Reviewer: Carolyn Newberry, MD; Assistant Professor of Medicine, Division of Gastroenterology, Weill Cornell Medical Center, New York, NY
Reference: Sotos-Prieto, M, Bhupathiraju SN, Mattei J et al. Association of Changes in Diet Quality with Total and Cause-Specific Mortality. NEJM. 2017 July 13. Doi:10.1056/NEJMosa1613502.
Why is this paper important? This large observational cohort study associates improved diet quality (as defined by the Alternate Healthy Eating Index-2010 (AHEI), Alternate Mediterranean Diet Score (AMD), and the Dietary Approaches to Stop Hypertension (DASH) Diet Score) with reduction in all-cause mortality.
Summary: This paper is a large observational cohort study that analyzes two commonly examined databases, the Nurses’ Health Study, a prospective study started in 1976 including 121,700 registered nurses between the ages of 30 and 55 years, and the Health Professionals Follow-Up Study, a prospective study initiated in 1986 enrolling 51,529 US Health Professional between the ages of 40 and 75 years. The study examines dietary quality over a 12 year period (1986-1998). Patients were excluded if they had history of cancer or cardiovascular disease at or before the baseline set in 1998, missing information regarding diet and lifestyle covariates, or very high calorie (>4200kcal/day in men or 3500kcal/day in women) or very low calorie (<800kcal/day in men, <500kcal/day in women) intake. In total, 47,994 women and 25,745 men were analyzed. Dietary assessment was performed at baseline and every 4 years thereafter utilizing a validated food frequency questionnaire. The three diet-quality scores were then calculated based on previously published standardized measures. These diet quality scores assess intake of fruits, vegetables, whole grains, nuts, legumes, and long chain n-3 fatty acids in comparison to sugar-sweetened beverages, fruit juices, red and processed meats, trans-fat, saturated to unsaturated fat ratios, sodium, and alcohol. Deaths were tabulated using national databases and reports by family and post office records. Information regarding lifestyle and risk factors for cardiovascular disease were evaluated and updated annually including: age, weight, smoking status, use of aspirin, multi-vitamins, post-menopausal status, physical activity, hypertension, hypercholesterolemia, diabetes. Statistical modeling assessed association between the three diet-quality scores and date of death or the end of follow up, whichever came first. Cox proportional-hazards models were used to establish hazard ratios and 95% confidence intervals with additional analysis to correct for confounding variables and confirm robustness of correlation. The pooled hazard ratios for all-cause mortality among participants who had the greatest improvement in diet quality (13-33% improvement) as compared to stable diet quality (0-3% improvement) were: 0.91 (95% CI: 0.85-0.97) according to the AHEI, 0.84 (95% CI 0.78-0.91) according to the AMD Score, and 0.89 (95% CI 0.84-0.95) according to the DASH Score. Among participants who maintained high quality diet as compared to a low quality diet, risk of death by any cause was significantly lower—14% (95% CI 8-19) by AHEI, 11% (95% CI 5-18) by AMD Score, and 9% (CI 2-15) by DASH Score.
Commentary: Considering the increased prevalence of western dietary practices, which are characterized by inadequate fruit, vegetable, and whole grain intake in favor of highly processed foods containing large amounts of saturated fats and simple carbohydrates, the association between diet quality and overall mortality becomes increasingly important. This paper highlights the reduction in mortality from any cause in association with both improvement in diet quality over time as well as maintenance of a healthy diet. Quality is defined by common scoring systems, which are easy to use and can be incorporated into both clinical practice and patient education tools. Although slight variations exist between these dietary models, overall themes emerge including increased intake of whole grains, vegetables, fruits, and n-3 fatty acid sources such as fish with concomitant reduction in processed meats, sugars, and excessive sodium intake. The current 2015-2020 Dietary Guidelines Advisory Committee mirrors such recommendations, confirming the components of healthy eating patterns as described and a recommendation to support Americans in shifting eating patterns. This national guidelines committee will meet once again in 2020 where it is poised to analyze personal, family, societal, and governmental changes that need to be addressed in order to enable such transformations. The goal is to promote a new paradigm in healthy lifestyle choices that provides accessible and affordable options at home, school, work, and in the community, thereby improving overall dietary patterns and subsequent risk of chronic disease and early mortality.
