The enteroendocrine axis and its effect on gastrointestinal function, nutrition, and inflammation.

PURPOSE OF REVIEW: Gastrointestinal (GI) dysfunction limits enteral nutrition (EN) delivery in critical illness and contributes to systemic inflammation. The enteroendocrine (EE) axis plays an integral role in this interface between nutrition, inflammation, and GI function in critical illness. In this review, we present an overview of the EE system with a focus on its role in GI inflammation and function. RECENT FINDINGS: Enteroendocrine cells have been primarily described in their role in macronutrient digestion and absorption. Recent research has expanded on the diverse functions of EE cells including their ability to sense microbial peptides and metabolites and regulate immune function and inflammation. Therefore, EE cells may be both affected by and contribute to many pathophysiologic states and interventions of critical illness such as dysbiosis , inflammation, and alternative EN strategies. In this review, we present an overview of EE cells including their growing role in nonnutrient functions and integrate this understanding into relevant aspects of critical illness with a focus on EN. SUMMARY: The EE system is key in maintaining GI homeostasis in critical illness, and how it is impacted and contributes to outcomes in the setting of dysbiosis , inflammation and different feeding strategies in critical illness should be considered.

Human coagulation factor X and CD5 antigen-like are potential new members of the zonulin family proteins.

Zonulin is a physiologic epithelial and endothelial permeability modulator. Zonulin increases antigen trafficking from the gut lumen into the bloodstream and in between body compartments, a mechanism linked to many chronic inflammatory diseases. Upon its initial discovery, it was noted that zonulin was not a single protein, but rather a family of structurally and functionally related proteins referred to as the zonulin family proteins (ZFPs). ZFPs are members of the mannose associated serine proteases (MASP) family and are the result of high mutation rates leading to many zonulin polymorphisms. Pre-haptoglobin 2, the precursor of haptoglobin 2, was identified as the first eukaryotic member of the ZFPs, and properdin, a key positive regulator of the alternative pathway, as a second member. In this study, we report two additional proteins that are likely ZFPs. Human coagulation factor X (FX) and CD5 antigen-like (CD5L). Both FX and CD5L recombinant proteins were detected by anti-zonulin antibody in Western immunoblot analysis, and both proteins decreased epithelial barrier competency of Caco-2 cell monolayers as established by the Trans Epithelial Electrical Resistance (TEER) assay. These results indicate that FX and CD5L have structural and functional similarities with previously identified ZFPs and, therefore, can be considered new members of this family of proteins.

Challenges and advances in nutrition for the critically ill child.

PURPOSE OF REVIEW: Malnutrition remains prevalent in critically ill children and is associated with worse clinical outcomes. Conversely, nutrition provision has been associated with improved survival. Nutritional challenges must be addressed to guide best nutrition practices for the critically ill child. In this narrative review, we summarize findings from research published between July 2020 and January 2022 on nutrition in critically ill children. Findings from these articles build on previous work to guide next steps in both research and clinical practice in this cohort. RECENT FINDINGS: A comprehensive literature review was performed. We identified the following common themes for research published between July 2020 and January 2022-metabolism, enteral nutrition, including timing, dosing, protein prescription and delivery in special populations, gastrointestinal function, and enteral nutrition adjunctive therapies. SUMMARY: Research continues to support early initiation and advancement of enteral nutrition. Achieving nutritional adequacy is challenging, but research associated with the timing and dosing of enteral nutrition, alternative methods of enteral nutrition delivery and the use of adjuncts are expanding our understanding of best practices for this cohort. Areas for further research continue to be the use of measured energy requirements, protein dosing and inclusion of functional outcomes to assess the benefit of nutritional interventions.

Association Between Anticholinergic Drug Burden and Adequacy of Enteral Nutrition in Critically Ill, Mechanically Ventilated Pediatric Patients.

