Cytokine storm associated with severe COVID-19 infections: The potential mitigating role of omega-3 fatty acid triglycerides in the ICU.

Cytokine storm during severe COVID-19 infection increases the risk of mortality in critically ill patients in the intensive care unit. Multiple therapeutic proposals include, for example, anti-inflammatory and immunosuppressive agents, selective inhibitors of key pro-inflammatory receptors, and key enzymes necessary for viral replication. Unfortunately, safe and effective therapy remains an elusive goal. An alternative anti-inflammatory approach vis á vis omega-3 fatty acids, which yields less pro-inflammatory mediators by altering eicosanoid metabolism, has been proposed. Although theoretically promising, enteral tube delivery or oral capsules containing specific doses of omega-3 fatty acids take precious time (7 days to 6 weeks) to be incorporated in plasma cell membranes to be most effective, making this route of administration in the acute care setting an unfeasible therapeutic approach. Parenteral administration of precise doses of omega-3 fatty acid triglycerides in an injectable emulsion can greatly accelerate the incorporation and potential therapeutic effects (within hours), but at present, there is no commercially available product designed for this purpose. We describe a potential formulation that may address this deficiency, while recognizing that the high incidence of hyperlipidemia that occurs during severe COVID-19 infection must be recognized as a complicating factor, and, therefore, caution is advised.

Regression of human coronary artery plaque is associated with a high ratio of (18-hydroxy-eicosapentaenoic acid + resolvin E1) to leukotriene B4.

Inflammation in arterial walls leads to coronary artery disease (CAD). We previously reported that a high omega-3 fatty index was associated with prevention of progression of coronary atherosclerosis, a disease of chronic inflammation in the arterial wall. However, the mechanism of such benefit is unclear. The two main omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of specialized pro-resolving lipid mediators (SPMs)-resolvins and maresins-which actively resolve chronic inflammation. To explore whether SPMs are associated with coronary plaque progression, levels of SPMs and proinflammatory mediators (leukotriene B4 [LTB4 ] and prostaglandins) were measured using liquid chromatography-tandem mass spectrometry in 31 statin-treated patients with stable CAD randomized to either EPA and DHA, 3.36 g daily, or no EPA/DHA (control). Coronary plaque volume was measured by coronary computed tomographic angiography at baseline and at 30-month follow-up. Higher plasma levels of EPA+DHA were associated with significantly increased levels of two SPMs-resolvin E1 and maresin 1-and 18-hydroxy-eicosapentaenoic acid (HEPE), the precursor of resolvin E1. Those with low plasma EPA+DHA levels had a low (18-HEPE+resolvin E1)/LTB4 ratio and significant plaque progression. Those with high plasma EPA+DHA levels had either low (18-HEPE+resolvin E1)/LTB4 ratios with significant plaque progression or high (18-HEPE+resolvin E1)/LTB4 ratios with significant plaque regression. These findings suggest that an imbalance between pro-resolving and proinflammatory lipid mediators is associated with plaque progression and potentially mediates the beneficial effects of EPA and DHA in CAD patients.

Cytokine Release Syndrome Associated With Immune-Modulating Chemotherapy: Potential Mitigating Role of Intravenous Omega-3 Fatty Acid Triglycerides.

BACKGROUND: Patient susceptibility to cytokine release syndrome (CRS) resulting from immune-modulating chemotherapy has profound implications for clinical outcome. This is particularly true for patients receiving CAR T-cell therapy. First-line pharmacotherapy for CRS includes the administration of the IL-6 receptor-binding monoclonal antibody tocilizumab, or tocilizumab and corticosteroids. Other agents, such as siltuximab, anakinra, and dasatinab are also being explored for refractory cases of CRS. This review summarizes the potential role of omega-3 fatty acids, that is, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at ameliorating CRS in cancer patients receiving immune-modulating chemotherapy, and is compared with current treatment strategies to reduce the severity of the inflammatory response. RECENT FINDINGS: Selective blockade of specific proinflammatory mediators (e.g., IL-6) is effective, but carries a significant risk of serious opportunistic infections. In contrast, omega-3 fatty acids affect multiple triggers underlying the inflammatory response (i.e., prostaglandins, leukotrienes, transcription factors, and specialized proresolving molecules), and its major limitation is avoidance of hypertriglyceridemia, which can be managed by reducing the rate of intravenous administration. This discussion proposes a novel approach by continuous infusion of omega-3 fatty acids to modulate the intensity of the severe systemic inflammatory response from CRS. The purpose of this review is to highlight the potential clinical benefits of a specialized omega-3 fatty acids dosage form to mitigate the severity of CRS as a hypothetical alternative to current treatment. CONCLUSION: Optimizing the formulation, for example, enriched fish oil that meets drug concentration standards for EPA and DHA, a continuous infusion rate, reductions in long-chain saturated fatty acids concentrations, and addition of medium-chain triglycerides to improve EPA + DHA utilization and physical stability are key pharmaceutical factors. This may result in a safer and more effective option than targeted abrogation of cytokines and consequent risks of adverse drug reactions, but will require formal study in randomized control trials in humans.