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Reviewer: Paul McCarthy, MD; Assistant Professor of Medicine; West Virginia University Heart and Vascular Institute, Morgantown, WV
Reference: Ohbe H, Jo T, Matsui H, Yasunaga H. Early Enteral Nutrition in Patients Undergoing Sustained Neuromuscular Blockade: A Propensity-Matched Analysis Using a Nationwide Inpatient Database. Crit Care Med. 2019 Aug;47(8):1072-1080. doi: 10.1097/CCM.0000000000003812
Why is this paper important? Due to the severity of illness of patients managed with sustained neuromuscular blocking agents (NMBAs) and the assumption of many clinicians that NMBA are associated with gastric dysfunction, it is common practice for many to delay enteral nutrition in patients receiving sustained NMBAs.
There is limited data supporting early or delayed enteral nutrition (EN) in this patient population. This large propensity-matched analysis showed that early EN was associated with a lower mortality than delayed EN is this patient population.
Summary: Since no consensus on the optimal timing of enteral nutrition in patients managed with sustained NMBAs exists, the authors evaluated the association between EN started within 2 days of sustained NMBAs treatment and after 2 days of NMBA and in-hospital mortality. The study was a retrospective review of an administrative database including over 1,200 acute care hospitals in Japan. The review included more than 2,300 patients from July 2010 to March 2016. In the database, there were 2,340 patients that receive sustained NMBA and a total of 378 patients (16%) had received early EN. A match of 374 early EN and 1122 delayed EN patients were paired for a one-to-three propensity score.
There was no significant difference in the rate of hospital pneumonia between the two groups (risk difference, 2.8%; 95% CI, –2.7% to 8.3%). There was also no significant difference in the intensive care unit (ICU) length of stay or duration of mechanical ventilation in survivors. There was a significantly lower mortality rate in the early EN group compared to the delayed EN group (risk difference, –6.3%; 95% CI, –11.7% to –0.9%). There was also a significantly shorter hospital length of stay for survivors in the early EN group compared to the delayed EN group (risk difference, –11.4 d; 95% CI, –19.1 to –3.7 d). From the analysis of this retrospective database the authors conclude that early EN may be associated with a lower in-hospital mortality.
Commentary: The sustained use of NMBAs is generally discouraged in the ICU due to complications such as ICU-acquired weakness and prolonged mechanical ventilation associated with the therapy. The therapy is, however, used for indications such as intracranial pressure management, reducing metabolic demands, shivering control in targeted temperature management and ventilator dysynchrony in early acute respiratory distress syndrome.
While studies in many ICU populations generally favor early EN this is the first study to my knowledge that specifically looks at patients undergoing sustained NMBAs. Many clinicians do not prescribe EN for patients on sustained NMBAs due to concern for decreased gastric and intestinal peristalsis. The movement of skeletal muscle is controlled by acetylcholine stimulating nicotinic receptors and smooth muscle in the gastrointestinal tract is controlled by acetylcholine stimulating muscarinic receptors. Nondepolarizing NMBAs are competitive antagonists of nicotinic receptors which are stimulated by acetylcholine which control skeletal muscle. They do not complete with muscarinic receptors and do not relax smooth muscle. Other factors that often accompany the use of NMBA use such as immobility, opioid use and positive fluid balance are associated with decreased gastric function, reflux and complications such as vomiting and pneumonia. This has not specifically been shown to occur because of NMBAs. This study showed no association with early EN and pneumonia. This review shows that early EN is likely safe and possibly could decrease mortality compared with a strategy of delayed EN. These results have been seen with early EN in other ICU populations.
This study was a retrospective observational study and does have limitations. The patients were primarily medical and patients with traumatic brain injury, burns, severe trauma and recent intraabdominal surgery were excluded. Total caloric and protein intake were not considered and baseline nutritional status was not addressed. There was no standard protocol for the delivery of EN and delayed EN may have occurred in patients due to reasons related to their specific illness while others may be related to physician practice. There was no consideration for the dose of NMBA or if NMBA were given as continuous infusion or bolus. The study does, however, support the consideration of early EN when NMBAs are used and continued study of the topic.
Reviewer: Berkeley N. Limketkai, MD, PhD; Associate Clinical Professor of Medicine, Division of Digestive Diseases; University of California Los Angeles, Los Angeles, CA.