OBJECTIVES: Enteral nutrition delivery is limited by intolerance and interruptions in critically ill children. Anticholinergic properties of frequently administered medications may contribute to altered gastric motility and enteral nutrition intolerance in this population. We examined the association between the anticholinergic burden of administered medications using the Anticholinergic Drug Scale and adequacy of enteral nutrition delivery. DESIGN: Secondary analysis of data from a previously characterized PICU cohort. SETTING: Multidisciplinary PICU in a quaternary academic medical center. PATIENTS: Younger than or equal to 18 years, on mechanical ventilation and received enteral nutrition within the first 3 days of PICU admission. MEASUREMENTS AND MAIN RESULTS: Daily Anticholinergic Drug Scale score, demographic data, and clinical data were obtained from the primary study. Percent enteral energy adequacy ([kcal delivered ÷ kcal prescribed] × 100) during the first 3 days of PICU admission was calculated. Forty-two patients received enteral nutrition, with median age (interquartile range) 5 years (1.09-12.54 yr), and 62% were male. Median Anticholinergic Drug Scale score was inversely correlated with energy adequacy, with a median 9% decline in energy adequacy per 1-point increase in Anticholinergic Drug Scale score (coefficient, -9.3; 95% CI, -13.43 to -5.27; R2 = 0.35; p < 0.0001). Median hours of enteral nutrition interruptions directly correlated with Anticholinergic Drug Scale score (coefficient, 1.5; 95% CI, 0.531-2.54; R2 = 0.19; p = 0.004). Severity score was greater in patients with less than or equal to 25% enteral energy adequacy and directly correlated with median Anticholinergic Drug Scale score. CONCLUSIONS: Anticholinergic burden from medications administered in the PICU is a potentially modifiable factor for suboptimal enteral nutrition delivery.

Body Composition in Children with Chronic Illness: Accuracy of Bedside Assessment Techniques.

OBJECTIVE: To evaluate the accuracy of estimated fat mass and fat-free mass from bedside methods compared with reference methods in children with chronic illnesses. STUDY DESIGN: Fat mass and fat-free mass values were obtained by skinfold, bioelectrical impedance analysis (BIA), dual-energy x-ray absorptiometry (DXA), and deuterium dilution method in children with spinal muscular atrophy, intestinal failure, and post hematopoietic stem cell transplantation (HSCT). Spearman's correlation and agreement analyses were performed between (1) fat mass values estimated by skinfold equations and by DXA and (2) fat-free mass values estimated by BIA equations and by DXA and deuterium dilution methods. Limits of agreement between estimating and reference methods within ±20% were deemed clinically acceptable. RESULTS: Fat mass and fat-free mass values from 90 measurements in 56 patients, 55% male, and median age of 11.6 years were analyzed. Correlation coefficients between the skinfold-estimated fat mass values and DXA were 0.93-0.94 and between BIA-estimated fat-free mass values and DXA were 0.92-0.97. Limits of agreement between estimated and DXA values of fat mass and fat-free mass were greater than ±20% for all equations. Correlation coefficients between estimated fat-free mass values and deuterium dilution method in 35 encounters were 0.87-0.91, and limits of agreement were greater than ±20%. CONCLUSION: Estimated body composition values derived from skinfold and BIA may not be reliable in children with chronic illnesses. An accurate noninvasive method to estimate body composition in this cohort is desirable.

The science and art of pediatric critical care nutrition.

PURPOSE OF REVIEW: Nutritional status and nutrient delivery during critical illness impact clinical outcomes. We have reviewed recent studies that may guide best practices regarding nutrition therapy in critically ill children. RECENT FINDINGS: Malnutrition is prevalent in the pediatric ICU population, and is associated with worse outcomes. Nutrition support teams, dedicated dietitians, and educational programs facilitate surveillance for existing malnutrition and nutrition risk, but specific tools for the pediatric ICU population are lacking. Estimation of macronutrient requirements is often inaccurate; novel strategies to accurately determine energy expenditure are being explored. Indirect calorimetry remains the reference method for measuring energy expenditure. Enteral nutrition is the preferred route for nutrition in patients with a functioning gut. Early enteral nutrition and delivery of adequate macronutrients, particularly protein, have been associated with improved clinical outcomes. Delivery of enteral nutrition is often interrupted because of fasting around procedures and perceived intolerance. Objective measures for detection and management of intolerance to nutrient intake are required. In low-risk patients who are able to tolerate enteral nutrition, supplemental parenteral nutrition may be delayed during the first week of critical illness. SUMMARY: Systematic research and consensus-based practices are expected to promote optimal nutritional practices in critically ill children with the potential to improve clinical outcomes.

