Personalized nutrition therapy in critical care: 10 expert recommendations.

Personalization of ICU nutrition is essential to future of critical care. Recommendations from American/European guidelines and practice suggestions incorporating recent literature are presented. Low-dose enteral nutrition (EN) or parenteral nutrition (PN) can be started within 48 h of admission. While EN is preferred route of delivery, new data highlight PN can be given safely without increased risk; thus, when early EN is not feasible, provision of isocaloric PN is effective and results in similar outcomes. Indirect calorimetry (IC) measurement of energy expenditure (EE) is recommended by both European/American guidelines after stabilization post-ICU admission. Below-measured EE (~ 70%) targets should be used during early phase and increased to match EE later in stay. Low-dose protein delivery can be used early (~ D1-2) (< 0.8 g/kg/d) and progressed to ≥ 1.2 g/kg/d as patients stabilize, with consideration of avoiding higher protein in unstable patients and in acute kidney injury not on CRRT. Intermittent-feeding schedules hold promise for further research. Clinicians must be aware of delivered energy/protein and what percentage of targets delivered nutrition represents. Computerized nutrition monitoring systems/platforms have become widely available. In patients at risk of micronutrient/vitamin losses (i.e., CRRT), evaluation of micronutrient levels should be considered post-ICU days 5-7 with repletion of deficiencies where indicated. In future, we hope use of muscle monitors such as ultrasound, CT scan, and/or BIA will be utilized to assess nutrition risk and monitor response to nutrition. Use of specialized anabolic nutrients such as HMB, creatine, and leucine to improve strength/muscle mass is promising in other populations and deserves future study. In post-ICU setting, continued use of IC measurement and other muscle measures should be considered to guide nutrition. Research on using rehabilitation interventions such as cardiopulmonary exercise testing (CPET) to guide post-ICU exercise/rehabilitation prescription and using anabolic agents such as testosterone/oxandrolone to promote post-ICU recovery is needed.

The Hypothalamus-pituitary-adrenocortical Response to Critical Illness: A Concept in Need of Revision.

Based on insights obtained during the past decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical axis in response to critical illness is in need of revision. After a brief central hypothalamus-pituitary-adrenocortical axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol-binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11ßHSD1, glucocorticoid receptor-α (GRα), and FK506 binding protein 5 (FKBP51) that appear to titrate increased GRα action in vital organs and tissues while reducing GRα action in neutrophils, possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of pro-opiomelanocortin into ACTH, thereby reducing ACTH-driven cortisol secretion, whereas ongoing central activation results in increased circulating pro-opiomelanocortin. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as "relative," as opposed to "absolute," adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. The findings also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.

Impact of Hydrocortisone and of CRH Infusion on the Hypothalamus-Pituitary-Adrenocortical Axis of Septic Male Mice.

PURPOSE: Sepsis is hallmarked by high plasma cortisol/corticosterone (CORT), low adrenocorticotropic hormone (ACTH), and high pro-opiomelanocortin (POMC). While corticotropin-releasing hormone-(CRH) and arginine-vasopressin (AVP)-driven pituitary POMC expression remains active, POMC processing into ACTH becomes impaired. Low ACTH is accompanied by loss of adrenocortical structure, although steroidogenic enzymes remain expressed. We hypothesized that treatment of sepsis with hydrocortisone (HC) aggravates this phenotype whereas CRH infusion safeguards ACTH-driven adrenocortical structure. METHODS: In a fluid-resuscitated, antibiotics-treated mouse model of prolonged sepsis, we compared the effects of HC and CRH infusion with placebo on plasma ACTH, POMC, and CORT; on markers of hypothalamic CRH and AVP signaling and pituitary POMC processing; and on the adrenocortical structure and markers of steroidogenesis. In adrenal explants, we studied the steroidogenic capacity of POMC. RESULTS: During sepsis, HC further suppressed plasma ACTH, but not POMC, predominantly by suppressing sepsis-activated CRH/AVP-signaling pathways. In contrast, in CRH-treated sepsis, plasma ACTH was normalized following restoration of pituitary POMC processing. The sepsis-induced rise in markers of adrenocortical steroidogenesis was unaltered by CRH and suppressed partially by HC, which also increased adrenal markers of inflammation. Ex vivo stimulation of adrenal explants with POMC increased CORT as effectively as an equimolar dose of ACTH. CONCLUSIONS: Treatment of sepsis with HC impaired integrity and function of the hypothalamic-pituitary-adrenal axis at the level of the pituitary and the adrenal cortex while CRH restored pituitary POMC processing without affecting the adrenal cortex. Sepsis-induced high-circulating POMC may be responsible for ongoing adrenocortical steroidogenesis despite low ACTH.