Reference: Levine A, Wine E, Assa A, et al. Crohn’s Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial. Gastroenterology. Aug 2019. doi: 10.1053/j.gastro.2019.04.021
Why is this paper important? Exclusion enteral nutrition (EEN) is effective for induction of remission in Crohn’s disease, but it is challenging for patients to consume long-term due to poor tolerability. This randomized trial demonstrated the benefit of partial enteral nutrition (PEN) with the Crohn’s disease exclusion diet (CDED) as an alternate therapeutic option.
Summary: In this randomized controlled trial, 78 pediatric patients with mild-to-moderate Crohn’s disease were randomly assigned to either receive PEN (n=40) or EEN (n=38) for 12 weeks. Patients in the PEN group received 50% enteral nutrition and 50% CDED for 6 weeks, followed by 25% enteral nutrition and 75% CDED for the subsequent 6 weeks. Patients in the EEN group received 100% enteral nutrition for 6 weeks followed by 25% enteral nutrition and unrestricted solid foods during weeks 6 and 12. Four patients in the EEN group withdrew within 48 hours of the trial due to inability to continue EEN. In the intention-to-treat analyses, PEN was significantly better tolerated than EEN after 6 weeks (97.5% vs. 73.7%; P=0.002). When comparing PEN with EEN, there was no difference in clinical response (85.0% vs. 85.3%; P=0.97) and corticosteroid-free remission (80.0% vs. 73.5%; P=0.51). By week 12, following the reduction of enteral nutrition in both treatment arms, patients receiving PEN with CDED had greater sustained remission than those receiving enteral nutrition and an unrestricted diet (75.6% vs. 45.1%; P=0.01). Median C-reactive protein and fecal calprotectin concentrations declined from baseline in both treatment groups. The microbiome profiles changed similarly in both groups at week 6, although Proteobacteria remained reduced in the PEN group and Proteobacteria rebounded toward baseline levels in the EEN group by week 12.
Commentary: EEN has previously been demonstrated to be effective for inducing remission in children with Crohn’s disease and European guidelines already recommend it as a first-line treatment. However, EEN – with its absolute restriction of solid foods – can be challenging to sustain over time. A premise of PEN is the combination of EEN’s putative benefits on inflammation with the improved tolerability of solid foods. Given that the hypothesized mechanism of action for EEN is the reduced consumption and intestinal exposure to more pro-inflammatory food antigens, PEN therapy would need to be coupled with a solid food diet with a low pro-inflammatory burden, such as the CDED. Fortunately, the trial demonstrated PEN with CDED to be effective for both induction and maintenance of remission in children with Crohn’s disease over a 12-week period. EEN was similarly effective for inducing remission by week 6, but when enteral nutrition was thereafter combined with an unrestricted solid food diet, it was found to be inferior for sustaining remission. These findings are consistent with the hypothesis that the reduction of food antigens in EEN, PEN, and CDED may facilitate mucosal healing in Crohn’s disease. The study thus presents PEN with CDED as a compelling alternative to EEN that is more tolerable yet similar in efficacy. PEN with CDED may also be more practical for longer-term consumption and maintenance of remission. This study additionally provides insight into an environmental factor that may contribute to the pathogenesis of Crohn’s disease: the diet. While the findings are compelling, there are several limitations to consider, such as the lack of endoscopic data to confirm mucosal healing, small sample size, and study population limited to children. Replication studies are needed to continue building evidence toward (or against) PEN and CDED becoming recommended practices. Moreover, as EEN has lower efficacy in adults than children, further research is needed in adults before similar conclusions of efficacy can be extrapolated to this population. The position of dietary therapy in the overall treatment algorithm for Crohn’s disease and the patient or disease characteristics that would benefit from such therapies are still unclear and unanswered. What the growing evidence nonetheless confirms is the fact that the diet matters.
Reviewer: Manpreet S. Mundi, MD; Associate Professor of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition; Mayo Clinic, Rochester, MN.
Reference: Koutoukidis DA, Astbury NM, Tudor KE, et al. Association of Weight Loss Interventions With Changes in Biomarkers of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. JAMA Intern Med. July 2019. doi:10.1001/jamainternmed.2019.2248
Why is this paper important? This meta-analysis reveals the beneficial impact of weight loss through any intervention on non-alcoholic fatty liver disease (NAFLD).
