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BACKGROUND: Inflammation is the hallmark of critical illness and triggers the neuro-endocrine stress response and an oxidative stress. Acute inflammation is initially essential for patient's survival. However, ongoing or exaggerated inflammation, due to persistent organ dysfunction, immune dysfunction or poor inflammation resolution, is associated to subsequent hypermetabolism and hypercatabolism that severely impact short and long-term functional status, autonomy, as well as health-related costs. Modulation of inflammation is thus tempting, with the goal to improve the short- and long-term outcomes of critically ill patients. FINDINGS: Inflammation can be modulated by nutritional strategies (including the timing of enteral nutrition initiation, the provision of some specific macronutrients or micronutrients, the use of probiotics) and metabolic treatments. The most interesting strategies seem to be n-3 polyunsaturated fatty acids, vitamin D, antioxidant micronutrients and propranolol, given their safety, their accessibility for clinical use, and their benefits in clinical studies in the specific context of critical care. However, the optimal doses, timing and route of administration are still unknown for most of them. Furthermore, their use in the recovery phase is not well studied and defined. CONCLUSION: The rationale to use strategies of inflammation modulation is obvious, based on critical illness pathophysiology and based on the increasingly described effects of some nutritional and pharmacological strategies. Regretfully, there isn't always substantial proof from clinical research regarding the positive impacts directly brought about by inflammation modulation. Some arguments come from studies performed in severe burn patients, but such results should be transposed to non-burn patients with caution. Further studies are needed to explore how the modulation of inflammation can improve the long-term outcomes after a critical illness.

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Malnutrition in visceral surgery is frequent; it calls for screening prior to an operation, and its postoperative occurrence should be sought out and prevented, if possible. Organization of an individualized nutritional support strategy is based on systematic nutritional assessment and adapted to the type of surgery, the objectives being to forestall malnutrition and to reduce induced morbidity (immunosuppression, delayed wound healing, anastomotic fistulas…). Nutritional support is part and parcel of enhanced recovery after surgery (ERAS), and has shown effectiveness in the field of visceral surgery. Oral feeding should always be privileged to the greatest possible extent, complemented if necessary by nutritional supplements. If nutritional support is required, enteral nutrition should be favored over parenteral nutrition. As for the role of pharmaco-nutrition or immuno-nutrition, it remains ill-defined. Lastly, each type of visceral surgery entails specific modifications of the anatomy of the digestive system and is liable to have specific functional consequences, which should be known and taken into account in view of effectively tailoring nutritional support.

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This systematic review and meta-analysis assessed the antidiabetic effect of pharmaconutrients as an add-on in type 2 diabetes mellitus patients by pooling data from currently available randomized controlled trials (RCTs). Data sources included the PubMed and EMBASE, Cochrane Central Register of Controlled Trials. RCTs reporting changes in glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), or homeostasis model assessment of insulin resistance (HOMA-IR) levels following add-on pharmaconutritional therapies for T2DM patients consuming antidiabetic drugs were targeted. Using random-effects meta-analyses, we identified pharmaconutrients with effects on glycemic outcomes. Heterogeneity among studies was presented using I2 values. Among 9537 articles, 119 RCTs with nine pharmaconutrients (chromium; coenzyme Q10; omega-3 fatty acids; vitamins C, D, and E; alpha-lipoic acid; selenium; and zinc) were included. Chromium (HbA1c, FBG, and HOMA-IR), coenzyme Q10 (HbA1c and FBG), vitamin C (HbA1c and FBG), and vitamin E (HbA1c and HOMA-IR) significantly improved glycemic control. Baseline HbA1c level and study duration influenced the effects of chromium and vitamin E on HbA1c level. Sensitivity analyses did not modify the pooled effects of pharmaconutrients on glycemic control. Administration of chromium, coenzyme Q10, and vitamins C and E for T2DM significantly improved glycemic control. This study has been registered in PROSPERO (CRD42018115229).