A guide to enteral nutrition in intensive care units: 10 expert tips for the daily practice.

The preferential use of the oral/enteral route in critically ill patients over gut rest is uniformly recommended and applied. This article provides practical guidance on enteral nutrition in compliance with recent American and European guidelines. Low-dose enteral nutrition can be safely started within 48 h after admission, even during treatment with small or moderate doses of vasopressor agents. A percutaneous access should be used when enteral nutrition is anticipated for ≥ 4 weeks. Energy delivery should not be calculated to match energy expenditure before day 4-7, and the use of energy-dense formulas can be restricted to cases of inability to tolerate full-volume isocaloric enteral nutrition or to patients who require fluid restriction. Low-dose protein (max 0.8 g/kg/day) can be provided during the early phase of critical illness, while a protein target of > 1.2 g/kg/day could be considered during the rehabilitation phase. The occurrence of refeeding syndrome should be assessed by daily measurement of plasma phosphate, and a phosphate drop of 30% should be managed by reduction of enteral feeding rate and high-dose thiamine. Vomiting and increased gastric residual volume may indicate gastric intolerance, while sudden abdominal pain, distension, gastrointestinal paralysis, or rising abdominal pressure may indicate lower gastrointestinal intolerance.

Altered cholesterol homeostasis in critical illness-induced muscle weakness: effect of exogenous 3-hydroxybutyrate.

BACKGROUND: Muscle weakness is a complication of critical illness which hampers recovery. In critically ill mice, supplementation with the ketone body 3-hydroxybutyrate has been shown to improve muscle force and to normalize illness-induced hypocholesterolemia. We hypothesized that altered cholesterol homeostasis is involved in development of critical illness-induced muscle weakness and that this pathway can be affected by 3-hydroxybutyrate. METHODS: In both human critically ill patients and septic mice, the association between circulating cholesterol concentrations and muscle weakness was assessed. In septic mice, the impact of 3-hydroxybutyrate supplementation on cholesterol homeostasis was evaluated with use of tracer technology and through analysis of markers of cholesterol metabolism and downstream pathways. RESULTS: Serum cholesterol concentrations were lower in weak than in non-weak critically ill patients, and in multivariable analysis adjusting for baseline risk factors, serum cholesterol was inversely correlated with weakness. In septic mice, plasma cholesterol correlated positively with muscle force. In septic mice, exogenous 3-hydroxybutyrate increased plasma cholesterol and altered cholesterol homeostasis, by normalization of plasma mevalonate and elevation of muscular, but not hepatic, expression of cholesterol synthesis genes. In septic mice, tracer technology revealed that 3-hydroxybutyrate was preferentially taken up by muscle and metabolized into cholesterol precursor mevalonate, rather than TCA metabolites. The 3-hydroxybutyrate protection against weakness was not related to ubiquinone or downstream myofiber mitochondrial function, whereas cholesterol content in myofibers was increased. CONCLUSIONS: These findings point to a role for low cholesterol in critical illness-induced muscle weakness and to a protective mechanism-of-action for 3-hydroxybutyrate supplementation.

Supplementation of vitamins, trace elements and electrolytes in the PEPaNIC Randomised Controlled Trial: Composition and preparation of the prescription.

