The Influence of Timing in Critical Care Nutrition.

Proper timing of critical care nutrition has long been a matter of controversy. Critical illness waxes and wanes in stages, creating a dynamic flux in energy needs that we have only begun to examine. Furthermore, response to nutrition support likely differs greatly at the level of the individual patient in regard to genetic status, disease stage, comorbidities, and more. We review the observational and randomized literature concerning timing in nutrition support, discuss mechanisms of harm in feeding critically ill patients, and highlight the role of precision nutrition for moving the literature beyond the realm of blunt population averages into one that accounts for the patient-specific complexities of critical illness and host genetics.

Combination of High-Calorie Delivery and Organ Failure Increases Mortality Among Patients With Acute Respiratory Distress Syndrome.

OBJECTIVES: Among critically ill patients, the benefits of nutrition support may vary depending on severity of organ dysfunction. The objective of the current article was to explore the relationship between organ failure and calories exposure with hospital mortality during the first week of acute respiratory distress syndrome. DESIGN: Retrospective observational study. SETTING: Single-center ICU. PATIENTS: Adults admitted to the ICU with a diagnosis of acute respiratory distress syndrome. INTERVENTIONS: Calorie delivery from enteral nutrition, parenteral nutrition, propofol, and dextrose containing fluids were collected for 7 days following intubation. Sequential Organ Failure Assessment score was calculated at ICU admit and for the same 7 days to describe organ dysfunction; four different Sequential Organ Failure Assessment variables were created 1) Sequential Organ Failure Assessment at ICU admit, 2) average Sequential Organ Failure Assessment for the first 7 days following intubation, 3) the highest Sequential Organ Failure Assessment for the first 7 days following intubation, and 4) change in Sequential Organ Failure Assessment from intubation to 7 days later. MEASUREMENTS AND MAIN RESULTS: A total of 298 patients were included. Sequential Organ Failure Assessment at ICU admit, average Sequential Organ Failure Assessment for the first 7 days following intubation, highest Sequential Organ Failure Assessment for the first 7 days following intubation, change in Sequential Organ Failure Assessment from intubation to 7 days later, and calorie delivery the first 7 days following intubation were all associated with increased likelihood of mortality. Compared with patients with low organ failure and low-calorie delivery, those with high-calorie delivery and low organ failure, low-calorie delivery and high organ failure, and the combination of both high organ failure with high-calorie delivery were associated with an incremental increase in the likelihood or mortality. CONCLUSIONS: Organ failure appears to modify the relationship between calorie exposure and ICU outcome. Additional research is needed to identify appropriate thresholds for safe calorie exposure with increased organ failure.

The relationship between home- and individual-level diet quality among African American and Hispanic/Latino households with young children.

BACKGROUND: The quality of most Americans' diets is far from optimal. Given that many Americans consume a significant portion of calories in the home, intervening in this setting could be beneficial. However, the relationship between the home food environment and diet quality is not well understood. This study examined the relationship between diet quality at the individual level with home-level diet quality using an index that measures compliance with federal dietary guidance. METHODS: This was a cross sectional study that enrolled 97 African American and Hispanic/Latino low-income parent-child dyads. Diet quality at the individual level was assessed through two 24-h dietary recalls collected for parents and children, respectively. Diet quality at the home level was assessed with two home food inventories conducted in participants' homes. Diet quality scores at the home and individual levels were computed by applying the Healthy Eating Index-2010 (HEI-2010) to these data. Linear models adjusted for potential confounding factors were used to examine the relationship between diet quality at the home and individual levels. RESULTS: Total HEI-2010 scores from parents and children's diets were positively associated with HEI-2010 scores based on home food inventories (parent diet: ß: 0.36, 95% CI: 012-0.60; child diet: 0.38 95% CI: 013-0.62). Positive associations were also observed between individual level and home level subcomponent HEI-2010 scores for total fruit (parent: 0.55 95% CI: 0.16-0.94; child: 0.49 95% CI: 0.03-0.94), whole fruit (parent only: 0.41 95% CI: 0.07-0.74), greens and beans (parent only: 0.39 95% CI: 0.05-0.74), and whole grain (children only: 0.33 95% CI: 0.04-0.63). CONCLUSION: This study demonstrated that individual level diet quality was positively associated with home-level diet quality. Findings from this study can help us to address modifiable targets of intervention in the home to improve diet quality.