Summary: The currently reviewed manuscript is a meta-analysis that included randomized control trials (RCTs) focused on treatment of adult patients with NAFLD through weight loss. They included trials focused on lifestyle modification through behavioral weight loss programs (BWLP), pharmacotherapy, bariatric surgery, or the combinations of these modalities. The following outcome variables were assessed; alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), the Enhanced Liver Fibrosis score, the NAFLD fibrosis score, the Fatty Liver Index, liver stiffness, radiologically or histologically measured steatosis, inflammation, ballooning, fibrosis, and the NAFLD Activity Score (NAS). Additional outcomes evaluated included body weight and insulin-resistance markers (hemoglobin A1c, fasting glucose, fasting insulin, and the homeostatic model assessment for assessing insulin resistance [HOMA-IR] or equivalent).
After screening 2096 titles, 22 studies (20 full text articles and 2 abstracts) were including consisting of 2588 participants. 15 studies tested BWLP, 6 tested pharmacotherapies (including liraglutide – 2 studies, Orlistat – 3 studies, and Sibutramine – 1 study), and one study tested intragastric balloon. The median (IQR) intervention duration was 6 (3-8) months and resulted in in significant weight loss (-3.61 kg; 95% CI, -5.11 to -2.12). Weight loss interventions were statistically significantly associated with improvements in biomarkers, including alanine aminotransferase (–9.81 U/L; 95% CI, –13.12 to –6.50), histologically or radiologically measured liver steatosis (standardized mean difference: –1.48; 95% CI, –2.27 to –0.70), histologic NAFLD activity score (–0.92; 95% CI, –1.75 to –0.09), and presence of nonalcoholic steatohepatitis (OR, 0.14; 95% CI, 0.04-0.49). No statistically significant change in histologic liver fibrosis was found (–0.13; 95% CI, –0.54 to 0.27).
Commentary: As the obesity epidemic continues to increase in prevalence worldwide, the health care community is underprepared for its full impact given association with a number of co-morbidities ranging from diabetes to endometrial cancer. One of these comorbidities is a spectrum of diseases categorized as non-alcoholic fatty liver disease (NAFLD) which ranges from fatty liver (steatosis) to inflammation and fibrosis (steatohepatitis; NASH) and can also progress to liver cirrhosis. NAFLD is a manifestation of metabolic syndrome with insulin resistance playing a key pathogenic role. As individuals gain weight and develop insulin resistance through consumption of excess calories and decrease caloric expenditure, there is increased free fatty acid (FFA) delivery to the liver. Key isotope labeled trials have shown that these FFA arrive from three distinct sources including release from adipose tissue, dietary fat, and de novo lipogenesis from excess carbohydrates. As FFA arrive, they are taken up by the liver in proportion to their rate of deliver and stimulate hepatocyte very low density lipoprotein (VLDL) triglyceride synthesis. Unfortunately, as the delivery of these energy substrates exceeds the liver’s capacity to handle them, the storage pool continues to grow, and their metabolites begin to cause liver injury. In addition to simply excess calories, certain combinations often found in fast food (red meat, trans-fat, high fructose corn syrup, highly refined carbohydrates, low fiber, and high energy density) may be the most deleterious when combined with sedentary behavior.
It is due to this direct correlation of NAFLD with weight gain and insulin resistance, that weight loss is the treatment of choice. Key studies like the one reviewed here are highlighting the benefits of even modest weight loss (5-10%) in reversing NAFLD. However, it is important to highlight that this level of weight loss cannot be achieved through simple advice from a clinician during one visit. Instead, intensive behavior therapy that typically consists of weekly visits for 3-6 months and focuses on improvement in diet (especially avoiding “fast-food”) and increase in activity level is needed to achieve 5-10% in most patients. Even despite the use of these intensive BWLP such as those offered by the LOOK Ahead trial and the Diabetes Prevention Program (DPP), not all patients will respond. Therefore, it is key for the clinical to follow their patients closely and if they are not losing weight to escalate the intensity by adding weight loss medications and/or proceed to endoscopic or surgical intervention. Additionally, even patients who respond initially may have weight regain over the long run. These patients often feel quite discouraged and may not seek additional care. It is important to follow these patients long-term as with weight regain, there is often return of weight related co-morbidities.