Census tract based income level and lipid levels in urban pediatric primary care: a retrospective study.

BACKGROUND: Lower socioeconomic status has been associated with adverse lipid levels in adult populations. Childhood dyslipidemia is a risk factor for future cardiovascular disease. However, studies examining relationships between socioeconomic indicators and lipid levels in children are limited. To examine the relationship between income level and lipid levels in childhood. METHODS: We conducted a retrospective chart review of primary care patients, ages 2 to 18 years, who had lipid levels drawn at two large pediatric practices in Boston, MA between August 01, 2008 and August 31, 2010. Income level was determined using geocoding census tract data. Analysis was performed using t-test, Anova and Spearman correlation coefficients. BMI percentile, age, sex, race/ethnicity, and site were adjusted for on multivariate analyses. RESULTS: Reviewing 930 charts of patients with measured lipid levels, 730 had a valid address, no previously diagnosed lipid disorder and met other study eligibility criteria. Mean total cholesterol level did not vary by income level (low 155.5 mg/dl ±26.9, moderate 153.5 mg/dl ±30.4, middle 155.3 mg/dl ±26.6 and high income 155.5 mg/dl ±27.9; p = .87) on multivariate analysis. Income level was not related to LDL, HDL, or triglycerides. CONCLUSIONS: In this analysis of children cared for in two urban pediatric primary practices, there was no association between income level determined by census tract and lipid levels in childhood. If confirmed in prospective investigations in other geographical locations, income level may not be a key driver of childhood lipid levels.

Metabolic assessment and individualized nutrition in children dependent on mechanical ventilation at home.

OBJECTIVE: To evaluate the nutritional and metabolic status and body composition of children on long-term mechanical ventilation using a home-based model. STUDY DESIGN: Children on home mechanical ventilation, for at least 12 hours a day, were eligible. We performed anthropometry, bioelectrical impedance analysis (BIA), actual energy intake (AEI), and indirect calorimetry in the subject's home. Agreement between measured energy expenditure (MEE) from indirect calorimetry, and estimated energy expenditure by the Schofield equation and a novel volumetric carbon dioxide production-based equation was examined. Agreement between fat mass estimates from anthropometry and BIA was examined and compared with population norms. RESULTS: We enrolled 20 children, 11 (55%) male; mean age 8.4 years (SD 4.8). Mean weight for age z-score was -0.26 (SD 1.48); 9/20 had z-scores <-1 or >+1. Thirteen were underfed (AEI:MEE <90%) or overfed (AEI:MEE >110%); 11 of 19 had protein intake that was less than recommended by guidelines. Fifteen subjects were hypo- or hypermetabolic. Mean (SD) fat mass % was 33.6% (8.6) by anthropometry, which was significantly greater than matched population norms (mean 23.0%, SD 6.1, P < .001). The estimated energy expenditure by a volumetric carbon dioxide production-based equation was in stronger agreement with the MEE than the Schofield equation (mean bias 0.06%, limits -15.98% to 16.16% vs mean bias -1.31%, limits -74.3% to 72%, respectively). BIA and anthropometric fat mass values were not in agreement. CONCLUSION: A majority of children on home ventilation are characterized by malnutrition, altered metabolic status, and suboptimal macronutrient intake, in particular low protein intake. A multidisciplinary home-based model facilitates individualized energy and protein delivery and may improve outcomes in this cohort.