Race-dependent association of sulfidogenic bacteria with colorectal cancer.

OBJECTIVE: Colorectal cancer (CRC) incidence is higher in African Americans (AAs) compared with non-Hispanic whites (NHWs). A diet high in animal protein and fat is an environmental risk factor for CRC development. The intestinal microbiota is postulated to modulate the effects of diet in promoting or preventing CRC. Hydrogen sulfide, produced by autochthonous sulfidogenic bacteria, triggers proinflammatory pathways and hyperproliferation, and is genotoxic. We hypothesised that sulfidogenic bacterial abundance in colonic mucosa may be an environmental CRC risk factor that distinguishes AA and NHW. DESIGN: Colonic biopsies from uninvolved or healthy mucosa from CRC cases and tumour-free controls were collected prospectively from five medical centres in Chicago for association studies. Sulfidogenic bacterial abundance in uninvolved colonic mucosa of AA and NHW CRC cases was compared with normal mucosa of AA and NHW controls. In addition, 16S rDNA sequencing was performed in AA cases and controls. Correlations were examined among bacterial targets, race, disease status and dietary intake. RESULTS: AAs harboured a greater abundance of sulfidogenic bacteria compared with NHWs regardless of disease status. Bilophila wadsworthia-specific dsrA was more abundant in AA cases than controls. Linear discriminant analysis of 16S rRNA gene sequences revealed five sulfidogenic genera that were more abundant in AA cases. Fat and protein intake and daily servings of meat were significantly higher in AAs compared with NHWs, and multiple dietary components correlated with a higher abundance of sulfidogenic bacteria. CONCLUSIONS: These results implicate sulfidogenic bacteria as a potential environmental risk factor contributing to CRC development in AAs.

Impact of Abdominal Adipose Depots and Race on Risk for Colorectal Cancer: A Case-Control Study.

Visceral adipose tissue (VAT) but not subcutaneous adipose tissue (SAT) is associated with obesity-related diseases including colorectal cancer (CRC). Superficial SAT (SSAT) and deep SAT (DSAT), components of SAT, also appear to independently influence disease risk. These abdominal adipose tissues (AATs) are not extensively studied in connection with CRC and have not been explored in the United States despite known racial variations in body composition. We conducted a case-control study that compared associations between AAT with CRC risk and race of African-American (AA) and non-Hispanic white (NHW) men with incident CRC matched by age, body mass index, and race (N = 158, 79/group). Cross-sectional computed tomography images were used for assessment of AAT. Overall cases and controls had similar VAT areas (140 ± 192 vs 149 ± 152 cm2, P-value = 0.93); however, cases had lower SSAT than controls (88 ± 39 vs 112 ± 65 cm2, P < 0.01). Among controls, AA had significantly lower VAT (114 ± 168 vs 180 ± 167, P < 0.01) than NHW. Conditional logistic regression revealed that AA men with greater SSAT had lower odds for CRC (odds ratio [OR]: 0.24, 95% confidence interval [CI] 0.07-0.85). Our findings indicate that VAT does vary between cases and controls by race; however, this variation is not a risk factor for CRC. The negative association between CRC and SSAT in AA men warrants further investigation.

Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Pediatric Critically Ill Patient: Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition.

This document represents the first collaboration between two organizations, American Society of Parenteral and Enteral Nutrition and the Society of Critical Care Medicine, to describe best practices in nutrition therapy in critically ill children. The target of these guidelines is intended to be the pediatric (> 1 mo and < 18 yr) critically ill patient expected to require a length of stay greater than 2 or 3 days in a PICU admitting medical, surgical, and cardiac patients. In total, 2,032 citations were scanned for relevance. The PubMed/Medline search resulted in 960 citations for clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1,661 citations. In total, the search for clinical trials yielded 1,107 citations, whereas the cohort search yielded 925. After careful review, 16 randomized controlled trials and 37 cohort studies appeared to answer one of the eight preidentified question groups for this guideline. We used the Grading of Recommendations, Assessment, Development and Evaluation criteria to adjust the evidence grade based on assessment of the quality of study design and execution. These guidelines are not intended for neonates or adult patients. The guidelines reiterate the importance of nutritional assessment, particularly the detection of malnourished patients who are most vulnerable and therefore potentially may benefit from timely intervention. There is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake. Indirect calorimetry, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recommended. Optimal protein intake and its correlation with clinical outcomes are areas of great interest. The optimal route and timing of nutrient delivery is an area of intense debate and investigations. Enteral nutrition remains the preferred route for nutrient delivery. Several strategies to optimize enteral nutrition during critical illness have emerged. The role of supplemental parenteral nutrition has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care population is heterogeneous, and a nuanced approach to individualizing nutrition support with the aim of improving clinical outcomes is necessary.