Pharmaceutical Considerations and Metabolic Fate of Parenteral Lipid Nanoparticle Dosage Forms.

The physical stability of parenteral dispersions for delivery of drugs to patients is of particular clinical importance, given their general overall superior bioavailability compared to other routes of administration. Although official pharmacopeial methods for lipid injectable emulsions have been established for triglyceride oil-in-water dispersions (i.e., "mini-emulsions") through USP Chapter <729>, no pharmaceopeial guidance exists for lipid nanoparticle (LNP)-based "micro-emulsions". At present, there are several LNP-based drugs approved for clinical use, including mRNA vaccines. Moreover, the increased interest in using mRNA as a platform technology for an array of potential therapeutic drug candidates increases the importance of developing appropriate methods to ensure their physical stability, safety and efficacy. For all dispersions and by various detection mechanisms (e.g., electrical, mechanical, mathematical), the fusion or growth of droplets/particles in the large-diameter tails of the particle size distribution (PSD) signals the onset of instability. Consequently, the measurement for LNP dispersions will require the use of a modified optical detection design in order to extend the lower particle detection limit into the "relative" large-diameter tail of the PSD for both light extinction and light-scattering methods based on single-particle optical sensing techniques. Fortunately, the technology is currently available and capable of providing the requisite quantitative analysis.

Iron homeostasis in obesity and metabolic and bariatric surgery: a narrative review.

Iron deficiency has been recognized as a potentially modifiable nutritional complication of metabolic and bariatric surgery (MBS) since prior to the turn of the century. Despite this, it remains the most common and clinically significant nutritional complication of this surgery with the potential to negate quality of life and the health benefits of surgical weight loss. This narrative review summarizes the current literature regarding iron deficiency as it relates to patients with severe obesity and those who undergo MBS. Advances in the clinical knowledge of iron homeostasis in severe obesity as a chronic disease, current diagnostic criteria for the diagnosis of iron deficiency in this patient population, the significance of preoperative iron deficiency, postoperative iron deficiency, and the status of supplementation and treatment will be reviewed with emphasis on gaps in knowledge and needed areas of further study.

Omega-3 Fatty Acids as Antiarrhythmic Drugs: Upstream Target Modulators Affecting Acute and Long-Term Pathological Alterations in Cardiac Structure and Function.

OBJECTIVES: Postoperative atrial fibrillation (POAF) is a common complication in the acute care period following coronary artery bypass grafting (CABG) surgery that is associated with significant morbidity and mortality in both short-term and long-term settings. Recently, the Vaughn Williams Classification of antiarrhythmic agents, first proposed in 1975 and widely viewed as the authoritative description of their electrophysiologic actions, was updated and notably omega-3 fatty acids (Ω-3 fatty acids) have been included in class VII, described as "upstream target modulators," to mitigate pathological structural and electrophysiological remodeling changes in the aged and/or injured myocardium. DATA SOURCES: A PubMed literature search was performed. STUDY SELECTION: Studies examining the significance of complications in patients undergoing isolated CABG surgery were selected for inclusion. DATA EXTRACTION: Relevant data were qualitatively assessed and narratively summarized. DATA SYNTHESIS: POAF occurs in approximately 30% of patients, and inflammation from chronic coronary artery disease preoperatively, as well as acute atrial inflammation from surgery postoperatively are the leading causes. Inflammation underlies its pathophysiology; therefore Ω-3 fatty acids not only exhibit antiarrhythmic properties but are an effective anti-inflammatory treatment that may reduce the clinical risks of POAF. CONCLUSIONS: At present no effective prophylaxis is available to address POAF following CABG surgery. Clinical approaches that focus on the inflammatory response in this setting may optimize the response to treatment. The current literature supports the hypothesis that Ω-3 fatty acids may acutely reduce the inflammatory response via favorable alterations in the metabolism of prostaglandins and leukotrienes (eicosanoids) and specialized pro-resolving mediators.