EATing in the ICU: TARGETs for Measuring Energy, Nutrition Dose, and Clinical Outcomes
Reviewer: Jayshil (Jay) Patel, MD
Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
Reference: Allingstrup MJ, Kondrup J, Wiis J et al. Early goal-directed nutrition versus standard of care in adult intensive care unit patients: the single-center, randomized, outcome assessor-blinded EAT-ICU trial. Intensive Care Med. 2017;43:1637-1647
Why is this paper important? The 2016 ASPEN and 2019 ESPEN critical care nutrition support guidelines agree that indirect calorimetry (IC) be used to assess energy requirements but disagree in nutrition dose during the first week of critical illness. The EAT-ICU trial was the first randomized controlled trial that compared IC-derived early-goal directed nutrition (EGDN) to meet full energy requirement versus standard of care nutrition delivery in mechanically ventilated critically ill adults with an expected length of ICU stay of 3 or more days.
Summary: Citing observational studies showing benefits of achieving IC-derived energy and protein goals in critically ill adults, the EAT-ICU study sought to answer the question: In mechanically ventilated critically ill adults expected to remain in the ICU for at least 3 days, does intervention with EGDN, compared to standard of care, improve the primary outcome of physical quality of life score6-months after randomization? There were numerous secondary outcomes, including 28-day, 90-day and 6-month mortality and length of ICU stay. Under concealed allocation, patients were randomized 1:1 to EGDN or standard nutrition therapy.
The EGDN arm aimed to deliver 100% of IC-derived energy requirements within 24-hours using enteral and supplemental parenteral nutrition. EGDN patients underwent daily 24-hour urea excretion and were prescribed protein at 1.5 g/kg/day regardless of urea excretion. The standard nutrition therapy arm had energy requirements calculated using 25 kcal/kg/day and had EN started within 24-hours and received supplemental PN if the calculated energy requirement goal was not met by day 7. Both arms had the same blood glucose targets, received trace elements as needed, had gastric residual volumes measured, and received prokinetic agents at the clinicians’ discretion.
Over approximately three years, 586 patients were eligible and 203 were randomized: 102 to EGDN and 101 to standard of care. The mixed medical-surgical ICU patients had comparable baseline characteristics: EGDN and standard nutrition therapy groups were 63 and 68 years old, respectively; and both groups had a median BMI of 22 kg/m2. Of all patients, 47% had severe sepsis and had a SOFA score of 8. Over the first 7-days of ICU admission, IC-derived energy requirement was 2069 kcal in the EGDN group, compared to 1887 kcal in standard of care. Calculated EGDN group energy requirement was 1950 kcal, compared to 1875 kcal in standard of care. Energy balance was -66 kcal/day in EGDN, compared to -787 kcal/day in standard of care. Protein intake was 1.47 g/kg/day in EGDN, compared to 0.50 g/kg/day in standard of care. There was no difference in the primary outcome of 6-month physical quality life score between EGDN and standard of care (22.9 vs 23, p=0.99). There were no differences in 28-day, 90-day, or 6-month mortality rate between groups. EGDN had better cumulative energy and protein balance compared to standard of care. More EGDN patients had at least one episode of hyperglycemia compared to standard of care (52 vs 25%, p=0.0001) and received higher doses of insulin (86 vs 0 international units, p=0.008).
The authors concluded EGDN, compared to standard of care, led to more energy and protein delivery and lower nutritional deficits in mechanically ventilated ICU adults but no differences in the primary outcome of physical quality of life at 6 months or secondary outcomes of mortality, organ failure, complications or length of ICU stay.
Commentary: The EAT-ICU trial results shed light on four important critical care nutrition questions:  Is IC needed to estimate energy requirements in critically ill patients?  What is the optimal nutrition dose during the first week of critical illness?  What is the role for supplemental parenteral nutrition during the first week of critical illness? and  What outcome measures should critical care nutrition trials evaluate?
First, the 2016 ASPEN and 2019 ESPEN critical care nutrition support guidelines recommend using IC to define energy requirement. Despite these recommendations, lack of resources and personnel and the cumbersome nature of conducting IC may limit widespread use, prompting bedside clinicians to utilize predictive equations to estimate energy requirements. EAT-ICU results challenge guidelines’ call for IC use to estimate energy requirements in critically ill patients by finding a difference of 119 kcal between IC-derived and calculated (25 kcal/kg/day) energy requirement in the EGDN group (2069 vs 1950 kcal), suggesting there’s no clinical difference in deriving energy estimation between the two methods. However, EAT-ICU was a single-center study where medical-surgical patients had a mean BMI of 22 kg/m2 and a SOFA score of 8. Therefore, it is important to consider the patient population before concluding IC and equation-derived energy requirements are equal. In fact, sicker patients with greater catabolic burden or those with lower or higher BMI may have drastically different IC- and equation-derived energy requirements. The EAT-ICU investigators should be congratulated for developing transparent and reproducible protocols to identify energy requirements, which paves the path for future EGDN studies.
