Key Publication Archive

2020 Reviews  | 2019 Reviews

MAY 2020

Reviewer: Manpreet Mundi, MD, Endocrinologist, Internist, Mayo Clinic

References: Martindale et al. Nutrition Therapy in the Patient with COVID-19 Disease Requiring ICU Care. Reviewed and Approved by the Society of Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition, published online April 2020.

Barazzoni, Rocco, Stephan C. Bischoff, Zeljko Krznaric, Matthias Pirlich, and Pierre Singer. ESPEN Expert Statements and Practical Guidance for Nutritional Management of Individuals with Sars-Cov-2 Infection. Clinical Nutrition, March 2020.

Commentary: As of May 11, there have been over 4 million confirmed cases of COVID-19 and over 280,000 deaths worldwide. The United States alone is fast approaching 80,000 deaths. Despite social distancing, which has flattened the case rate and mortality curves, the end of the pandemic is not yet in sight. Like other frontline healthcare workers, the nutrition community must be prepared and remain dynamic to manage patients in the new landscape that has been created by the COVID-19 pandemic.

Approximately 5% of those who contract the SARS-CoV-2 virus require critical care services, often related to respiratory failure requiring prolonged endotracheal intubation. In the absence of definitive therapy for COVID-19, good supportive care remains the cornerstone of caring for critically ill COVID-19 patients. Nutrition support is an essential component of good supportive care. In a recent article published jointly by the Society of Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition, Martindale and colleagues provide recommendations relating to nutritional support for critically ill patients with COVID-19. Their recommendations are rooted in key guiding principles that are relevant to COVID-19, including limiting patient exposure and protecting healthcare workers by ‘clustering’ care, following CDC and WHO guidelines for utilizing personal protective equipment (PPE), and preserving PPE. They outline 12 key recommendations and highlight that the timing of nutrition support is one of the most important issues. They recommend enteral nutrition be initiated within 24-36 hours of intensive care unit (ICU) admission in a patient unable to maintain volitional oral intake. The authors point out some unique circumstances related to COVID-19, including gastrointestinal symptoms (related to COVID-19), circulatory shock, and characteristics of the affected, such as older age, anorexia, and pre-existing co-morbidities. These patient and disease characteristics lead to a greater risk for enteral feeding intolerance. Consequently, the authors underscore the recommendation for early transition to parenteral nutrition (PN) when gastric feeding is not tolerated. This recommendation is anchored on the key guiding principle of limiting patient-healthcare provider interactions since insertion of a naso-jejunal tube places healthcare staff at higher risk of direct exposure to the SARS-CoV-2 virus. Next, authors recommend that enteral feeds be started slowly and advanced to an energy goal of 15-20 kcal/kg (70-80% of caloric requirements) and protein goal of 1.2-2.0 g/kg/day. For PN, conservative dextrose and volume should be used early in the disease and slowly advanced as tolerated. Other key COVID-19 relevant recommendations include not checking gastric residual volumes and, based on safety data, starting early EN in patients undergoing extracorporeal membrane oxygenation and prone positioning, both of which are modalities used in COVID-19 related refractory hypoxemic respiratory failure.

Similar to hospitalized patients, the “clustering” approach should also be followed with outpatient nutrition support. Nutrition support providers should make every effort to conduct as much care as possible through telehealth in order to prevent unnecessary exposure. Routine laboratory studies, if they cannot be deferred, should be conducted at the patient’s home or local facility. Additionally, providers should be aware that patients with SARS-CoV-2 infection may present with nonspecific symptoms such as respiratory changes, fever, and GI deterioration. Thus, given the high prevalence of COVID-19, nutrition patients reporting these symptoms should be assessed for both SARS-CoV-2 infection and other nutrition related complications such as central line associated bloodstream infections.

The COVID-19 pandemic has limited family and medical access to patients and has created resource shortages. The nutrition community, as an essential front-line service, has been called upon to create new guidelines in order to optimize patient outcomes and protect health care staff. In addition to implementing key recommendations outlined in recent publications, we must also appreciate the emotional toll of the pandemic and use compassion and a non-judgmental approach with our patients and colleagues in order to support each other through the challenges with which we are now faced.


APRIL 2020

Reviewer: John K. DiBaise, MD, Professor of Medicine, Division of Gastroenterology, Mayo Clinic in Arizona

Reference: Molina-Infante J, Arias A, Alcedo J, et al. Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: The 2-4-6 study. J Allergy Clin Immun 2018;141:1365-1372.