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Advancement in the understanding of inflammation regulation during tuberculosis (TB) treatment has led to novel therapeutic approaches being proposed. The use of immune mediators like anti-inflammatory and pro-resolving molecules for such, merits attention. Drug repurposing is a widely used strategy that seeks to identify new targets to treat or manage diseases. The widely explored nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and a more recently explored pharmaconutrition therapy using omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs), have the potential to modulate the immune system and are thus considered potential repurposed drugs in this context. These approaches may be beneficial as supportive therapy to the already existing treatment regimen to improve clinical outcomes. Here, we applied adjunct ibuprofen and n-3 LCPUFA therapy, respectively, with standard anti-TB treatment, in a C3HeB/FeJ murine model of TB. Bacterial loads, lung pathology, lung cytokines/chemokines and lung lipid mediators were measured as outcomes. Lung bacterial load on day 14 post-treatment (PT) was lower in the n-3 LCPUFA, compared to the ibuprofen group (p = 0.039), but was higher in the ibuprofen group than the treated control group (p = 0.0315). Treated control and ibuprofen groups had more free alveolar space initially as compared to the n-3 LCPUFA group (4 days PT, p= 0.0114 and p= 0.002, respectively); however, significantly more alveolar space was present in the n-3 LCPUFA group as compared to the ibuprofen group by end of treatment (14 days PT, p = 0.035). Interleukin 6 (IL-6) was lower in the ibuprofen group as compared to the treated control, EPA/DHA and untreated control groups at 4 days PT (p = 0.019, p = 0.019 and p = 0.002, respectively). Importantly, pro-resolving EPA derived 9-HEPE, 11-HEPE, 12-HEPE and 18-HEPE lipid mediators (LMs) were significantly higher in the EPA/DHA group as compared to the ibuprofen and treated control groups. This suggests that n-3 LCPUFAs do improve pro-resolving and anti-inflammatory properties in TB, and it may be safe and effective to co-administer as adjunct therapy with standard TB treatment, particularly longer-term. Also, our results show host benefits upon short-term co-administration of ibuprofen, but not throughout the entire TB treatment course.

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Host-directed therapies (HDTs) enhance the host response to tuberculosis (TB) infection to reduce disease severity. For instance, the manipulation of lipid mediator production diminishes the hyperactive immune response which is a known pathological feature of TB that generates lung tissue damage. Non-steroidal anti-inflammatory drugs (NSAIDs) and omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) are examples of such HDTs. In this mini-review, we recapitulate the literature available on the effects of NSAIDs and n-3 LCPUFA in TB as well as the immunological pathways underpinning these effects. Many NSAIDs have a great deal of data describing their effects and safety and in many jurisdictions are inexpensive, and sold over the counter in neighborhood convenience stores and supermarkets. The potential benefits of NSAIDs in TB are well-documented in pre-clinical studies. The reduction of pro-inflammatory lipid mediator production by inhibiting cyclooxygenase (COX) pathways with NSAIDs has been found to improve lung histopathology, bacterial control, and survival. Additionally, n-3 LCPUFA and its novel bioactive metabolites produced by COX and lipoxygenase (LOX) have been identified as safe and effective pro-resolving and antibacterial pharmaconutrients. Nevertheless, heterogeneous results have been reported in pre-clinical TB studies. Recently, the importance of the correct timing of NSAIDs and n-3 LCPUFA administration in TB has also been highlighted. This mini-review will provide a better understanding of the potential contribution of these therapies toward reducing inflammatory lung damage and improving bactericidal activity, especially during later stages of TB infection. It further highlights that clinical trials are required to confirm benefit and safety in TB patients.

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Coronavirus disease 2019 (COVID-19) is a global pandemic causing one of the biggest challenges for critical care medicine. Mortality from COVID-19 is much greater in elderly men, many of whom succumb to acute respiratory distress syndrome (ARDS) triggered by the viral infection. Because there is no specific antiviral treatment against COVID-19, new strategies are urgently needed. Selenium is an essential trace element with antioxidant and immunomodulatory effects. Poor nutritional status increases the pathogenicity of viruses and low selenium in particular can be a determinant of viral virulence. In the past decade, selenium pharmaconutrition studies have demonstrated some reduction in overall mortality, including how reduced incidence of ventilator-associated pneumonia and infectious complications such as ARDS in the critically ill. Consequently, we postulate that intravenous selenium therapy, could be part of the therapeutic fight against COVID-19 in intensive care unit patients with ARDS and that outcomes could be affected by age, sex, and body weight. Our working hypothesis addresses the question: Could high-dose selenite pharmaconutrition, as an early pharmacologic intervention, be effective at reducing the incidence and the progression from type 1 respiratory failure (non-ARDS) to severe ARDS, multiorgan failure, and new infectious complications in patients with COVID-19 patients?