Gastric Dysmotility in Critically Ill Children: Pathophysiology, Diagnosis, and Management.

OBJECTIVE: We aimed to review gastric dysmotility in critically ill children: 1) its pathophysiology, with a focus on critical care diseases and therapies that affect gastric motility, 2) diagnostic methodologies, and 3) current and future potential therapies. DATA SOURCES: Eligible studies were identified from PubMed and MEDLINE. STUDY SELECTION: Literature search included the following key terms: "gastric emptying," "gastric motility/dysmotility," "gastrointestinal motility/dysmotility," "nutrition intolerance," and "gastric residual volume." DATA EXTRACTION: Studies since 1995 were extracted and reviewed for inclusion by the authors related to the physiology, pathophysiology, diagnostic methodologies, and available therapies for gastric emptying. DATA SYNTHESIS: Delayed gastric emptying, a common presentation of gastric dysmotility, is present in up to 50% of critically ill children. It is associated with the potential for aspiration, ventilator-associated pneumonia, and inadequate delivery of enteral nutrition and may affect the efficacy of enteral medications, all of which may be result in poor patient outcomes. Gastric motility is affected by critical illness and its associated therapies. Currently available diagnostic tools to identify gastric emptying at the bedside have not been systematically studied and applied in this cohort. Gastric residual volume measurement, used as an indirect marker of delayed gastric emptying in PICUs around the world, may be inaccurate. CONCLUSIONS: Gastric dysmotility is common in critically ill children and impacts patient safety and outcomes. However, it is poorly understood, inadequately defined, and current therapies are limited and based on scant evidence. Understanding gastric motility and developing accurate bedside measures and novel therapies for gastric emptying are highly desirable and need to be further investigated.

Impact of Individualized Diet Intervention on Body Composition and Respiratory Variables in Children With Respiratory Insufficiency: A Pilot Intervention Study.

OBJECTIVES: Diet modification may improve body composition and respiratory variables in children with respiratory insufficiency. Our objective was to examine the effect of an individualized diet intervention on changes in weight, lean body mass, minute ventilation, and volumetric CO2 production in children dependent on long-term mechanical ventilatory support. DESIGN: Prospective, open-labeled interventional study. SETTING: Study subjects' homes. PATIENTS: Children, 1 month to 17 years old, dependent on at least 12 hr/d of transtracheal mechanical ventilatory support. INTERVENTIONS: Twelve weeks of an individualized diet modified to deliver energy at 90-110% of measured energy expenditure and protein intake per age-based guidelines. MEASUREMENTS AND MAIN RESULTS: During a multidisciplinary home visit, we obtained baseline values of height and weight, lean body mass percent by bioelectrical impedance analysis, actual energy and protein intake by food record, and measured energy expenditure by indirect calorimetry. An individualized diet was then prescribed to optimize energy and protein intake. After 12 weeks on this interventional diet, we evaluated changes in weight, height, lean body mass percent, minute ventilation, and volumetric CO2 production. Sixteen subjects, mean age 9.3 years (SD, 4.9), eight male, completed the study. For the diet intervention, a majority of subjects required a change in energy and protein prescription. The mean percentage of energy delivered as carbohydrate was significantly decreased, 51.7% at baseline versus 48.2% at follow-up, p = 0.009. Mean height and weight increased on the modified diet. Mean lean body mass percent increased from 58.3% to 61.8%. Minute ventilation was significantly lower (0.18 L/min/kg vs 0.15 L/min/kg; p = 0.04), and we observed a trend toward lower volumetric CO2 production (5.4 mL/min/kg vs 5.3 mL/min/kg; p = 0.06) after 12 weeks on the interventional diet. CONCLUSIONS: Individualized diet modification is feasible and associated with a significant decrease in minute ventilation, a trend toward significant reduction in CO2 production, and improved body composition in children on long-term mechanical ventilation. Optimization of respiratory variables and lean body mass by diet modification may benefit children with respiratory insufficiency in the ICU.