BACKGROUND AND AIMS: Following the results of the paediatric early versus late parenteral nutrition in critical illness (PEPaNIC) multicentre, randomised, controlled trial, the new ESPGHAN/ESPEN/ESPR/CSPEN and ESPNIC guidelines recommend to consider withholding parenteral macronutrients for 1 week, while providing micronutrients, in critically ill children if enteral nutrition is insufficient. Critically ill children are suspected to be vulnerable to micronutrient deficiencies due to inadequate enteral nutrition, increased body's demands and excessive losses. Hitherto, micronutrient requirements in PICU are estimated based on recommended daily intakes for healthy children and expert opinion. We aimed to provide an overview of the current practice of micronutrient administration and practical considerations in the three participating centres of the PEPaNIC study, and compare these therapies with the recommendations in the new ESPGHAN/ESPEN/ESPR/CSPEN guidelines. METHODS: We describe the current composition and preparation of the prescribed parenteral micronutrients (consisting of vitamins, trace elements and electrolytes) in the three centres (Leuven, Rotterdam and Edmonton) that participated in the PEPaNIC RCT, and compare this per micronutrient with the ESPGHAN/ESPEN/ESPR/CSPEN guidelines recommendations. RESULTS: The three centres use a different micronutrient supplementation protocol during the first week of critical illness in children, with substantial differences regarding the amounts administered. Leuven administers commercial vitamins, trace elements and electrolytes in separate infusions both in 4 h. Rotterdam provides commercial vitamins and trace elements simultaneously via 8-h infusion and electrolytes continuously over 24 h. Lastly, Edmonton administers commercial vitamins and institutionally prepared trace elements solutions in 1 h and electrolytes on demand. Comparison with the ESPGHAN/ESPEN/ESPR/CSPEN guidelines yields in differences between the recommendations and the administered amounts, which are most substantial for vitamins. CONCLUSION: The practice of intravenous micronutrient administration differs substantially between the three PEPaNIC centres and in comparison with the current guideline recommendations. This deviation is at least partially explained by the inability to provide all recommended amounts with the currently available commercial products and by the lack of strong evidence supporting these recommendations.

Early neuromuscular electrical stimulation reduces the loss of muscle mass in critically ill patients - A within subject randomized controlled trial.

PURPOSE: To investigate the effect of Neuromuscular Electrical Stimulation (NMES) on muscle thickness, strength and morphological and molecular markers of the quadriceps. MATERIALS AND METHODS: Adult critically ill patients with an expected prolonged stay received unilateral quadriceps NMES sessions for 7 consecutive days. Before and after the intervention period, quadriceps thickness was measured with ultrasound. After the intervention period, strength was assessed in cooperative patients and muscle biopsies were taken. Multivariable regression was performed to identify factors affecting muscle thickness loss. RESULTS: Muscle thickness decreased less in the stimulated leg (-6 ± 16% versus -12 ± 15%, p = 0.014, n = 47). Strength was comparable. Opioid administration, minimal muscle contraction and more muscle thickness loss in the non-stimulated muscle were independently associated with better muscle thickness preservation. Stimulated muscles showed a shift towards larger myofibers and higher MyHC-I gene expression. NMES did not affect gene expression of other myofibrillary proteins, MuRF-1 or atrogin-1. Signs of myofiber necrosis and inflammation were comparable for both muscles. CONCLUSIONS: NMES attenuated the loss of muscle mass, but not of strength, in critically ill patients. Preservation of muscle mass was more likely in patients receiving opioids, patients with a minimal muscle contraction during NMES and patients more prone to lose muscle mass. TRIAL REGISTRATION: clinicaltrials.govNCT02133300.

Effect of Intravenous 25OHD Supplementation on Bone Turnover and Inflammation in Prolonged Critically Ill Patients.

Critically ill patients have low circulating 25-hydroxyvitamin D (25OHD), vitamin D binding protein (DBP), and 1,25-dihydroxyvitamin D [1,25(OH)2D]. Low 25OHD is associated with poor outcomes, possibly explained by its effect on bone and immunity. In this prospective, randomized double-blind, placebo-controlled study, we investigated the feasibility of normalizing 25OHD in prolonged (>10 days) critically ill patients and the effects thereof on 1,25(OH)2D, bone metabolism, and innate immunity. Twenty-four patients were included and compared with 24 matched healthy subjects. Patients were randomized to either intravenous bolus of 200 µg 25OHD followed by daily infusion of 15 µg 25OHD for 10 days, or to placebo. Parameters of vitamin D, bone and mineral metabolism, and innate immune function were measured. As safety endpoints, ICU length of stay and mortality were registered. Infusion of 25OHD resulted in a sustained increase of serum 25OHD (from median baseline 9.2 -16.1 ng/ml at day 10), which, however, remained below normal levels. There was no increase in serum 1,25(OH)2D but a slight increase in serum 24,25(OH)2D. Mineral homeostasis, innate immunity and clinical safety endpoints were unaffected. Thus, intravenous 25OHD administration during critical illness increased serum 25OHD concentrations, though less than expected from data in healthy subjects, which suggests illness-induced alterations in 25OHD metabolism and/or increased 25OHD distribution volume. The increased serum 25OHD concentrations were not followed by a rise in 1,25(OH)2D nor were bone metabolism or innate immunity affected, which suggests that low 25OHD and 1,25OHD levels are part of the adaptive response to critical illness.