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The last 25 years have seen an increasing number of publications attesting the benefits of pharmaconutrition in the management of patients undergoing elective oncological gastrointestinal surgery. A number of randomized controlled trials and meta-analyses suggest the use of pharmaconutrition in this group of patients produces superior outcomes to standard nutritional formulations in terms of postoperative infective complications, anastomotic breakdown and length of hospital stay. The use of pharmaconutrition products, therefore, has gained increasing acceptance for use in elective gastrointestinal oncological surgical populations and been incorporated into practice guidelines. However, there remains doubts as to the robustness of such data supporting these recommendation. This is because studies reporting improved outcomes with pharmaconutrition (I) frequently compare this intervention with non-equivalent control groups; (II) do not report on the actual nutritional provision received by study participants; (III) overlook the potential impact of industry funding on research conducted and (IV) do not adopt a multi-disciplinary approach to the research undertaken. For these reasons, a critical re-appraisal of the use and recommendations of pharmaconutrition in this group of patients is urgently warranted to resolve some of the above mentioned issues. The aim of this review was to analyse meta-analyses published until the end of 2016 in this area to highlight the strengths and weakness of the present research and prioritize certain areas which will benefit from future research.

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Nutrition support is increasingly recognized as a clinically relevant aspect of the intensive care treatment of cardiac surgery patients. However, evidence from adequate large-scale studies evaluating its clinical significance for patients’ mid- to long-term outcome remains sparse. Considering nutrition support as a key component in the perioperative treatment of these critically ill patients led us to review and discuss our understanding of the metabolic response to the inflammatory burst induced by cardiac surgery. In addition, we discuss how to identify patients who may benefit from nutrition therapy, when to start nutritional interventions, present evidence about the use of enteral and parenteral nutrition and the potential role of pharmaconutrition in cardiac surgery patients. Although the clinical setting of cardiac surgery provides advantages due to its scheduled insult and predictable inflammatory response, researchers and clinicians face lack of evidence and several limitations in the clinical routine, which are critically considered and discussed in this paper.

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Nutrition support is a necessary therapy for critically ill cardiac surgery patients. However, conclusive evidence for this population, consisting of well-conducted clinical trials is lacking. To clarify optimal strategies to improve outcomes, an international multidisciplinary group of 25 experts from different clinical specialties from Germany, Canada, Greece, USA and Russia discussed potential approaches to identify patients who may benefit from nutrition support, when best to initiate nutrition support, and the potential use of pharmaco-nutrition to modulate the inflammatory response to cardiopulmonary bypass. Despite conspicuous knowledge and evidence gaps, a rational nutritional support therapy is presented to benefit patients undergoing cardiac surgery.

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BACKGROUND: Functional recovery after aneurysmal subarachnoid hemorrhage (SAH) remains a significant problem. We tested a novel therapeutic approach with long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) to assess the safety and feasibility of an effectiveness trial. METHODS: We conducted a multicentre, parallel, randomized, open-label pilot trial. Patients admitted within 72 hours after SAH with modified Fisher scale scores of 3 or 4 who were selected for scheduled aneurysm clipping were allocated to receive either n-3 PUFA treatment (parenteral perioperative: 5 days; oral: 8 weeks) plus usual care or usual care alone. Exploratory outcome measures included major postoperative intracranial bleeding complications (PIBCs), cerebral infarction caused by delayed cerebral ischemia, shunt-dependent hydrocephalus, and consent rate. The computed tomography evaluator was blinded to the group assignment. RESULTS: Forty-one patients were randomized, but one patient had to be excluded after allocation. Twenty patients remained for intention to treat analysis in each trial arm. No PIBs (95% confidence interval [CI]: 0.00 to 0.16) or other unexpected harm were observed in the intervention group (IG). No patient suspended the intervention due to side effects. There was a trend towards improvements in all benefit-related outcomes in the IG. The overall consent rate was 0.91 (95% CI: 0.78 to 0.96), and there was no consent withdrawal. CONCLUSIONS: Although the balance between the benefit and harm of the intervention appears highly favourable, further testing on SAH patients is required. We recommend proceeding with amendments in a dose-finding trial to determine the optimal duration of parenteral treatment.