Changes in Global Nutrition Practices in Critically Ill Children and the Influence of Emerging Evidence: A Secondary Analysis of the Pediatric International Nutrition Studies, 2009-2018.

BACKGROUND: The timeline of the 3 Pediatric International Nutrition Studies (PINS) coincided with the publication of 2 major guidelines for the timing of parenteral nutrition (PN) and recommended energy and protein delivery dose. OBJECTIVE: The study's main objective was to describe changes in the nutrition delivery practice recorded in PINS1 and PINS2 (PINS1-2) (conducted in 2009 and 2011, preexposure epoch) vs PINS3 (conducted in 2018, postexposure epoch), in relation to the published practice guidelines. DESIGN: This study is a secondary analysis of data from a multicenter prospective cohort study. PARTICIPANTS/SETTING: Data from 3650 participants, aged 1 month to 18 years, admitted to 100 unique hospitals that participated in 3 PINS was used for this study. MAIN OUTCOME MEASURES: The time in days from pediatric intensive care unit admission to the initiation of PN and enteral nutrition delivery were the primary outcomes. Prescribed energy and protein goals were the secondary outcomes. STATISTICAL ANALYSES PERFORMED: A frailty model with a random intercept per hospital with stratified baseline hazard function by region for the primary outcomes and a mixed-effects negative binomial regression with random intercept per hospital for the secondary outcomes. RESULTS: The proportion of patients receiving enteral nutrition (88.3% vs 80.6%; P < .001) was higher, and those receiving PN (20.6% vs 28.8%; P < .001) was lower in the PINS3 cohort compared with PINS1-2. In the PINS3 cohort, the odds of initiating PN during the first 10 days of pediatric intensive care unit admission were lower, compared with the PINS1-2 cohort (hazard ratio 0.8, 95% CI 0.67 to 0.95; P = .013); and prescribed energy goal was lower compared with the PINS1-2 cohort (incident rate ratio 0.918, 95% CI 0.874 to 0.965; P = .001). CONCLUSIONS: The likelihood of initiation of PN delivery significantly decreased during the first 10 days after admission in the PINS3 cohort compared with PINS1-2. Energy goal prescription in children receiving mechanical ventilation significantly decreased in the postguidelines epoch compared with the preguidelines epoch.

Biomarkers and Functional Assays of Epithelial Barrier Disruption and Gastrointestinal Dysmotility in Critical Illness-A Narrative Review.

Enteral nutrition in critically ill children has been associated with improved clinical outcomes. Gastrointestinal dysfunction often impedes the timely initiation and advancement of enteral nutrition and can contribute to immune dysregulation and systemic inflammation. Therefore, assessing gastrointestinal function, at a cellular and functional level, is important to provide optimal enteral nutrition therapy and reduce the gastrointestinal tract's contribution to the inflammatory cascade of critical illness. In this narrative review, we present an overview of biomarker and functional assays for gastrointestinal dysfunction, including epithelial barrier disruption and gastrointestinal dysmotility, that have been considered for critically ill patients.

Postpyloric vs gastric enteral nutrition in critically ill children: A single-center retrospective cohort study.