Adipose tissue protects against sepsis-induced muscle weakness in mice: from lipolysis to ketones.

BACKGROUND: ICU-acquired weakness is a debilitating consequence of prolonged critical illness that is associated with poor outcome. Recently, premorbid obesity has been shown to protect against such illness-induced muscle wasting and weakness. Here, we hypothesized that this protection was due to increased lipid and ketone availability. METHODS: In a centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we compared markers of lipolysis and fatty acid oxidation in lean and obese septic mice (n = 117). Next, we compared markers of muscle wasting and weakness in septic obese wild-type and adipose tissue-specific ATGL knockout (AAKO) mice (n = 73), in lean septic mice receiving either intravenous infusion of lipids or standard parenteral nutrition (PN) (n = 70), and in lean septic mice receiving standard PN supplemented with either the ketone body 3-hydroxybutyrate or isocaloric glucose (n = 49). RESULTS: Obese septic mice had more pronounced lipolysis (p ≤ 0.05), peripheral fatty acid oxidation (p ≤ 0.05), and ketogenesis (p ≤ 0.05) than lean mice. Blocking lipolysis in obese septic mice caused severely reduced muscle mass (32% loss vs. 15% in wild-type, p < 0.001) and specific maximal muscle force (59% loss vs. 0% in wild-type; p < 0.001). In contrast, intravenous infusion of lipids in lean septic mice maintained specific maximal muscle force up to healthy control levels (p = 0.6), whereas this was reduced with 28% in septic mice receiving standard PN (p = 0.006). Muscle mass was evenly reduced with 29% in both lean septic groups (p < 0.001). Lipid administration enhanced fatty acid oxidation (p ≤ 0.05) and ketogenesis (p < 0.001), but caused unfavorable liver steatosis (p = 0.01) and a deranged lipid profile (p ≤ 0.01). Supplementation of standard PN with 3-hydroxybutyrate also attenuated specific maximal muscle force up to healthy control levels (p = 0.1), but loss of muscle mass could not be prevented (25% loss in both septic groups; p < 0.001). Importantly, this intervention improved muscle regeneration markers (p ≤ 0.05) without the unfavorable side effects seen with lipid infusion. CONCLUSIONS: Obesity-induced muscle protection during sepsis is partly mediated by elevated mobilization and metabolism of endogenous fatty acids. Furthermore, increased availability of ketone bodies, either through ketogenesis or through parenteral infusion, appears to protect against sepsis-induced muscle weakness also in the lean.

Glucose control in the ICU.

PURPOSE OF REVIEW: Critically ill patients usually develop hyperglycemia, which is associated with adverse outcome. Controversy exists whether the relationship is causal or not. This review summarizes recent evidence regarding glucose control in the ICU. RECENT FINDINGS: Despite promising effects of tight glucose control in pioneer randomized controlled trials, the benefit has not been confirmed in subsequent multicenter studies and one trial found potential harm. This discrepancy could be explained by methodological differences between the trials rather than by a different case mix. Strategies to improve the efficacy and safety of tight glucose control have been developed, including the use of computerized treatment algorithms. SUMMARY: The ideal blood glucose target remains unclear and may depend on the context. As compared with tolerating severe hyperglycemia, tight glucose control is well tolerated and effective in patients receiving early parenteral nutrition when provided with a protocol that includes frequent, accurate glucose measurements and avoids large glucose fluctuations. All patient subgroups potentially benefit, with the possible exception of patients with poorly controlled diabetes, who may need less aggressive glucose control. It remains unclear whether tight glucose control is beneficial or not in the absence of early parenteral nutrition.

Phthalate and alternative plasticizers in indwelling medical devices in pediatric intensive care units.