Next, ASPEN and ESPEN guidelines provide disparate recommendations for nutrition dose in critically ill adults. When IC is used, the ESPEN guideline recommends isocaloric nutrition be progressively implemented after the early phase of acute illness, but when a predictive equation is used to estimate energy requirements, hypocaloric nutrition is preferred (over isocaloric) during the first week of ICU admission. The ASPEN guideline does not distinguish between IC- or predictive equation-based energy requirements and nutrition dose. Rather, the 2016 ASPEN guideline calls for determining nutritional risk using NUTRIC or NRS-2002 scores and recommends optimizing nutrition dose (>80% estimated or calculated energy goal) within 48-72 hours in patients deemed high-nutritional risk. EAT-ICU did not find any difference in primary or secondary outcomes despite EGDN patients receiving 90% of both energy and protein prescriptions, compared to standard of care receiving 56 and 43% of energy and protein prescriptions, respectively. A “one size fits all” nutrition dose may not be appropriate since no two ICU patients are alike. EAT-ICU randomized medical-surgical ICU patients to EGDN or standard of care and a signal for benefit may have been lost in patient heterogeneity. Rather, sicker patients at nutritional risk may derive greater benefit from energy and protein optimization. Observational studies using NUTRIC to stratify patients to high and low nutritional found an association between more energy and protein and reduced mortality. Studies comparing EGDN to standard of care in patients most likely to benefit from nutrition optimization (i.e., high nutritional risk) are warranted.
Third, both ASPEN and ESPEN critical care guidelines recommend commencing enteral nutrition within 24-48 hours in critically ill adults unable to maintain volitional intake. ASPEN recommends waiting 7-10 days and ESPEN recommends starting supplemental PN on a case-by-case basis. As with other supplemental PN trials (EPaNIC, SPN, TOP-UP), EAT-ICU weaves an important thread into the fabric of critical care nutrition trials that have demonstrated feasibility of using supplemental PN to meet energy requirements during the first week of critical illness. The EGDN nutrition protocol were started 16 hours after ICU admission (table S2) and 95% of EGDN patients adhered to the protocol to achieve >90% IC-measured energy requirement during the first week of critical illness. However, findings from the EAT-ICU trial challenge guideline recommendations for supplemental PN use during the first week of critical illness. EAT-ICU showed no differences in primary or secondary outcomes between EGDN and standard of care arms despite greater nutrition delivery using supplemental PN in the EGDN group during the first week of critical illness. Even though there were no significant differences in nosocomial infections between groups, there were more hyperglycemia episodes and greater insulin use in the EGDN group, which are likely due to PN use. The contrast in blood glucose level was not associated with differences in clinical outcomes but does suggest pushing nutrition dose closer to full energy requirement during the first week of critical illness may worsen intolerance.
Finally, the EAT-ICU investigators evaluated the effect of greater nutrition during the first week of critical illness on physical functioning at 6-months. With enhanced vigilance and better support systems, ICU mortality has decreased over time. In EAT-ICU, the observed 28-day mortality was approximately 20%. In general, a lower baseline event rate makes it challenging to design critical care nutrition trials that are powered for mortality benefit. Stated differently, to test the hypothesis that nutrition therapy reduces mortality a few percentage points (from a baseline 20% mortality) would require thousands of patients. EAT-ICU assessed a patient-centered outcome like physical function, which holds biologic plausibility as a primary outcome for a nutrition intervention. Greater protein and energy delivery during critical illness could, in theory, maintain, if not enhance, lean muscle function; which may augment physical function. However, the lack of benefit observed in EAT-ICU may lie in the timing of the primary outcome. In other words, does a difference of 498 kcal at ICU day 7 translate into a difference in physical function at 6-months? Future studies should evaluate the impact of nutrition dose on short and long-term non-mortality outcomes, including muscle content and bioenergetics and physical function.
Reviewer: Stephen A. McClave, MD; University of Louisville, Louisville, KY
Reference: Chapman M, Peake S, and the Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Energy-Dense versus Routine Enteral Nutrition in the Critically Ill. The TARGET Trial. NEJM 2018;379:1823-34.