BACKGROUND: We aimed to describe enteral nutrition (EN) delivery in patients receiving postpyloric EN (PPEN) vs gastric EN (GEN). METHODS: Single-center retrospective study including patients aged <21 years admitted to an intensive care unit in a pediatric quaternary care hospital for ≧48 h who received PPEN or GEN as a first approach, as guided by a nutrition algorithm. PPEN patients were 1:1 propensity score matched to GEN patients on demographics, clinical characteristics, and disease severity. Days to EN initiation from admission, percentage of EN adequacy (delivered EN volume/prescribed EN volume) on days 1-3 and 7 after EN initiation, and time to achieving 60% of prescribed EN volume were compared between the two groups using Wilcoxon Mann-Whitney tests and a Cox proportional hazards model. Data are presented as median (IQR1, IQR3). RESULTS: Forty-six PPEN and 46 GEN patients were matched. Median time to EN initiation was 3.25 (2, 6.8) days for PPEN and 4.15 (1.5, 7.1) days for GEN (P = 0.6). Percentage of EN adequacy was greater for PPEN than GEN patients (day 1 PPEN 59.4% [18.8, 87.5] vs GEN 21.1% [7.8, 62.8], day 2 PPEN 54.3% [16.7, 95.8] vs GEN 24% [5.4, 56.7], day 3 PPEN 65.4% [14.7, 100] vs GEN 16% [0, 64.6], day 7 PPEN 77.8% [11.1, 100] vs GEN 13.8% [0, 74.5]; P < 0.05). PPEN patients had greater likelihood of achieving 60% of their prescribed EN volume than GEN patients (hazard ratio 1.84, 95% CI 1.07-3.15; P = 0.028). CONCLUSION: PPEN was associated with greater EN delivery compared with GEN.

Impact of implementing an evidence-based definition of enteral nutrition intolerance on nutrition delivery: A prospective, cross-sectional cohort study.

BACKGROUND: Enteral nutrition (EN) interruptions because of EN intolerance impede nutrient delivery. We aimed to examine whether revising the EN intolerance definition of an algorithm would decrease EN interruptions and improve nutrient delivery in critically ill children. METHODS: We performed a cross-sectional cohort study including patients who were admitted to our intensive care unit (ICU) for >24 h and received EN. The EN intolerance definition in our nutrition algorithm was modified to include two symptoms of EN intolerance. We compared time to 60% EN adequacy (EN delivered/EN prescribed x 100) and EN interruptions before and after this intervention. RESULTS: We included 150 eligible patients, 78 and 72 patients in the preimplementation and postimplementation cohorts, respectively. There were no significant differences in demographics and clinical characteristics. The preimplementation and postimplementation cohorts achieved 60% EN adequacy 4 (2-5) days and 3 (2-5) days after ICU admission, respectively (P = 0.59). The preimplementation cohort had a median of 1 (1-2) interruption per patient and the postimplementation cohort 2 (1-3; P = 0.08). The frequency of interruptions because of EN intolerance within the first 8 days of ICU admission was 17 in the preimplementation and 10 in the postimplementation cohorts. CONCLUSION: Modifying the EN intolerance definition of a nutrition algorithm did not change the time to 60% EN adequacy or total number of EN interruptions in critically ill children. EN intolerance and interruptions continue to limit nutrient delivery. Research on the best definition for EN intolerance and its effect on nutrition outcomes is needed.

Intermittent versus continuous enteral nutrition in critically ill children: A pre-planned secondary analysis of an international prospective cohort study.

BACKGROUND & AIMS: Intermittent enteral nutrition (EN) may have physiologic benefits over continuous feeding in critical illness. We aimed to compare nutrition and infection outcomes in critically ill children receiving intermittent or continuous EN. METHODS: International, multi-center prospective observational study of mechanically ventilated children, 1 month to 18 years of age, receiving EN. Percent energy or protein adequacy (energy or protein delivered/prescribed × 100) and acquired infection rates were compared between intermittent and continuous EN groups using adjusted-multivariable and 4:1 propensity-score matched (PSM) analyses. Sensitivity analyses were performed after excluding patients who crossed over between intermittent and continuous EN. RESULTS: 1375 eligible patients from 66 PICUs were included. Patients receiving continuous EN (N = 1093) had a higher prevalence of respiratory illness and obesity, and lower prevalence of neurologic illness and underweight status on admission, compared to those on intermittent EN (N = 282). Percent energy or protein adequacy, proportion of patients who achieved 60% of energy or protein adequacy in the first 7 days of admission, and rates of acquired infection were not different between the 2 groups in adjusted-multivariable and propensity score matching analyses (P > 0.05). CONCLUSION: Intermittent versus continuous EN strategy is not associated with differences in energy or protein adequacy, or acquired infections, in mechanically ventilated, critically ill children. Until further evidence is available, an individualized feeding strategy rather than a universal approach may be appropriate.