The present study aimed to identify plasticizers present in indwelling plastic medical devices commonly used in the pediatric intensive care unit (PICU). We have analyzed a wide range of medical devices (n = 97) daily used in the PICUs of two academic hospitals in Belgium and the Netherlands. Identified compounds varied between the samples. Most of the indwelling medical devices and essential accessories were found to actively leach phthalates and alternative plasticizers. Results indicated that DEHP was predominantly present as plasticizer (60 of 97 samples), followed by bis(2-ethylhexyl) adipate (DEHA, 32 of 97), bis(2-ethylhexyl) terephthalate (DEHT, 24 of 97), tris(2-ethylhexyl) trimellitate (TOTM, 20 of 97), and tributyl-O-acetyl citrate (ATBC, 10 of 97). Other plasticizers, such as di-isononyl-cyclohexane-1,2-dicarboxylate (DINCH, 2 of 97), di-isononyl phthalate (DiNP, 4 of 97), di(2-propylheptyl) phthalate (DPHP, 4 of 97) and di-isodecyl phthalate (DiDP, 2 of 97) were detected in < 5% of the investigated samples. Several devices contained multiple plasticizers, e.g. devices containing TOTM contained also DEHP and DEHT. Our data indicate that PICU patients are exposed to a wide range of plasticizers, including the controversial DEHP. Future studies should investigate the exposure to APs in children staying in the PICU and the possible health effects thereof.

Prevalence and Prognostic Value of Abnormal Liver Test Results in Critically Ill Children and the Impact of Delaying Parenteral Nutrition.

OBJECTIVES: In the Early versus Late Parenteral Nutrition in the Pediatric ICU randomized controlled trial, delaying parenteral nutrition to beyond day 7 (late parenteral nutrition) was clinically superior to supplemental parenteral nutrition initiated within 24 hours (early parenteral nutrition), but resulted in a higher rise in bilirubin. We aimed to document prevalence and prognostic value of abnormal liver tests in the PICU and the impact hereon of withholding early parenteral nutrition. DESIGN: Preplanned secondary analysis of the Early versus Late Parenteral Nutrition in the Pediatric ICU randomized controlled trial. Total bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, alkaline phosphatase plasma concentrations were measured systematically in PICU. Liver test analyses were adjusted for baseline characteristics including severity of illness. SETTING: Three PICUs in Belgium, the Netherlands, and Canada. PATIENTS: As neonatal jaundice was considered a confounder, only the 1,231 of the 1,440 Early versus Late Parenteral Nutrition in the Pediatric ICU-patients 28 days to 17 years old were included. INTERVENTIONS: Late parenteral nutrition as compared with early parenteral nutrition. MEASUREMENTS AND MAIN RESULTS: During the first seven PICU days, the prevalence of cholestasis (> 2 mg/dL [34.2 µmol/L] bilirubin) ranged between 3.8% and 4.9% and of hypoxic hepatitis (≥ 20-fold upper limit of normality for alanine aminotransferase and aspartate aminotransferase) between 0.8% and 2.2%, both unaffected by the use of parenteral nutrition. Throughout the first week in PICU plasma bilirubin concentrations were higher in late parenteral nutrition patients (p < 0.05), but became comparable to early parenteral nutrition patients as soon as parenteral nutrition was started on day 8. Plasma concentrations of gamma-glutamyl transpeptidase, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase were unaffected by parenteral nutrition. High day 1 plasma concentrations of gamma-glutamyl transpeptidase, alanine aminotransferase, and aspartate aminotransferase (p ≤ 0.01), but not alkaline phosphatase, were independent risk factors for PICU mortality. Day 1 plasma bilirubin concentrations displayed a U-shaped association with PICU mortality, with higher mortality associated with bilirubin less than 0.20 mg/dL and greater than 0.76 mg/dL (< 3.42 µmol/L and > 13 µmol/L) (p ≤ 0.01). CONCLUSIONS: Overt cholestasis and hypoxic hepatitis were rare and unrelated to the nutritional strategy. However, withholding parenteral nutrition up to 1 week in PICU increased plasma bilirubin. A mild elevation of bilirubin on the first PICU day was associated with lower risk of death and may reflect a stress response, rather than true cholestasis.

Amino acid supplements in critically ill patients.

Observational studies have associated a low amino acid intake with adverse outcome of critical illness. Although this finding could theoretically be explained by differences in feeding tolerance related to illness severity, guidelines have recommended to administer sufficient amounts of amino acids from early onwards in the disease course. Recently, however, several high quality randomized controlled trials have not shown benefit by early amino acid supplementation and some trials even found potential harm, thus questioning this recommendation. These negative results could be related to amino acid-induced suppression of autophagy, to the inability to suppress bulk catabolism by exogenous amino acids, or to the administration of an amino acid mixture with an inappropriate composition. Currently, there is no evidence supporting administration of individual amino acid supplements during critical illness and glutamine administration may be harmful. The optimal timing, dose and composition of the amino acid mixture for critically ill patients remain unclear.