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The research to improve outcomes in critically ill patients through nutrition support has steadily progressed over the past 4 decades. One current approach to this problem is the addition of specific nutrients as primary therapy to improve host defenses and improve the outcomes of critically ill patients. The field is referred to as“pharmaconutrition”,focusing investigations on each nutrient to understand its pharma-cological effects on immune and clinical outcomes. The purpose of this review was to introduce some of the known pharmaconutrients such as glutamine,arginine,ω-3 fatty acids,vitamin C,zinc,and selenium,regard-ing critical ill adults and children.

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The aim of the present lecture is to review the changes in perioperative nutritional policy throughout years. Many advances on both knowledge and clinical practice occurred with time, particularly on preoperative patient assessment and preparation, modulation of surgical stress, identification of the gut as regulator of postoperative inflammatory response, and perioperative fasting policy. Improvement of patient's condition should be obtained by recognizing and treating undernutrition, optimizing body composition, and encouraging physical activity perioperatively. The use of specific nutrients with metabolic effects as well as reducing both preoperative and postoperative fasting within an enhanced recovery pathway can help to modulate postsurgical stress.

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The review article covers specific methods of artificial nutrition in current advances in intensive care. This area of care is somewhat specific, and indications for pharmaconutrients are different from classical artificial nutrition. The pharmaconutrients of amino acid and polyenoic fatty acid groups are described. The components of nutritional pharmacology, based on exceedingly high doses of pure nutritional substrates, are a useful and safe means of modifying selected mechanisms, such as fluidocoagulation, inflammatory reactions or vasomotorics.

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Many new enteral nutrition (EN) formulas have been created over the past several decades with a variety of intended uses. Although each is intended to promote improved outcomes, research is often unclear and, in many cases, conflicting. It is important to note that EN products are considered medical foods by the U.S. Food and Drug Administration and therefore do not have to complete premarket review or approval and are not regulated to the same extent as pharmaceuticals. While standard EN formulas are designed to meet the basic macro- and micronutrient requirements of individuals who cannot meet nutrition needs orally, specialty EN products have been developed to exhibit pharmacologic properties, such as immune-enhancing formulas containing arginine, glutamine, nucleotides, and ω-3 fatty acids. With the vast number of products available, rising costs of healthcare, and the drive toward evidence-based practice, it is imperative that clinicians carefully consider research regarding use of specialty formulas, paying close attention to the quality, patient population, clinical end points, and cost to patient and/or facility.

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Reviewing the literature of nutrition therapy one can conclude that during the last decade the pharmacological action of several nutrients has been demonstrated. However, research activity is still at the beginning and it could be verified in a restricted number of nutrients only that in which conditions (illnesses), dose and duration we can expect therapeutic effect in addition to nutrition. The examples of glutamine, arginine, taurine, leucine, ω-3 fatty acids, however, support the possibility that complex reactions and treatment results observed in certain patients are not purely due to nutritional support but the consequence of additional pharmacological action as well. Evaluation of results of therapeutic intervention is especially difficult because in the everyday practice physicians try to use several therapeutic modalities that can be beneficial for the patient. Therefore, retrospective separation of beneficial components of the therapeutic agents is almost impossible. Only well designed, randomized and multicentric studies can verify specific therapeutic action of certain ingredients ie. nutrients.

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BACKGROUND: Pharmaconutrition has previously been reported in elective surgery to reduce postoperative infective complications and duration of hospital length of stay. OBJECTIVE: To update previously published meta-analyses and elucidate potential benefits of providing arginine-dominant pharmaconutrition in surgical patients specifically with regard to the timing of administration of pharmaconutrition. DESIGN: Randomized controlled trials comparing the use of pharmaconutrition with standard nutrition in elective adult surgical patients between 1980 and 2011 were identified. The meta-analysis was prepared in accordance with Preferred Reporting of Systematic Reviews and Meta-Analyses (PRISMA) recommendations. RESULTS: Twenty studies yielding 21 sets of data met inclusion criteria. A total of 2005 patients were represented (pharmaconutrition, n = 1010; control, n = 995), in whom pharmaconutrition was provided preoperatively (k = 5), perioperatively (k = 2), or postoperatively (k = 14). No differences were seen in postoperative mortality with the provision of pharmaconutrition irrespective of timing of administration. Statistically significant reductions in infectious complications and length of stay were found with perioperative and postoperative administration. Perioperative administration was also associated with a statistically significant reduction in anastomotic dehiscence, whereas a reduction in noninfective complications was demonstrated with postoperative administration. Preoperative pharmaconutrition demonstrated no notable advantage over standard nutrition provision in any of the clinical outcomes assessed. CONCLUSIONS: This meta-analysis highlights the importance of timing as a clinical consideration in the provision of pharmaconutrition in elective gastrointestinal surgical patients and identifies areas where further research is required.