Why this paper is important: While study results indicate that an energy-dense formula is a successful strategy for meeting caloric requirements in critical illness, no outcome benefits were realized. The study suggests that feeding less calories is safe and better tolerated than full feeds and leads to a strategy that may pose less risk to the patient in the early phases of critical illness.
Summary: After completing a pilot trial which showed that a calorically-dense formula delivered calories closer to goal than a routine formula resulting in reduced mortality, the ANZICS group set up this TARGET Trial, a 4000 patient DBPRCT in 46 ICUs in Australia and New Zealand involving critically ill patients receiving invasive mechanical ventilation on EN, randomized to Augmented EN 1.5 kcal/ml (Fresubin® Energy Fibre) vs Standard EN 1.0 kcal/ml (Fresubin® 1000 Complete) with content of protein similar at 56 g/L vs 55 g/L, respectively. Patients on average were 75% medical, 67 years of age, had a BMI 29 with APACHE II score 22, and 62% were on vasopressor support. EN was started within 15 hours of admission to ICU and given for average of 6 days. Study patients got 29.1 kcal/kg IBW/d while controls got 19.6, a difference of 46.7% more calories, both groups getting the same protein at 1.1 gm/kg IBW/d. The primary endpoint, 90-day all-cause mortality, was no different at 26.8% for study patients vs 25.7% for controls (with no differences found on 7 different subgroup analyses for age, disease severity, BMI, admission diagnosis, etc.). No other outcomes were different between groups. Study patients on the energy-dense formula showed evidence of greater intolerance with increased gastric residual volumes, regurgitation, need for promotility agents, elevated glucose levels, and higher dose of insulin required than controls. Researchers concluded that use of the energy-dense formula was a successful strategy for delivering EN closer to goal than routine formulas, but the practice provided no mortality benefit.
Commentary: In their power analysis prior to the study which indicated that an enrollment of 3774 patients was needed, the authors accurately estimated the event rate for their primary endpoint of 90-day mortality between 20-30 % (actual study results 25.7%) but overestimated the treatment effect as being a reduction of 17% (actual was only 1.1%). This means that despite the 3957 patients that ultimately were entered, the study was still underpowered to show a difference between groups. As patients in the control group received 47% less calories than study patients, the study represents yet another trial where the permissive underfeeding of calories yields the same outcome as patients receiving full feeds. Such findings suggest that the amount of feeding is less important than timing, which may be explained by the possibility that underfeeding still provides the non-nutritional benefits of enteral feeding at a low dose (to maintain gut defenses and microbiome) and that the nutritional benefits at full dose (to maintain lean body mass and maximize protein synthesis) are less important in the early phases of critical illness. Slower ramp-ups and less feeding may be a more optimal strategy to avoid overfeeding, risk of ischemia or refeeding syndrome, to support autophagy, and to monitor tolerance as feedings are advanced. Reaching the protein goal may be more important early in the ICU than reaching caloric goal, and keeping the caloric goal at less than 70-80% of energy requirements may have better outcome than delivering full caloric regimen. Mitochondrial failure in the early phases of critical illness may mean that patients are not ready to assimilate full nutritional therapy. An emphasis on getting EN started shortly after admission to the ICU should quickly shift to adding supplemental therapy to maintain the gut barrier, prevent disordered immune responses, and promote commensalism (such as soluble prebiotic fiber, probiotics, pegylated phosphate, intact food formulas, and even fecal microbial transplantation).
Reviewers: D. Clark Files, MD; Wake Forest School of Medicine, Winston-Salem NC 27157
Sadeq Quraishi, MD, MHA, MMSc; Harvard Medical School, Boston MA 02114
Authors: Arabi YM, Al-Balwi M, Hajeer AH, Jawdat D, Sadat M, Al-Dorzi HM, Tamim H, Afesh L, Almashaqbeh W, Alkadi H, Alwadaani D, UdayaRaja GK, Abdulkareem IBA, Al-Dawood A.
Title: Differential Gene Expression in Peripheral White Blood Cells with Permissive Underfeeding and Standard Feeding in Critically Ill Patients: A Descriptive Sub-study of the PermiT Randomized Controlled Trial. Sci Rep. 2018;8(1):17984.