Reduced flow-and acetylcholine-induced dilations in visceral compared to subcutaneous adipose arterioles in human morbid obesity.

BACKGROUND AND AIMS: The hypothesis of this study was that microvascular FID and AChID is impaired in visceral (VAT) compared to SAT arterioles in morbidly obese women. An Additional aim was to determine the mechanisms contributing to FID and AChID in VAT and SAT arterioles. METHODS AND RESULTS: Arterioles were obtained from SAT and VAT biopsies from women (BMI > 35 kg/m(2) ) undergoing bariatric surgery. Microvessels were cannulated for reactivity measurements in response to flow (pressure gradients of 10-100 cmH2 O) and to ACh (10(-9) -10(-4 ) M) with and without l-NAME, INDO, and PEG-catalase. NO and H2 O2 generation were detected in arterioles by fluorescence microscopy. FID and AChID of arterioles from VAT were reduced compared to SAT arterioles. In SAT arterioles, l-NAME, INDO, and PEG-catalase significantly reduced FID and AChID but had no effect individually on VAT arterioles' vasodilator reactivity. INDO +l-NAME reduced FID in VAT arterioles. NO-fluorescence was greater in arterioles from SAT compared to VAT arterioles. Vascular H2 O2 generation during flow was similar in both VAT and SAT. CONCLUSION: Our results suggest that VAT arterioles display reduced vasodilator reactivity to flow and ACh compared to SAT arterioles, mediated by different regulatory mechanisms in human obesity.

The accuracy of vitamin D assays of circulating 25-hydroxyvitamin D values: influence of 25-hydroxylated ergocalciferol concentration.

Serum samples from 74 obese women were assayed for 25-hydroxyvitamin D [25(OH)D] concentrations using an automated immunoassay [Architect (Abbott)] and ELISA (Alpco Diagnostics), and results were compared with the LC/MS/MS reference method (Quest Diagnostics). The Architect values were significantly lower (mean difference: -13 nmol/L; 95% limits: -54; 28 nmol/L) and the ELISA values were significantly higher (mean difference: 24 nmol/L; 95% limits: -36; 84 nmol/L) than the LC/MSIMS values. The slope of the Passing-Bablok regression line relative to LC/MSIMS was 0.5 [95% confidence interval (CI): 0.41; 0.60] and 1.17 (95% CI: 0.87; 1.56) for Architect and ELISA, respectively, with an intercept of approximately 16 for both assays. Using 50 nmol/L as the cut-point for deficiency, Architect and ELISA misclassified 20 and 27% of the subjects, respectively. In subjects with low circulating 25-hydroxylated ergocalciferol [25(OH)D2] (<10 nmol/L), a Bland-Altman plot and Kappa statistics (Kappa = 0.73; 95% CI: 0.49-0.97) showed good agreement between Architect and LC/MS/MS. However, in subjects with high circulating 25(OH)D2 (>or=10 nmol/L), Architect demonstrated poor agreement (Kappa = 0.40; 95% CI: 0.16-0.65). ELISA demonstrated a higher degree of overestimation in women with minimal 25(OH)D2 than those with high 25(OH)D2, suggesting that ELISA overestimates 25-hydroxylated cholecalciferol [25(OH)D3] but underestimates 25(OH)D2.

Guidelines for the provision of nutrition support therapy in the adult critically ill patient: The American Society for Parenteral and Enteral Nutrition.

