 80% lower mRNA expression of FNDC5, KYAT1, and amylases than controls (P < .0001). Critically ill mice showed time-dependent reductions in all mRNAs compared with healthy mice (P ≤ .04). The lower FNDC5 expression in patients was independently associated with a higher ICU mortality (P = .015) and ICU-acquired weakness (P = .012), whereas the lower amylase expression in ICU survivors was independently associated with a longer ICU stay (P = .0060). Lower amylase expression was independently associated with a lower risk of death (P = .048), and lower KYAT1 expression with a lower risk of weakness (P = .022). NMES increased FNDC5 expression compared with unstimulated muscle (P = .016), and late PN patients had a higher KYAT1 expression than early PN patients (P = .022). Conclusion: Expression of the studied myokines was affected by critical illness and associated with clinical outcomes, with limited effects of interventions that attenuate muscle wasting or weakness.

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.

Clinical nutrition issues in 2022: What is missing to trust supplemental parenteral nutrition (SPN) in ICU patients?

A multidisciplinary group of international physicians involved in the medical nutrition therapy (MNT) of adult critically ill patients met to discuss the value, role, and open questions regarding supplemental parenteral nutrition (SPN) along with oral or enteral nutrition (EN), particularly in the intensive care unit (ICU) setting. This manuscript summarizes the discussions and results to highlight the importance of SPN as part of a comprehensive approach to MNT in critically ill adults and for researchers to generate new evidence based on well-powered randomized controlled trials (RCTs). The experts agreed on several key points: SPN has shown clinical benefits, resulting in this strategy being included in American and European guidelines. Nevertheless, its use is heterogeneous across European countries, due to the persistence of uncertainties, such as the optimal timing and the risk of overfeeding in absence of indirect calorimetry (IC), which results in divergent opinions and barriers to SPN implementation. Education is also insufficient. The experts agreed on actions needed to increase evidence quality on SPN use in specific patients at a given time point during acute critical illness or recovery.

Management of moderate to severe traumatic brain injury: an update for the intensivist.

Traumatic brain injury (TBI) remains one of the most fatal and debilitating conditions in the world. Current clinical management in severe TBI patients is mainly concerned with reducing secondary insults and optimizing the balance between substrate delivery and consumption. Over the past decades, multimodality monitoring has become more widely available, and clinical management protocols have been published that recommend potential interventions to correct pathophysiological derangements. Even while evidence from randomized clinical trials is still lacking for many of the recommended interventions, these protocols and algorithms can be useful to define a clear standard of therapy where novel interventions can be added or be compared to. Over the past decade, more attention has been paid to holistic management, in which hemodynamic, respiratory, inflammatory or coagulation disturbances are detected and treated accordingly. Considerable variability with regards to the trajectories of recovery exists. Even while most of the recovery occurs in the first months after TBI, substantial changes may still occur in a later phase. Neuroprognostication is challenging in these patients, where a risk of self-fulfilling prophecies is a matter of concern. The present article provides a comprehensive and practical review of the current best practice in clinical management and long-term outcomes of moderate to severe TBI in adult patients admitted to the intensive care unit.

ESPEN micronutrient guideline.

BACKGROUND: Trace elements and vitamins, named together micronutrients (MNs), are essential for human metabolism. Recent research has shown the importance of MNs in common pathologies, with significant deficiencies impacting the outcome. OBJECTIVE: This guideline aims to provide information for daily clinical nutrition practice regarding assessment of MN status, monitoring, and prescription. It proposes a consensus terminology, since many words are used imprecisely, resulting in confusion. This is particularly true for the words "deficiency", "repletion", "complement", and "supplement". METHODS: The expert group attempted to apply the 2015 standard operating procedures (SOP) for ESPEN which focuses on disease. However, this approach could not be applied due to the multiple diseases requiring clinical nutrition resulting in one text for each MN, rather than for diseases. An extensive search of the literature was conducted in the databases Medline, PubMed, Cochrane, Google Scholar, and CINAHL. The search focused on physiological data, historical evidence (published before PubMed release in 1996), and observational and/or randomized trials. For each MN, the main functions, optimal analytical methods, impact of inflammation, potential toxicity, and provision during enteral or parenteral nutrition were addressed. The SOP wording was applied for strength of recommendations. RESULTS: There was a limited number of interventional trials, preventing meta-analysis and leading to a low level of evidence. The recommendations underwent a consensus process, which resulted in a percentage of agreement (%): strong consensus required of >90% of votes. Altogether the guideline proposes sets of recommendations for 26 MNs, resulting in 170 single recommendations. Critical MNs were identified with deficiencies being present in numerous acute and chronic diseases. Monitoring and management strategies are proposed. CONCLUSION: This guideline should enable addressing suboptimal and deficient status of a bundle of MNs in at-risk diseases. In particular, it offers practical advice on MN provision and monitoring during nutritional support.

DNA methylation alterations in muscle of critically ill patients.

BACKGROUND: Intensive care unit (ICU)-acquired weakness can persist beyond ICU stay and has been associated with long-term functional impairment of ICU survivors. Recently, DNA methylation alterations were found in the blood of ICU patients, partially explaining long-term developmental impairment of critically ill children. As illness-induced aberrant DNA methylation theoretically could also be involved in long-term weakness, we investigated whether the DNA methylation signature in muscle of adult critically ill patients differs from that in muscle of healthy controls. METHODS: Genome-wide methylation was determined (Infinium® HumanMethylationEPIC BeadChips) in DNA extracted from skeletal muscle biopsies that had been collected on Day 8 ± 1 in ICU from 172 EPaNIC-trial patients [66% male sex, median age 62.7 years, median body mass index (BMI) 25.9 kg/m2 ] and 20 matched healthy controls (70% male sex, median age 58.0 years, median BMI 24.4 kg/m2 ). Methylation status of individual cytosine-phosphate-guanine (CpG) sites of patients and controls was compared with F-tests, using the Benjamini-Hochberg false discovery rate to correct for multiple comparisons. Differential methylation of DNA regions was assessed with bump hunting, with 1000 permutations assessing uncertainty, expressed as family-wise error rate. Gene expression was investigated for 10 representative affected genes. RESULTS: In DNA from ICU patients, 565 CpG sites, associated with 400 unique genes, were differentially methylated as compared with controls (average difference 3.2 ± 0.1% ranging up to 16.9%, P < 0.00005). Many of the associated genes appeared highly relevant for muscle structure and function/weakness, including genes involved in myogenesis, muscle regeneration, nerve/muscle membrane excitability, muscle denervation/re-innervation, axon guidance/myelination/degeneration/regeneration, synapse function, ion channelling with especially calcium signalling, metabolism (glucose, protein, and fat), insulin signalling, neuroendocrine hormone regulation, mitochondrial function, autophagy, apoptosis, oxidative stress, Wnt signalling, transcription regulation, muscle fat infiltration during regeneration, and fibrosis. In patients as compared with controls, we also identified two hypomethylated regions, spanning 18 and 3 CpG sites in the promoters of the HIC1 and NADK2 genes, respectively (average differences 5.8 ± 0.01% and 12.1 ± 0.04%, family-wise error rate <0.05). HIC1 and NADK2 play important roles in muscle regeneration and postsynaptic acetylcholine receptors and in mitochondrial processes, respectively. Nine of 10 investigated genes containing DNA methylation alterations were differentially expressed in patients as compared with controls (P ≤ 0.03). CONCLUSIONS: Critically ill patients present with a different DNA methylation signature in skeletal muscle as compared with healthy controls, which in theory could provide a biological basis for long-term persistence of weakness in ICU survivors. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00512122, registered on 31 July 2007.