Whyis this paper important? Numerous dietary restrictions and endoscopies limit the implementation of empiric elimination diets in patients with eosinophilic esophagitis (EoE). This paper provides supporting evidence for a step-up diet elimination approach that results in early identification of a majority of responders to an empiric diet with few food triggers, avoiding unnecessary dietary restrictions, reducing endoscopies and shortening the diagnostic process.

Summary: This was a prospective multicenter study conducted in adult (106) and pediatric (25) patients who underwent a 6-week 2-food-group elimination diet (TFGED; milk and gluten-containing cereals). Clinicopathologic response was defined by symptom improvement and less than 15 eosinophils/high-power field on esophageal biopsy. Nonresponders were offered a 4-food-group elimination diet (FFGED; TFGED plus egg and legumes) and then a 6-food-group elimination diet (SFGED; FFGED plus nuts and fish/seafood). In responders, eliminated food groups were reintroduced individually, followed by endoscopy. Ninety-seven patients completed all phases of the study. A TFGED achieved EoE remission in 56 (43%) patients, with no differences between children and adults. Food triggers in TFGED responders were milk (52%), gluten-containing grains (16%), and both (28%). Per-protocol remission rates with FFGEDs and SFGEDs were 60% and 79%, with increasing food triggers. Overall, 55 (91.6%) of 60 of the TFGED/FFGED responders had 1 or 2 food triggers. Compared with the initial SFGED, a step-up strategy reduced endoscopies and diagnostic evaluation time by 20%.

Commentary: Eosinophilic esophagitis is a chronic immune-mediated disease characterized most commonly by dysphagia with or without recurrent esophageal food bolus impaction and eosinophil-predominant mucosal inflammation histologically. EoE, now the leading cause of dysphagia among children and adults in Western countries, has been demonstrated to be a distinct form of food allergy (non-IgE, delayed, cell-mediated hypersensitivity). Unlike pharmacologic therapies such as proton pump inhibitors and topical/systemic corticosteroids that target the inflammatory consequences, diet therapy targets the cause of the disease. While effective, an elemental diet has not gained widespread use, and use of food allergy testing-guided diet elimination has not yielded good clinical outcomes. The standard elimination diet used in EoE since 2006 is the SFGED. Currently, food groups to be avoided long-term can only be identified by individual food reintroduction followed by endoscopic histologic reevaluation. Despite the reproducible effectiveness of this strategy, because of the large number of endoscopies/biopsies required to document histologic response after serial food reintroduction, its use in clinical practice has been limited. Importantly, it has been found that nearly three-quarters of responders to a SFGED have just 1 or 2 food triggers, most commonly cow’s milk, wheat, egg and soy/legumes. This led to the development of the FFGED. Because cow’s milk and gluten-containing grains are the most common food triggers in reports to date, Molina-Infante et al. aimed to start with the TFGED and gradually step up to a FFGED and eventually to a SFGED in nonresponders in order to determine both the effectiveness and resource-savings of this approach. This was the first multicenter, prospective study investigating the step-up dietary approach. Strengths of the study include the large sample size, the systematic approach, and the inclusion of both children and adults. Limitations are lack of a control group, the nearly 30% drop-out rate which undoubtedly leads to an overestimation of the success rate of the diet, lack of measuring compliance with diet recommendations, and uncertain generalizability of the results to other geographical areas with different food consumption habits.

MARCH 2020

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, Rhodes JM, Lindsay JO, et al. Dietary Guidance for Patients with Inflammatory Bowel Disease from the International Organization for the Study of Inflammatory Bowel Disease. Clin Gastroenterol Hepatol. Feb 2020. doi: 10.1016/j.cgh.2020.01.046

Why is this paper important? In the absence of clear data about solid foods beneficial for inflammatory bowel diseases (IBD), patients are often faced with the need to explore and experiment with tenuous recommendations about foods prudent to consume or avoid. This endeavor is further complicated by the myriad and often conflicting sources of information available in the clinic, in print, and online. This study comprises a systematic effort by the International Organization of Inflammatory Bowel Diseases (IOIBD) to evaluate existing data and provide consensus-based recommendations on different food components for patients with IBD.