BACKGROUND: This guideline updates recommendations from the 2016 American Society for Parenteral and Enteral Nutrition (ASPEN)/Society of Critical Care Medicine (SCCM) critical care nutrition guideline for five foundational questions central to critical care nutrition support. METHODS: The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) process was used to develop and summarize evidence for clinical practice recommendations. Clinical outcomes were assessed for (1) higher vs lower energy dose, (2) higher vs lower protein dose, (3) exclusive isocaloric parenteral nutrition (PN) vs enteral nutrition (EN), (4) supplemental PN (SPN) plus EN vs EN alone, (5A) mixed-oil lipid injectable emulsions (ILEs) vs soybean oil, and (5B) fish oil (FO)-containing ILE vs non-FO ILE. To assess safety, weight-based energy intake and protein were plotted against hospital mortality. RESULTS: Between January 1, 2001, and July 15, 2020, 2320 citations were identified and data were abstracted from 36 trials including 20,578 participants. Patients receiving FO had decreased pneumonia rates of uncertain clinical significance. Otherwise, there were no differences for any outcome in any question. Owing to a lack of certainty regarding harm, the energy prescription recommendation was decreased to 12-25 kcal/kg/day. CONCLUSION: No differences in clinical outcomes were identified among numerous nutrition interventions, including higher energy or protein intake, isocaloric PN or EN, SPN, or different ILEs. As more consistent critical care nutrition support data become available, more precise recommendations will be possible. In the meantime, clinical judgment and close monitoring are needed. This paper was approved by the ASPEN Board of Directors.

Suppressed cytokine production in whole blood cultures may be related to iron status and hepcidin and is partially corrected following weight reduction in morbidly obese pre-menopausal women.

OBJECTIVE: Assess ex vivo whole-blood (WB) cytokine production and its association with iron status and serum hepcidin in obese versus non-obese women. Determine the change in ex vivo WB cytokine production 6 months after restrictive bariatric surgery in the obese group. SUBJECTS: Seventeen obese (BMI: 46.6±7.9 kg/m²) and 19 non-obese (BMI: 22.5±3.0 kg/m²), pre-menopausal women; frequency matched for hemoglobin, age and race. MEASUREMENTS: At baseline control and ex vivo stimulated IL-6, IL-10, IL-22, IFNγ, and TNFα from heparinized WB cultures, hemoglobin from finger-stick and transferrin receptor, hepcidin, CRP, IL-6, HOMA-IR from fasted serum samples and anthropometric parameters were assessed in the women. All parameters were reassessed 6-months following restrictive bariatric surgery in the obese women only. RESULTS: Whole blood ex vivo LPS and ZY stimulated production of IL-6, TNFα, and IFNγ was reduced, IL-22 increased, and IL-10 was unaffected in obese compared with the non-obese women. Furthermore, ex vivo stimulated production of IL-6 and TNFα normalized, but IFNγ production remained unchanged with weight loss following restrictive bariatric surgery. In the obese women, serum transferrin receptor (a marker of iron status) and serum hepcidin were correlated with ex vivo stimulated IFNγ production at baseline. CONCLUSION: Ex vivo LPS and ZY stimulated cytokine production from WB cultures was altered in pre-menopausal women with morbid obesity. Significant weight loss resulted in normalization of some but not all observed alterations. Furthermore, iron status and serum hepcidin were associated with ex vivo LPS and ZY stimulated IFNγ in obesity.

Orally fed patients are at high risk of calorie and protein deficit in the ICU.

PURPOSE OF REVIEW: Malnutrition can lead to serious complications in the ICU. Less than half of patients admitted to ICU require ventilation and for many, their optimal route of feeding is oral medical nutrition therapy, rather than enteral or parenteral nutrition. Inadequate oral intake is a prevalent and often difficult problem within this population, as increased calorie deficits are common in the ICU and associated with worse outcomes. RECENT FINDINGS: Consuming less than 75% of daily calorie requirements in the hospital setting is associated with worse outcomes. Unfortunately, oral intake is often inadequate. Little is known about the consequences of inadequate oral intake in the ICU; however, data have described worse outcomes with large calorie deficits from enteral and parenteral nutrition. Whether or not these data can be extrapolated to patients in the ICU with poor oral intake remains uncertain. SUMMARY: Despite evidence-based guidelines directing the delivery of nutrition support in the ICU, there is limited research focused on oral intake during this time of hospitalization. Future research is needed to determine the long-term associations of inadequate versus adequate oral intake in the ICU.

Effect of variable energy served on 24-hour energy intake in 16 preschools, Chicago, Illinois, 2007.