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BACKGROUND: Enteral supply of ω-3 polyunsaturated fatty acids has been used in an attempt to modulate inflammation and improve outcome in critically ill patients. However, enteral administration may be slow to change membrane composition and therefore may not be the best route to supply these fatty acids in patients with acute conditions. This study evaluated the effects of short-term intravenous (IV) administration of fish oil-based lipid emulsion (FLE) as pharmaconutrition on cytokine levels in critically ill elderly patients. METHODS: Enterally fed patients (n = 40; aged 60-80 years) were recruited in the first 48 hours of intensive care unit (ICU) admission. Fifteen patients received IV FLE (0.2 g/kg body weight) over 6 hours for 3 consecutive days, and 25 patients did not receive IV lipid (control). Samples were collected before and 24 hours and 72 hours after the third FLE infusion. Nutrient intakes, clinical parameters, and serum cytokine concentrations were measured. RESULTS: Compared with the control, FLE resulted in higher energy intake, lower serum tumor necrosis factor-α and interleukin (IL)-8 concentrations, and higher serum IL-10. These differences occurred around 7-9 days of ICU stay at the time of the patient's extubation. ICU stay, mortality, and markers of coagulation and liver function did not differ between groups. CONCLUSIONS: Short-term IV FLE modulates some inflammatory markers in critically ill elderly patients receiving enteral nutrition (EN), suggesting an anti-inflammatory effect. This may be a benefit and suggests a role for FLE administration as a supplement in elderly ICU patients receiving standard EN.

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Critical illness is characterized by oxidative stress which leads to multiple organ failure, and sepsis-related organ dysfunction remains the most common cause of death in the intensive care unit. Over the last 2 decades, different antioxidant therapies have been developed to improve outcomes in septic patients. According to recent evidence, selenium therapy should be considered the cornerstone of the antioxidant strategies. Selenium given as selenious acid or sodium selenite should be considered as a drug or pharmaconutrient with prooxidant and cytotoxic effects when a loading dose in intravenous bolus form is administered, particularly in the early stage of severe sepsis/septic shock. To date, several phase ii trials have demonstrated that selenium therapy may be able to decrease mortality, improve organ dysfunction and reduce infections in critically ill septic patients. The effect of selenium therapy in sepsis syndrome must be confirmed by large, well designed phase iii clinical trials. The purpose of this review is to discuss current evidence on selenium pharmaconutrition in sepsis syndrome.

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BACKGROUND: There is emerging evidence that glutamine supplementation should be considered in patients with acute and critical illness associated with a catabolic response. There are reports of glutamine supplementation in acute pancreatitis but the results of these studies are conflicting. The aim of this study was to systematically review the randomised controlled trials (RCT) of glutamine in patients with acute pancreatitis. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, SCOPUS and 3 major Chinese databases were searched. The outcomes studied were mortality, total infectious complications, and length of hospital stay. A random effects model was used for meta-analysis of the outcomes in the included trials. A number of pre-specified subgroup analyses were also conducted. The summary estimates were reported as risk ratio (RR) for categorical variables and mean difference (MD) for continuous variables together with the corresponding 95% confidence interval. RESULTS: Twelve RCT that enrolled 505 patients with acute pancreatitis were included in the final analysis. Overall, glutamine supplementation resulted in a significantly reduced risk of mortality (RR 0.30; 95% CI, 0.15 to 0.60; P < 0.001) and total infectious complications (RR 0.58; 95% CI, 0.39 to 0.87; P = 0.009) but not length of hospital stay (MD -1.35; 95% CI, -3.25 to 0.56, P = 0.17). In the subgroup analyses, only patients who received parenteral nutrition and those who received glutamine in combination with other immunonutrients demonstrated a statistically significant benefit in terms of all the studied outcomes. CONCLUSIONS: This meta-analysis demonstrates a clear advantage for glutamine supplementation in patients with acute pancreatitis who receive total parenteral nutrition. Patients with acute pancreatitis who receive enteral nutrition do not require glutamine supplementation. Further studies are warranted to determine whether patients who receive combined enteral and parenteral nutrition need glutamine supplementation.

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