Summary: The 12-member IOIBD Nutrition Cluster evaluated the research data on 7 food groups and 5 food additives related to their effects on intestinal inflammation. Where human data were sparse, more emphasis was placed on animal data. Recommendations were made based on consensus in group discussion and provided in 4 categories: prudent to increase consumption, prudent to decrease or avoid consumption, safe to consume, or insufficient evidence to make a claim. The level of evidence was classified as “high” for randomized controlled trials (RCTs), “low” for observational human studies, and “very low” otherwise. In brief, the IOIBD suggested moderate-to-high consumption of fruits and vegetables (low evidence) for Crohn’s disease (CD), except in the presence of significant fibrostricturing disease. There was however insufficient evidence to make any recommendations about fruit and vegetable consumption for ulcerative colitis (UC). High-level evidence indicated that restriction of moderate amounts of unprocessed red meats, lean chicken meat, and eggs is unnecessary for CD; reduction of red and processed meat was advised for UC (low evidence). There were recommendations to reduce saturated fats (low evidence) and avoid trans fats (very low evidence) for CD and to reduce myristic acid (low evidence) for UC. Increased consumption of omega-3 fatty acids from fish (low evidence) but not supplements (high evidence) and avoidance of trans fat (very low evidence) was also advised for UC. The group recommended limited intake of maltodextrin-containing foods, artificial sweeteners, emulsifiers, thickeners, and processed foods containing titanium dioxide and sulfites for both CD and UC (very low evidence). Consensus was not obtained for pasteurized dairy products. There was no evidence of unpasteurized dairy products, but the group advised against its consumption. There was insufficient evidence to make any recommendations regarding consumption of refined carbohydrates, wheat, gluten, alcohol, 

Commentary: The study presents a systematic attempt at assessing the current state of evidence for various food groups to allow clinicians and patients to understand beneficial and detrimental foods for IBD. Notably, the quality of evidence was predominantly either low, very low, or insufficient; these disappointing findings illustrate the key challenges and underlying reasons for much confusion about dietary recommendations. Even fruits and vegetables, which would be highly suspected to provide anti-inflammatory effects in UC, were noted to have insufficient evidence to make a recommendation. On the other hand, despite the low quality of evidence available, patients cannot await RCTs to be performed for each food group prior to deciding on their next meal. Dietary recommendations for IBD are thus a dynamic process, integrating available data and acting on hypotheses on how certain foods may interact with the gastrointestinal system. This is also a call for more funding and research to further clarify our evolving understanding on this topic.


Reviewer: Jeffrey I. Mechanick, M.D., Professor of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY

Reference: Deelen J. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals. Nat Communic 2019; 10:3346;

Why is this paper important? Nutrition refers to the intersection of dietary factors and metabolism in the context of disease prevention, disease management, and health promotion. Within this framework, a new, accurate model to predict 5- and 10-year mortality is presented based on metabolomics, where each of the 14 biomarkers has a nutritional implication.

Summary: This is a large metabolomics study of 44,168 individuals from 12 different cohorts, spanning a wide age range (18-109), and where there were 5,512 deaths during follow-up. Using a high-throughput, well-standardized nuclear magnetic resonance platform, and a stepwise (forward-backward) analytic procedure based on meta-analysis results, 14 metabolic biomarkers were identified that when combined into a biomarker score, were highly associated with, and accurately predicted all-cause mortality, for men and women and across all ages:   

  1. total lipids in chylomicrons and extremely large VLDLs;
  2. total lipids in small HDLs;
  3. mean diameter of VLDLs;
  4. ratio of polyunsaturated to total fatty acids;
  5. glucose;
  6. lactate;
  7. 5 amino acids – histidine, isoleucine, leucine, valine, and phenylalanine;
  8. acetoacetate;
  9. albumin; and
  10. glycoprotein acetyls.

The precision accuracy for this new model exceeded that previously described using conventional risk factors.

Commentary: There are several important take-away messages from this study. First, this predictive model represents an improvement over previous models due to (1) a larger number of individuals, from a diverse and numerous set of well-established cohorts, with a relatively large number of deaths with follow-up and (2) a revised premise that intermediate- and long-term predictions are complicated, especially in older individuals who typically have multiple and interacting chronic diseases, prompting study of more proximal drivers for health/wellness (e.g., immunity, inflammation, metabolism, and nutrition), instead of distal drivers for specific disease (e.g., diabetes and cardiovascular disease). Second, that the successful implementation of predictive models, using relatively inexpensive biomarker platforms as in this study, to identify patients at higher risk for mortality can trigger early case finding and preventive care for a sustainable effect. Third, the role of nutrition in the crux of this predictive model emphasizes the central role of nutritional medicine in early, preventive strategies and tactics.