Effect of early supplemental parenteral nutrition in the paediatric ICU: a preplanned observational study of post-randomisation treatments in the PEPaNIC trial.

BACKGROUND: Large randomised controlled trials have shown that early supplemental parenteral nutrition in patients admitted to adult and paediatric intensive care units (PICUs) is harmful. Overdosing of energy with too little protein was suggested as a potential reason for this. This study analysed which macronutrient was associated with harm caused by early supplemental parenteral nutrition in the Paediatric Early versus Late Parenteral Nutrition In Critical Illness (PEPaNIC) randomised trial. METHODS: Patients in the initial randomised controlled trial were randomly assigned to receive suppplemental parenteral nutrition (PN) within 24 h of PICU admission (early PN) or to receive such PN after 1 week (late PN) when enteral nutrition was insufficient. In this post-randomisation, observational study, doses of glucose, lipids, and aminoacids administered during the first 7 days of PICU stay were expressed as % of reference doses from published clinical guidelines for age and weight. Independent associations between average macronutrient doses up to each of the first 7 days and likelihood of acquiring an infection in the PICU, of earlier live weaning from mechanical ventilation, and of earlier live PICU discharge were investigated using multivariable Cox proportional hazard analyses. The three macronutrients were included in the analysis simultaneously and baseline risk factors were adjusted for. FINDINGS: From June 18, 2012, to July 27, 2015, 7519 children aged between newborn and 17 years were assessed for eligibility. 6079 patients were excluded, and 1440 children were randomly assigned to receive either early PN (n=723) or late PN (n=717). With increasing doses of aminoacids, the likelihood of acquiring a new infection was higher (adjusted hazard ratios [HRs] per 10% increase between 1·043-1·134 for days 1-5, p≤0·029), while the likelihood of earlier live weaning from mechanical ventilation was lower (HRs 0·950-0·975 days 3-7, p≤0·045), and the likelihood of earlier live PICU discharge was lower (HRs 0·943-0·972 days 1-7, p≤0·030). By contrast, more glucose during the first 3 days of PICU stay was independently associated with fewer infections (HRs 0·870-0·913, p≤0·036), whereas more lipids was independently associated with earlier PICU discharge (HRs 1·027-1·050, p≤0·043 days 4-7). Risk of harm with aminoacids was also shown for low doses. INTERPRETATION: These associations suggest that early administration of aminoacids, but not glucose or lipids, could explain harm caused by early supplemental parenteral nutrition in critically ill children. FUNDING: Flemish Agency for Innovation through Science and Technology; UZLeuven Clinical Research Fund; Research Foundation Flanders; Methusalem Programme Flemish Government; European Research Council; Fonds-NutsOhra; Erasmus-MC Research Grant; Erasmus Trustfonds.

Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice.

BACKGROUND: Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. However, histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. The efficacy of the angiotensin receptor type 1 blocker losartan is controversial because of varying results in a few animal and human studies. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model. METHODS: Male C57BL/6 J mice with high fat-high sucrose diet (HF-HSD) induced NASH, obesity, insulin resistance and hypercholesterolemia were subjected to dietary intervention (switch from HF-HSD to normal chow diet (NCD)) (n = 9), continuation HF-HSD together with losartan (30 mg/kg/day) (n = 9) or continuation HF-HSD only (n = 9) for 8 weeks. 9 mice received NCD during the entire experiment (20 weeks). We assessed the systemic metabolic effects and performed a detailed hepatic histological and molecular profiling. A P-value of < 0.05, using the group with continuation of HF-HSD only as control, was considered as statistically significant. RESULTS: Dietary intervention normalized obesity, insulin resistance, and hypercholesterolemia (for all P < 0.001), and remarkably, completely reversed all histological features of pre-existent NASH (for all P < 0.001), including fibrosis measured by quantification of collagen proportional area (P < 0.01). At the hepatic molecular level, dietary intervention targeted fibrogenesis with a normalization of collagen type I alpha 1, transforming growth factor ß1, tissue inhibitor of metalloproteinase 1 mRNA levels (for all P < 0.01), lipid metabolism with a normalization of fatty acid translocase/CD36, fatty acid transport protein 5, fatty acid synthase mRNA levels (P < 0.05) and markers related to mitochondrial function with a normalization of hepatic ATP content (P < 0.05) together with sirtuin1 and uncoupling protein 2 mRNA levels (for both P < 0.001). Dietary intervention abolished p62 accumulation (P < 0.01), suggesting a restoration of autophagic flux. Losartan did not significantly affect obesity, insulin resistance, hypercholesterolemia or any histological NASH feature. CONCLUSIONS: Dietary intervention, and not losartan, completely restores the metabolic phenotype in a representative mouse model with pre-existent NASH, obesity, insulin resistance and hypercholesterolemia.