Nutrition support teams: Institution, evolution, and innovation.

The historical institution, evolution, and innovations of nutrition support teams (NSTs) over the past six decades are presented. Focused aspects of the transition to transdisciplinary and patient-centered care, NST membership, leadership, and the future of NSTs are further discussed. NSTs were instituted to address the need for the safe implementation and management of parenteral nutrition, developed in the late 1960s, which requires the expertise of individuals working collaboratively in a multidisciplinary fashion. In 1976, the American Society for Parenteral and Enteral Nutrition (ASPEN) was established using the multidisciplinary model. In 1983, the United States established the inpatient prospective payment system with associated diagnosis-related groupings, which altered the provision of nutrition support in hospitals with funded NSTs. The number of funded NSTs has waxed and waned since; yet hospitals and healthcare have adapted, as additional education and experience grew, primarily through ASPEN's efforts. Nutrition support was not administered in some instances by the "core of four" (physician, nurse, dietitian, pharmacist). The functions may be carried out by a member of the core of four not associated with the parent discipline, in accordance with licensure/privileging. This cross-functioning has evolved into the adaptation of the concept of transdisciplinarity, emphasizing function over form, supported and enhanced by "top-of-license" practice. In some institutions, nutrition support has been incorporated into other healthcare teams. Future innovations will assist NSTs in providing the right nutrition support for the right patient in the right way at the right time, recognizing that nutrition care is a human right.

Application of creatinine height index in patients with trauma for the evaluation of psoas muscle mass: A clinical validation study.

BACKGROUND: The creatinine height index (CHI) is an estimate of lean body mass. We hypothesize that a modified CHI estimate using serum creatinine (sCr) levels in patients with normal renal function when performed soon after injury would reflect preinjury protein nutrition status. METHODS: The urine CHI (uCHI) was calculated using the 24-h urine sample. The serum-derived estimated CHI (sCHI) was calculated using the sCr on admission. Correlation between abdominal computed tomography images at specific lumbar vertebral levels and total body fat and muscle content was used for comparison as an independent measurement of nutrition status unlikely to be substantially altered by trauma. RESULTS: A total of 45 patients were enrolled, all with a significant injury burden (median injury severity score [ISS] = 25; interquartile range, 17-35). The calculated sCHI on admission was 71.0% (SD = 26.9%) and likely underestimates the CHI when compared with uCHI (mean = 112.5%, SD = 32.6%). Stratifying by degree of stress demonstrated that in a group of 23 moderately and severely stressed patients, uCHI (mean = 112.7%, SD = 5.7%) and sCHI (mean = 60.8%, SD = 1.9%) were significantly different and without correlation (r = -0.26, P = 0.91). In patients without stress, there was a significant negative correlation between sCHI and psoas muscle area (r = -0.869, P = 0.03), and in patients with severe stress there was a significant positive correlation between uCHI and psoas muscle area (r = 0.733, P = 0.016). CONCLUSION: The CHI calculated from the initial sCr is not an appropriate estimate of uCHI in critically ill trauma patients and is not a valid measure of psoas muscle mass in this setting.

Clinical significance of iron deficiency among candidates for metabolic surgery.

BACKGROUND: Iron deficiency (ID), a known complication after metabolic surgery, is common among preoperative patients in the presence of inflammation. Evidence is now accumulating that preoperative ID may adversely affect perioperative outcomes. OBJECTIVES: To investigate the relationship between preoperative iron status and the risk of postoperative severe anemia. In addition, this study investigates the relationship between preoperative iron status and length of surgical stay SETTING: A large regional tertiary health system. METHODS: Among patients who underwent metabolic surgery between 2004 and 2020, 5171 patients had a full iron nutritional assessment prior to surgery. Study patients were divided into multiple smaller groups (10 female groups and 7 male groups) on the basis of levels of serum ferritin and Transferrin Saturation (T Sat) < or ≥20%. Study patients were followed after surgery and the time to the development of severe anemia (hemoglobin < 8 gm/dL) was recorded. Hospital length of stay (LOS) was analyzed in relation to preoperative iron status. RESULTS: Lower ferritin levels were associated with older age in males (P = .0001) and younger age in females (P < .0001). For males, after adjustment for age, body mass index (BMI), and year of surgery, surgical LOS was prolonged in those with T Sat <20% (P = .0041). For females the time until the development of severe anemia was associated with baseline iron status (P < .0001). CONCLUSIONS: Male preoperative patients for metabolic surgery with T Sat <20% are at risk for increased surgical LOS. Females with low ferritin levels consistent with ID are at increased risk for the development of postoperative severe anemia.