Reviewer: Ryan T. Hurt, MD, PhD; Professor of Medicine, Division of General Internal Medicine, Mayo Clinic, Rochester, MN

Reference: Reignier J et al Enteral versus parenteral early nutrition in ventilated adults with shock: a randomized, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Lancet. 2018; 391: 133-143. 

Why is this paper important? The optimal route and timing of nutrition support has been shown to impact clinical outcomes in the intensive care unit (ICU). NUTRIREA-2 follows the large randomized controlled trial (RCT) CALORIES from England comparing 28 day mortality enteral nutrition (EN) and parenteral nutrition (PN) in ventilated ICU patients. NUTRIREA-2 enrolled participants who were receiving a vasoactive agent within 24 hours of intubation to study the effects of route of nutrition on mortality in this group of patients. Many clinicians have concerns about starting early nutrition in this patient population.  

Summary: The large (n=2400) English RCT (CALORIES) of ICU patients provided strong evidence that the there was no difference in early EN and PN outcomes such as infection. The French NUTRIREA-2 trial was designed to examine those who specifically who were on vasoactive agents in addition to being ventilated. Not all of the CALORIES trial participants required vasoactive agents. The NUTRIREA-2 authors hypothesized that outcomes in early EN would be improved compared to early PN. The primary aim of the study was mortality at study day 28.  The study design was a multicenter, open-label (blinding for EN and PN was deemed possible), parallel-group, RCT conducted in 44 French ICUs. To be included in the trial the participants had to be >18 years old, mechanically ventilated, receiving a vasoactive agent for shock, and be able to start early EN or PN within 24 hours of onset of critical illness (defined as when the patient was intubated). Those meeting inclusion criteria were randomly assigned (n=2410; EN=1202, PN= 1208) in a 1:1 fashion to either PN or EN within 24 hours after intubation. The target calorie range for both EN and PN was 20–25 kcal/kg per day. Participants that were randomized to PN could be transitioned to EN after 72 hours of PN if there was resolution of the shock and they were off vasopressors for > 24 hours. Participants in the PN group received more calories over the entire study period compared to the EN group (EN=17.8 kcal/kg/d vs PN= 19.6 kcal/kg/d PN; p <0.0001). In addition PN participants received more protein (EN= 0.7 g/kg/d vs PN= 0.8 g/kg/d; p<0.0001). There was no significant difference in the primary outcome according to feeding route.  At day 28 the PN group had 422 participants (422/1208= 34.9%) and the EN group had 443 (443/1202=36.9%) that died. There were no significant differences in the secondary outcome of ICU acquired infections (PN =194; EN= 173). The secondary outcomes associated with GI tolerance all favored PN. These included incidence of vomiting (PN= 246, 20% vs EN= 406, 34%; HR 1.89 [1.62–2.20]; p<0·0001), diarrhea (PN= 393, 33% vs EN = 432, 36%; HR 1.20 [1.05–1.37]; p=0·009), acute colonic pseudo-obstruction (PN= 3, <1% vs 11, 1%; HR 3.7 [1.03-13.2; p =0.04), and bowel ischemia (PN=5, <1% vs EN= 19, 2%; HR 3.84 [1.43-10.3] p=0.007. Greater than twice as many hypoglycemic events were reported in the EN group (EN=29/1202 vs PN= 13/1208; p=0.006). Based on these results the authors stated conclusion was in ICU patients with shock requiring vasoactive agents early isocaloric EN did not reduce mortality or infections compared to PN. They did note that early EN was associated with risk of GI complications when compared to early PN.              

Commentary: The NUTRIREA-2 trial is the second recent large RCT demonstrating that early EN did not improve ICU outcomes such as mortality or infections. Although early PN did have improved outcomes such as diarrhea, bowel obstruction, and hypoglycemia these did not lead to improvements such as ICU length of stay or duration of mechanical ventilation.  One of the reasons that clinicians hesitate to place patients who require vasopressor support in the ICU on early enteral nutrition is the fear of intestinal ischemia. NUTRIREA-2 did demonstrate that those placed on early enteral nutrition did have a higher incidence of bowel ischemia compared to those randomized to parental nutrition.  One of the things to highlight from a practical clinical purpose is that NUTRIREA-2 was aggressive in early feeding with goal calories set at 20-25 kcals/kg/day.  There is an emerging set of data that suggest early hypocaloric (as it pertains to the goal calories) feeding strategies may have lower rates of gastrointestinal complications especially in the situation of continued vasoactive support following resuscitation from shock.  In the 2 years since the publication of NUTRIREA-2 it has raised as many questions as it has answered. 