INTRODUCTION: The effect of varying portion size in a natural environment on the self-regulation of 24-hour energy intake has not been evaluated. We studied students at 16 preschools in Chicago to determine the effect of meals with variable energy and macronutrients on the amount consumed over a 24-hour period (ie, at preschool and outside of preschool). METHODS: The food items and portion sizes served at 16 preschools in the Chicago Public Schools early childhood education programs were observed for 3 to 8 days. Children were assessed for total energy and selected macronutrients consumed at preschool and outside of preschool for a 24-hour period; their data were pooled and reported by school. RESULTS: The students were predominantly African American (96%); on average, 32 students (range, 21-38) participated at each of the 16 preschools, and the age range of students was 4.0 to 4.5 years. The energy served at preschools ranged from 48% to 90% of the daily recommended energy allowance (REA). The mean energy intake at school was significantly higher (39% of REA) at 2 preschools, including 1 that served 90% of the REA. Mean energy consumption outside of preschool and total 24-hour energy consumption did not differ by preschool, adjusting for body mass index z score and sex. CONCLUSION: The preschools served meals that widely varied by portion size and energy; however, this variation did not result in differences in mean 24-hour nutrient intakes for the students attending these schools.

Relationship between blood glucose variability and muscle composition in ICU patients receiving nutrition support: A pilot study.

BACKGROUND AND AIMS: Many critically ill patients experience increased blood glucose variability (BGV). The objective of the current pilot study was to assess the relationship between muscle composition (defined as average Hounsfield units (HU)) among ICU patients with an abdominal CT scan within seven days of intubation, and BGV (defined as coefficient of variation (CV)) calculated from blood glucose levels measured each morning while intubated. METHODS: The first serum blood glucose measurement obtained each day during intubation was recorded, blood glucose CV ((mean/SD)∗100) was calculated. Cross-sectional muscle area (CSA; cm2) at the third lumbar region was identified using the -29 to +150 HU range; muscle composition was calculated as the average HU. BGV predictors were determined using linear regression. RESULTS: Eighty-two patients were included (53% female), with a median age of 64 (25th, 75 percentile (IQR): 51, 70) years. The median CV was 29% (IQR: 20, 37); 40% of subjects required insulin. The median CSA was 100.4 cm2 (IQR: 84.0, 120.8) and muscle composition was 20.4 HU (IQR: 12.2, 29.4). Patients received only 36% of estimated calorie requirements. Insulin administration, history of diabetes, and muscle composition were significant BGV predictors. CONCLUSION: Among these adult intubated ICU patients, higher muscle composition was associated with lower BGV. Future research is needed to corroborate these findings, determine other factors associated with poor muscle quality, and identify methods to describe muscle composition for all ICU patients.

Impact of MnSOD and GPx1 Genotype at Different Levels of Enteral Nutrition Exposure on Oxidative Stress and Mortality: A Post hoc Analysis From the FeDOx Trial.

BACKGROUND: Converting nutrition support to energy results in mitochondrial free radical production, possibly increasing oxidative stress. Highly prevalent single nucleotide variants (SNV) exist for the genes encoding antioxidant enzymes responsible for the detoxification of reactive oxygen species. Our objective was to explore the interaction between nutrition support and genetic SNV's for two anti-oxidant proteins (rs4880 SNV for manganese superoxide dismutase and rs1050450 SNV for glutathione peroxidase 1) on oxidative stress and secondarily on intensive care unit (ICU) mortality. METHODS: We performed a post-hoc analysis on 34 mechanically ventilated sepsis patients from a randomized control feeding trial. Participants were dichotomized into those who carried both the rs4880 and the rs1050450 at-risk alleles (Risk Group) versus all others (Nonrisk Group). We explored the interaction between genotype and percent time spent in the upper median of energy exposure on oxidative stress and ICU mortality. RESULTS: Adjusting for confounders, the slope of log F2-isoprostane levels across percentage of days spent in the upper median of daily kilocalories per kilogram (kcal/kg) was 0.01 higher in the Risk Group compared to the Non-Risk Group (p=0.01). Every 1 percent increase in days spent in the upper median of daily kcal/kg was associated with an adjusted 10.3 percent increased odds of ICU mortality amongst participants in the Risk Group (odds ratio [OR]=1.103, p=0.06) but was highly insignificant in the Nonrisk group (OR=0.991, P=0.79). CONCLUSION: Nutrition support may lead to increased oxidative stress and worse clinical outcomes in a large percent of ICU patients with an at-risk genotype.

Real-Time Energy Exposure Is Associated With Increased Oxidative Stress Among Feeding-Tolerant Critically Ill Patients: Results From the FEDOX Trial.