Early metabolic support for critically ill trauma patients: A prospective randomized controlled trial.

BACKGROUND: There is a lack of consensus regarding the optimal nutritional support for trauma patients. We hypothesize that early postinjury metabolic support focusing on adequate protein would modify the metabolic signature and alter the inflammatory environment for critically ill trauma patients. METHODS: We conducted a prospective randomized controlled pilot trial for adult patients admitted to the surgical intensive care unit following traumatic injury. Patients were randomized to receive early metabolic support (EMS) (peripheral amino acid infusions) or standard of care (enteral nutrition as soon as feasible). Routine laboratory assessments, nitrogen balance, cytokines, and metabolomic analyses were assessed at baseline and day 5 after intervention. RESULTS: A total of 42 trauma patients were randomized into well-balanced groups with similar age (32 years), Injury Severity Score (25), and body mass index (27.4 kg/m2). Early metabolic support provided significantly more protein (1.43 g/kg vs. 0.35 g/kg; p < 0.0001) and more calories (12.6 kcal/kg vs. 7.5 g/kg; p = 0.0012) over the first 5 days as compared with the standard of care. Early metabolic support modified protein catabolism and synthesis as demonstrated by a larger median negative nitrogen balance (-16.3 g vs. -5.3 g; p = 0.03) and a unique metabolomic profile at day 5. The biochemical profile of patients who received EMS was defined by greater declines in circulating levels of stress hormone precursors and increased levels of amino acids. The inflammatory response following EMS resulted in a greater decrease in interleukin-1B (p = 0.02) and increase in soluble interleukin-6 receptor (p = 0.01) between baseline and day 5 as compared with the standard of care. The EMS group had a decreased length of stay (15 vs. 22 days) and decreased surgical intensive care unit length of stay (8 vs. 9 days); however, this disappeared after adjustment for Injury Severity Score in this small population. CONCLUSIONS: Early metabolic support with amino acid is safe, modifies metabolism, and may downregulate the inflammatory state associated with significant trauma, warranting a larger trial to assess for improved outcomes. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level II.

Is total parenteral nutrition protective against hypoglycemia during intensive insulin therapy? A hypothesis.

INTRODUCTION: It appears that enteral nutrition is more likely to produce hypoglycemia during intensive insulin therapy than is total parenteral nutrition. POINT OF VIEW: Although this consequence may in part be the result of frequent discontinuation of feeding or to variability of gastrointestinal absorption of nutrients, there are also distinct physiological differences between total parenteral nutrition and enteral nutrition that are more likely to be responsible, including much higher serum insulin responses to total parenteral nutrition than with enteral nutrition that approach submaximal response levels and direct appearance of administered glucose into the systemic circulation with total parenteral nutrition at rates that approximate usual postabsorptive rates and that avoid first-pass hepatic clearance. CONCLUSIONS: These factors may make total parenteral nutrition more efficacious, at least initially, with intensive insulin therapy and may justify setting a higher limit for glucose control when enteral feeding is principally used.

Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities.

OBJECTIVE: To measure the changes in whole blood fatty acid levels in premature infants and evaluate associations between these changes and neonatal morbidities. STUDY DESIGN: This was a retrospective cohort study of 88 infants born at <30 weeks' gestation. Serial fatty acid profiles during the first postnatal month and infant outcomes, including chronic lung disease (CLD), retinopathy of prematurity, and late-onset sepsis, were analyzed. Regression modeling was applied to determine the association between fatty acid levels and neonatal morbidities. RESULTS: Docosahexaenoic acid (DHA) and arachidonic acid levels declined rapidly in the first postnatal week, with a concomitant increase in linoleic acid levels. Decreased DHA level was associated with an increased risk of CLD (OR, 2.5; 95% CI, 1.3-5.0). Decreased arachidonic acid level was associated with an increased risk of late-onset sepsis (hazard ratio, 1.4; 95% CI, 1.1-1.7). The balance of fatty acids was also a predictor of CLD and late-onset sepsis. An increased linoleic acid:DHA ratio was associated with an increased risk of CLD (OR, 8.6; 95% CI, 1.4-53.1) and late-onset sepsis (hazard ratio, 4.6; 95% CI, 1.5-14.1). CONCLUSION: Altered postnatal fatty acid levels in premature infants are associated with an increased risk of CLD and late-onset sepsis.