Should PN be used instead of EN early inICU patient requiring vasoactive support? Besides the gastrointestinal complications there was no significant difference in mortality, infection, length of stay in the ICU, or ventilator time.  As mentioned above the better question is should we be aggressively feeding this patient population within 24 hours of ventilation by either route.  There are number of other considerations to be made as well including the non- nutritional benefits of enteral nutrition over parental nutrition as well as the increased cost of PN verses EN.  Based on this most nutritional guidelines and society will likely conclude that EN should still be the preferred route once it is determined the patient is safe to be fed.

If my patient cannot tolerate EN due togastrointestinal complications in ICU can I consider PN? The ASPEN 2016 critical care guidelines did not have either the CALORIES or NUTRIREA-2 trial included as part of it is analysis and thus recommendations.  It does seem reasonable that if early nutrition is needed in situations (such as malnutrition prior to intubation) and patients are unable to tolerate EN that PN could be considered.  We have improved the safe delivery of parenteral nutrition over the past 30 years which have included better care of central venous catheters and being mindful of not over feeding.  Probably the biggest take home point from both CALORIES and NUTRIREA-2 is that PN delivery in the ICU has improved and clinicians should consider it a more safe and viable option.           


Reviewer: Sara Bonnes, MD, MS, Assistant Professor of Medicine, Mayo Clinic, Rochester, MN 

Reference: Francis HM, Stevenson RJ, Chambers JR, Gupta D, Newey B, Lim CK (2019) A brief diet intervention can reduce symptoms of depression in young adults – A randomised controlled trial. PLoS ONE 14(10): e0222768. 

Why is this paper important? Lifestyle interventions and improving diet quality are associated with weight loss and reduced risk of mortality; however we may not consider or discuss with patients the other benefits. This study showed that improving dietary patterns was associated with a reduction in symptoms of depressed mood. 

Summary: This study included 76 individuals enrolled in tertiary education in Australia and New Zealand between ages 17-35 recruited through a psychology course or flyers elsewhere on campus that demonstrated evidence of depressive symptoms based on Depression Anxiety and Stress Scale– 21 depression subscale (DASS-21-D)>7 and evidence of poor diet as defined by a score >57 on the Dietary

Fat and Sugar Screener (DFS).  Participants were randomized into a control group that received no diet instruction and an intervention group that received instruction on a healthy diet via a 13 minute video created by a registered dietitian that followed the recommendations of the Australian Guide for Healthy Eating and emphasized the importance of omega 3 fatty acids, increasing consumption of fruits, vegetables and whole grains and also consuming regular amounts of cinnamon and turmeric while decreasing consumption of refined carbohydrates, fatty or processed meats and soft drinks.  Dietary compliance in the intervention group was assessed via questionnaire and there was phone call follow up on Days 7 and 14. The intervention group also received a gift card to help offset the cost of these foods and a small gift basket containing some of these food items. DASS-21 was reassessed on day 21 and the group undergoing dietary intervention had significantly lower DASS-21 scores as compared to the beginning of the study and compared to the control group, where scores were stable from the beginning of the study.  DASS scores for anxiety and stress also significantly improved. There was no significant change in measures for memory or other mood assessment tools. They did try 3 month phone follow up and were able to reach 33 participants. Those in the dietary intervention group did still have significant improvement in mood. Reduction in processed foods was most strongly correlated with the decrease in depressive scores. 

Commentary: While this is a small study with short term follow up, it is among the limited randomized controlled trials looking at dietary interventions and depressive symptoms. Certainly for many patients with depressive symptoms, psychotherapy and pharmacotherapy will be important aspects of treatment, but as we are working with patients, it is important to consider the other potential benefits of working to improve diet quality. It is also important for us to consider the impact of diet on mood in patients who are transitioning from oral intake to enteral or parenteral nutrition. Significant health changes can certainly impact mood and outlook, but potentially nutrient intake may also impact mood. As patients are undergoing significant life changes, we should assess the impact and mood and consider a multi-faceted approach to address these issues.      


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.             


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.  

JULY 2019

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: [1] Is IC needed to estimate energy requirements in critically ill patients? [2] What is the optimal nutrition dose during the first week of critical illness? [3] What is the role for supplemental parenteral nutrition during the first week of critical illness? and [4] 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.

JUNE 2019

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). 

MAY 2019

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.

Arabi 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.

Levine B, Kroemer G. Biological Functions of Autophagy Genes: A Disease Perspective. Cell. 2019;176(1-2):11-42.

Keil 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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