BACKGROUND: Prospective randomized controlled trials (PRCTs) that found harm in patients receiving higher levels of energy exposure have been largely ignored, in part because of the lack of a known mechanism of harm. OBJECTIVE: The current 7-day pilot study is a PRCT and post hoc analysis designed to explore the relationship between energy exposure and oxidative stress (as plasma total F2-isoprostanes) in mechanically ventilated intensive care unit patients with systemic inflammatory response syndrome. METHODS: Thirty-five participants were randomized to receive either 100% or 40% of their estimated energy needs. Our intent-to-treat model found no differences in F2-isoprostanes between groups. A post hoc analysis revealed that on days when participants were in the highest tertile of daily kcal/kg, the real-time energy flow rate within 2 hours of the blood draw was predictive of increased oxidative stress. On these days, participants in the second or third vs the first tertile of real-time energy flow rate experienced a 41.8% (P = .006) or 26.5% (P = .001) increase in F2-isoprostane levels, respectively. This was confirmed through a within-group subanalysis restricted to participants with measurements on both sides of the median of real-time energy flow rate that found a 28.2% F2-isoprostane increase on days in the upper vs lower median of flow rate (P = .002). CONCLUSION: The benefits of feeding may be more nuanced than previously suspected. Our findings imply a potential mechanism of harm in meeting the current recommendations for nutrition support in the critically ill that warrants further investigation.

American Society for Parenteral and Enteral Nutrition Clinical Guidelines: The Validity of Body Composition Assessment in Clinical Populations.

On behalf of the American Society for Parenteral and Enteral Nutrition (ASPEN), a systematic review was conducted to evaluate the best available evidence regarding the validity of relevant body composition methods (eg, dual energy X-ray absorptiometry [DXA], ultrasound [US], and bioelectrical impedance analysis [BIA]) in clinical populations. The guidelines targeted adults >18 years of age with a potentially inflammatory condition or pathological end point associated with a specific disease or clinical condition. In total, 7375 studies were retrieved, and 15 DXA, 7 US, and 23 BIA studies provided applicable data. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses was used to assess the diagnostic accuracy of the test method against a "gold standard" reference. The Grading of Recommendations, Assessment, Development and Evaluation criteria were used to separate the evaluation of the body of evidence from the recommendations. Based on a limited number of studies and expert opinion, DXA is recommended for the assessment of fat mass in patients with a variety of disease states; however, the validity of DXA for lean mass assessment in any clinical population remains unknown. No recommendations can be made at this time to support the use of US or BIA in the clinical setting, as data to support its validity in any specific patient population are limited in scope or by the proprietary nature of manufacture-specific BIA regression models to procure body composition data, respectively. Directions for future research are provided. These clinical guidelines were approved by the ASPEN Board of Directors.

Higher Caloric Exposure in Critically Ill Patients Transiently Accelerates Thyroid Hormone Activation.

INTRODUCTION: The inflammatory response of critical illness is accompanied by nonthyroidal illness syndrome (NTIS). Feeding has been shown to attenuate this process, but this has not been explored prospectively over time in critically ill patients. OBJECTIVE: To explore the impact of calorie exposure on NTIS over time in critically ill patients. METHODS: Mechanically ventilated patients with systemic inflammatory response syndrome (SIRS) were randomized to receive either 100% or 40% of their estimated caloric needs (ECN). Thyroid hormones were measured daily for 7 days or until intensive care unit discharge or death. Mixed level regression modeling was used to explore the effect of randomization group on plasma triiodothyronine (T3), reverse triiodothyronine (rT3), thyroxine (T4), and thyroid stimulating hormone (TSH), as well as the T3/rT3 ratio. RESULTS: Thirty-five participants (n=19 in 100% ECN; n=16 in 40% ECN) were recruited. Adjusting for group differences in baseline T3/rT3 ratio, the parameters defining the fitted curves (intercept, linear effect of study day, and quadratic effect of study day) differed by randomization group (P = 0.001, P = 0.01, and P = 0.02 respectively). Plots of the fitted curves revealed that participants in the 100% ECN group had a 54% higher T3/rT3 ratio on postintervention day 1 compared with the 40% ECN group, a difference which attenuated over time. This was driven by a 23% higher plasma T3 and 10% lower plasma rT3 levels on postintervention 1. CONCLUSIONS: Higher caloric exposure in NTIS patients transiently attenuates the drop of the plasma T3/rT3 ratio, an effect that is minimized and finally lost over the following 3 days of continued higher caloric exposure.