Effect of Early Parenteral Nutrition on the HPA Axis and on Treatment With Corticosteroids in Intensive Care Patients.

BACKGROUND: Nutrition can affect the hypothalamus-pituitary-adrenal axis. We hypothesized that early administration of parenteral nutrition (PN) during critical illness reduces plasma ACTH and cortisol concentrations and thereby increases the use of corticosteroids. METHODS: This is a preplanned substudy of a randomized controlled trial (EPaNIC) that compared early PN with late PN in 4640 critically ill patients. We investigated the effect of early vs late PN on any steroid treatment and on treatment for ≥ 5 days to capture patients with clinical suspicion of adrenal insufficiency, and assessed whether this was related to an effect on septic shock. Also, in a propensity score-matched subgroup (n=174) of patients not receiving steroids, plasma ACTH and (free) cortisol were quantified. RESULTS: Compared with late PN, more patients on early PN received treatment with corticosteroids (26.2% vs 23.8%; P = .05) and with corticosteroids for ≥ 5 days (14.0% vs 11.9%; P = .03). However, plasma ACTH and (free) cortisol concentrations were unaffected and thus could not explain the higher use of corticosteroids with early PN. Instead, more patients developed new septic shock with early PN (17.0%) than with late PN (14.2%) (P = .01). In multivariate logistic regression analysis, new septic shock was an independent determinant for ≥ 5 days steroid treatment (odds ratio, 6.25; 95% confidence interval, 4.93-7.94; P < .0001), statistically explaining the effect of early PN on steroid treatment. CONCLUSIONS: Early PN did not affect plasma concentrations of ACTH and (free) cortisol, but increased the incidence of septic shock, which statistically explained why more patients on early PN received corticosteroids.

Impact of withholding early parenteral nutrition completing enteral nutrition in pediatric critically ill patients (PEPaNIC trial): study protocol for a randomized controlled trial.

BACKGROUND: The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the incidence of new infections and accelerates recovery. METHODS/DESIGN: The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency. The sample size (n = 1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections, with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned interim-analysis focusing on the incidence of new infections in the control group only. DISCUSSION: Clinical evidence in favor of early administration of PN in critically ill children is currently lacking, despite potential benefit but also known side effects. This large international RCT will help physicians to gain more insight in the clinical effects of omitting PN during the first week of critical illness in children. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01536275 on 16 February 2012.

Interventions for preventing critical illness polyneuropathy and critical illness myopathy.