Iron deficiency is highly prevalent among candidates for metabolic surgery and may affect perioperative outcomes.

BACKGROUND: The presence of chronic low-grade inflammation, commonly identified in patients with severe obesity, alters iron homeostasis and indicators of iron status, fostering the development of updated guidelines for the diagnosis of iron deficiency (ID). Current recommended diagnostic thresholds for ID in obesity derived from expert opinion include a ferritin level of <30 ng/mL and/or transferrin saturation (TSAT) < 20%. Earlier studies of ID among candidates for metabolic surgery using low levels of ferritin or iron as diagnostic thresholds demonstrated a prevalence of 5%-20%. OBJECTIVES: Using the current recommended diagnostic thresholds for ID, this study measures the prevalence of ID in a large cohort of surgical candidates and its relationship to surgical outcomes. SETTING: Geisinger Medical Center, Danville, Pennsylvania. METHODS: The study cohort included 3,723 patients who underwent pre- operative nutritional assessment which included markers of iron nutrition over the period 2004-2018. RESULTS: The cohort included 2,988 women (80.3%) and 735 men (19.7%); body mass index: 49.4 ± 9 kg/m2. The diagnosis of ID was based on ferritin level <30 ng/mL (true ID) and/or TSAT < 20% representing a combination of true ID and inflammation (serum ferritin ≥ 30 ng/mL and TSAT < 20%). A total of 399 patients (10.8%) were anemic. A serum ferritin level of < 30 ng/mL was found in 488 patients (13%; 481 women and 7 men). Of these, 122 patients (25.2%) were also anemic. An additional 1,204 had serum ferritin ≥ 30 ng/mL and TSAT < 20%. Overall, 1,692 patients (45.4%) in this cohort had laboratory evidence of ID by current criteria that adjusts for the very high prevalence of inflammation. Men with serum ferritin levels ≥30 ng/mL with TSAT < 20% had an increased surgical length of stay. CONCLUSION: The prevalence of ID among surgical candidates (45.4%) is more than twice that identified as ID in earlier studies. ID was commonly identified in the absence of anemia. The most severe ID was found in those with a serum ferritin level <30 ng/mL and TSAT < 20%. ID in the presence of inflammation is often unrecognized and has implications regarding surgical outcomes after metabolic surgery.

Alternative Dietary Patterns for Americans: Low-Carbohydrate Diets.

The decades-long dietary experiment embodied in the Dietary Guidelines for Americans (DGA) focused on limiting fat, especially saturated fat, and higher carbohydrate intake has coincided with rapidly escalating epidemics of obesity and type 2 diabetes (T2D) that are contributing to the progression of cardiovascular disease (CVD) and other diet-related chronic diseases. Moreover, the lack of flexibility in the DGA as it pertains to low carbohydrate approaches does not align with the contemporary trend toward precision nutrition. We argue that personalizing the level of dietary carbohydrate should be a high priority based on evidence that Americans have a wide spectrum of metabolic variability in their tolerance to high carbohydrate loads. Obesity, metabolic syndrome, and T2D are conditions strongly associated with insulin resistance, a condition exacerbated by increased dietary carbohydrate and improved by restricting carbohydrate. Low-carbohydrate diets are grounded across the time-span of human evolution, have well-established biochemical principles, and are now supported by multiple clinical trials in humans that demonstrate consistent improvements in multiple established risk factors associated with insulin resistance and cardiovascular disease. The American Diabetes Association (ADA) recently recognized a low carbohydrate eating pattern as an effective approach for patients with diabetes. Despite this evidence base, low-carbohydrate diets are not reflected in the DGA. As the DGA Dietary Patterns have not been demonstrated to be universally effective in addressing the needs of many Americans and recognizing the lack of widely available treatments for obesity, metabolic syndrome, and T2D that are safe, effective, and sustainable, the argument for an alternative, low-carbohydrate Dietary Pattern is all the more compelling.