Why is the paper important: This secondary mechanistic analysis of gene expression from patients enrolled in the PermiT trial suggests broad biological differences that occur in response to feeding strategies, supporting the central importance of enteric nutrition on regulation of critical biological pathways.
Summary and Commentary:
In this study1, Arabi et al., performed a secondary analysis of peripheral blood mononuclear cell (PBMC) gene expression from participants included in the PermiT trial.2 PermiT was a 7 center, international, randomized, controlled trial of mechanically ventilated patients (n=894) comparing a permissive underfeeding strategy (40-60% of caloric targets) to standard feeding strategy (70-100% of caloric targets). The PermiT investigators reported that 90-day mortality, as well as a number of secondary outcomes, did not differ between the treatment arms.
For the current manuscript, Arabi et al., analyzed over 1,700 peripheral blood mononuclear cell (PBMC) gene transcripts from 25 permissively underfed and 25 standard feeding participants in the PermiT trial. The most notable downregulated genes in the “underfed” group included those involved in phospholipase pathways (membrane associated phospholipase A1), autophagy inhibition (GADD45B), glycolysis (muscle pyruvate kinase), and inflammation (sPLA2-IIE), as compared to the standard feeding group. On the other hand, the most notable upregulated genes with “underfeeding” included Pan2, Cytochrome C, and VEGF-C, suggesting increased protein catabolism, mitochondrial activity, and endothelial cell proliferation, respectively, as compared to the standard feeding group.
Although the study suggests a potentially beneficial metabolic profile and autophagy promotion in the “underfed” group, several limitations are worth noting. First, the study cohort was limited to only 50 patients. Second, there was only a small difference between groups in terms of actual calories delivered, i.e. 57: IQR 51-59 % of calculated requirements in the “underfed” group vs. 68: IQR 57-90 % in the standard feeding group (p <0.001). Third, while protein delivery was not statistically significant between groups (82: IQR 69-89 % vs. 66: IQR 50-84 %; p=0.07, respectively), the “underfed” group received significantly higher amounts of protein as additional enteral supplements (31: IQR 22-40 g/day vs. 0: IQR 0-6 g/day; p<0.0001, respectively). And fourth, though not statistically significant, the “underfed” group had a numerically lower median age compared to the standard feeding group (28: IQR 23-58 years vs. 45: IQR 38-65 years; p=0.21, respectively). This may be important since impaired autophagy is implicated as an underlying driver of aging in multiple studies.3
Taken all together, these findings suggest that how protein is delivered, and potentially age, in addition to differences in caloric delivery may have played a role in the observed results. Of note, the authors suggest that a downregulation of GADD45B in the “underfed” group may signal enhanced autophagy. While GADD45B is an important regulator at the later parts of the autophagy pathway,4autophagy is a complex pathway involving many proteins. Therefore, it may be premature to conclude that this study demonstrates that “underfeeding” promotes autophagy through inhibition of this single gene. Nonetheless, these data support the concept that nutritional interventions delivered to critically ill patients likely have meaningful and broad impacts on important biological pathways. As such, more studies of this type are needed to better understand the biology of nutrition during acute illness.
1Arabi YM, Al-Balwi M, Hajeer AH, Jawdat D, Sadat M, Al-Dorzi HM, Tamim H, Afesh L, Almashaqbeh W, Alkadi H, Alwadaani D, UdayaRaja GK, Abdulkareem IBA, Al-Dawood A. Differential Gene Expression in Peripheral White Blood Cells with Permissive Underfeeding and Standard Feeding in Critically Ill Patients: A Descriptive Sub-study of the PermiT Randomized Controlled Trial. Sci Rep. 2018;8(1):17984.
2Arabi YM, Aldawood AS, Haddad SH, Al-Dorzi HM, Tamim HM, Jones G, Mehta S, McIntyre L, Solaiman O, Sakkijha MH, Sadat M, Afesh L. Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults. New England Journal of Medicine. 2015.
3Levine B, Kroemer G. Biological Functions of Autophagy Genes: A Disease Perspective. Cell. 2019;176(1-2):11-42.
4Keil E, Hocker R, Schuster M, Essmann F, Ueffing N, Hoffman B, Liebermann DA, Pfeffer K, Schulze-Osthoff K, Schmitz I. Phosphorylation of Atg5 by the Gadd45beta-MEKK4-p38 pathway inhibits autophagy. Cell Death Differ. 2013;20(2):321-32.
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