BACKGROUND: Critical illness polyneuropathy or myopathy (CIP/CIM) is a frequent complication in the intensive care unit (ICU) and is associated with prolonged mechanical ventilation, longer ICU stay and increased mortality. This is an interim update of a review first published in 2009 (Hermans 2009). It has been updated to October 2011, with further potentially eligible studies from a December 2013 search characterised as awaiting assessment. OBJECTIVES: To systematically review the evidence from RCTs concerning the ability of any intervention to reduce the incidence of CIP or CIM in critically ill individuals. SEARCH METHODS: On 4 October 2011, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We checked the bibliographies of identified trials and contacted trial authors and experts in the field. We carried out an additional search of these databases on 6 December 2013 to identify recent studies. SELECTION CRITERIA: All randomised controlled trials (RCTs), examining the effect of any intervention on the incidence of CIP/CIM in people admitted to adult medical or surgical ICUs. The primary outcome was the incidence of CIP/CIM in ICU, based on electrophysiological or clinical examination. Secondary outcomes included duration of mechanical ventilation, duration of ICU stay, death at 30 and 180 days after ICU admission and serious adverse events from the treatment regimens. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and assessed the risk of bias in included studies. MAIN RESULTS: We identified five trials that met our inclusion criteria. Two trials compared intensive insulin therapy (IIT) to conventional insulin therapy (CIT). IIT significantly reduced CIP/CIM in the screened (n = 825; risk ratio (RR) 0.65, 95% confidence interval (CI) 0.55 to 0.77) and total (n = 2748; RR 0.70, 95% CI 0.60 to 0.82) population randomised. IIT reduced duration of mechanical ventilation, ICU stay and 180-day mortality, but not 30-day mortality compared with CIT. Hypoglycaemia increased with IIT but did not cause early deaths.One trial compared corticosteroids with placebo (n = 180). The trial found no effect of treatment on CIP/CIM (RR 1.27, 95% CI 0.77 to 2.08), 180-day mortality, new infections, glycaemia at day seven, or episodes of pneumonia, but did show a reduction of new shock events.In the fourth trial, early physical therapy reduced CIP/CIM in 82/104 evaluable participants in ICU (RR 0.62. 95% CI 0.39 to 0.96). Statistical significance was lost when we performed a full intention-to-treat analysis (RR 0.81, 95% CI 0.60 to 1.08). Duration of mechanical ventilation but not ICU stay was significantly shorter in the intervention group. Hospital mortality was not affected but 30- and 180-day mortality results were not available. No adverse effects were noticed.The last trial found a reduced incidence of CIP/CIM in 52 evaluable participants out of a total of 140 who were randomised to electrical muscle stimulation (EMS) versus no stimulation (RR 0.32, 95% CI 0.10 to 1.01). These data were prone to bias due to imbalances between treatment groups in this subgroup of participants. After we imputed missing data and performed an intention-to-treat analysis, there was still no significant effect (RR 0.94, 95% CI 0.78 to 1.15). The investigators found no effect on duration of mechanical ventilation and noted no difference in ICU mortality, but did not report 30- and 180-day mortality.We updated the searches in December 2013 and identified nine potentially eligible studies that will be assessed for inclusion in the next update of the review. AUTHORS' CONCLUSIONS: There is moderate quality evidence from two large trials that intensive insulin therapy reduces CIP/CIM, and high quality evidence that it reduces duration of mechanical ventilation, ICU stay and 180-day mortality, at the expense of hypoglycaemia. Consequences and prevention of hypoglycaemia need further study. There is moderate quality evidence which suggests no effect of corticosteroids on CIP/CIM and high quality evidence that steroids do not affect secondary outcomes, except for fewer new shock episodes. Moderate quality evidence suggests a potential benefit of early rehabilitation on CIP/CIM which is accompanied by a shorter duration of mechanical ventilation but without an effect on ICU stay. Very low quality evidence suggests no effect of EMS, although data are prone to bias. Strict diagnostic criteria for CIP/CIM are urgently needed for research purposes. Large RCTs need to be conducted to further explore the role of early rehabilitation and EMS and to develop new preventive strategies.

Impact of early parenteral nutrition on metabolism and kidney injury.

A poor nutritional state and a caloric deficit associate with increased morbidity and mortality, but a recent multicenter, randomized controlled trial found that early parenteral nutrition to supplement insufficient enteral nutrition increases morbidity in the intensive care unit, including prolonging the duration of renal replacement therapy, compared with withholding parenteral nutrition for 1 week. Whether early versus late parenteral nutrition impacts the incidence and recovery of AKI is unknown. Here, we report a prespecified analysis from this trial, the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) study. The timing of parenteral nutrition did not affect the incidence of AKI, but early initiation seemed to slow renal recovery in patients with stage 2 AKI. Early parenteral nutrition did not affect the time course of creatinine and creatinine clearance but did increase plasma urea, urea/creatinine ratio, and nitrogen excretion beginning on the first day of amino acid infusion. In the group that received late parenteral nutrition, infusing amino acids after the first week also increased ureagenesis. During the first 2 weeks, ureagenesis resulted in net waste of 63% of the extra nitrogen intake from early parenteral nutrition. In conclusion, early parenteral nutrition does not seem to impact AKI incidence, although it may delay recovery in patients with stage 2 AKI. Substantial catabolism of the extra amino acids, which leads to higher levels of plasma urea, might explain the prolonged duration of renal replacement therapy observed with early parenteral nutrition.