Novel role of zonulin in the pathophysiology of gastro-duodenal transit: a clinical and translational study.

We examined the relationship between zonulin and gastric motility in critical care patients and a translational mouse model of systemic inflammation. Gastric motility and haptoglobin (HP) 2 isoform quantification, proxy for zonulin, were examined in patients. Inflammation was triggered by lipopolysaccharide (LPS) injection in C57Bl/6 zonulin transgenic mouse (Ztm) and wildtype (WT) mice as controls, and gastro-duodenal transit was examined by fluorescein-isothiocyanate, 6 and 12 h after LPS-injection. Serum cytokines and zonulin protein levels, and zonulin gastric-duodenal mRNA expression were examined. Eight of 20 patients [14 years, IQR (12.25, 18)] developed gastric dysmotility and were HP2 isoform-producing. HP2 correlated with gastric dysmotility (r = - 0.51, CI - 0.81 to 0.003, p = 0.048). LPS injection induced a time-dependent increase in IL-6 and KC-Gro levels in all mice (p < 0.0001). Gastric dysmotility was reduced similarly in Ztm and WT mice in a time-dependent manner. Ztm had 16% faster duodenal motility than WT mice 6H post-LPS, p = 0.01. Zonulin mRNA expression by delta cycle threshold (dCT) was higher in the stomach (9.7, SD 1.4) than the duodenum (13.9, SD 1.4) 6H post-LPS, p = 0.04. Serum zonulin protein levels were higher in LPS-injected mice compared to vehicle-injected animals in a time-dependent manner. Zonulin correlated with gastric dysmotility in patients. A mouse model had time-dependent gastro-duodenal dysmotility after LPS-injection that paralleled zonulin mRNA expression and protein levels.

Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.

BACKGROUNDWeeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODSHere, we analyzed biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient's clinical response.RESULTSWe showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSIONThese mechanistic data on MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.

Bedside Postpyloric Tube Placement and Enteral Nutrition Delivery in the Pediatric Intensive Care Unit.

BACKGROUND: Enteral nutrition (EN) delivery may be more effective via a postpyloric (PP) feeding tube in critically ill children, but tube placement can be challenging. We aimed to describe PP tube placement and EN practices in a multidisciplinary pediatric intensive care unit (PICU) after the implementation of a nurse-led bedside PP tube-placement program. METHODS: In a single-center retrospective study, we identified 100 consecutive patients admitted to the PICU for >48 hours and for whom PP tube placement was attempted. Demographics, clinical characteristics, and details of PP tube placement and EN delivery were examined. RESULTS: The study cohort had a median age (25th, 75th percentiles) of 3.89 years (0.55, 14.86); 66% were male. Respiratory illness was the primary diagnosis of admission (55%); 92% were on respiratory support. Risk of aspiration was the primary indication for PP tube placement (48%). Bedside placement was the initial technique for PP tube placement in 93% of patients (successful for 84.9%) and was not associated with serious complications. Eighty-seven patients with a PP tube started EN and received a median 73.9% (12.3%, 100%) of prescribed energy goal on day 3 after EN initiation. PP EN allowed 14 of 39 patients receiving parenteral nutrition (PN) to transition off PN 7 days after EN initiation. Thirty-five percent of EN interruptions were due to feeding-tube dysfunction. CONCLUSION: Bedside PP tube placement is safe and feasible and allows for effective EN delivery and decreased PN use when applicable. Interruptions in PP EN due to tube malfunction are prevalent.

Gastrointestinal Hormone Profiles Associated With Enteral Nutrition Tolerance and Gastric Emptying in Pediatric Critical Illness: A Pilot Study.

BACKGROUND: Enteral nutrition (EN) intolerance and delayed gastric emptying are prevalent in pediatric critical illness and limit EN delivery. Gastrointestinal (GI) hormones may be associated with EN intolerance and delayed gastric emptying in this cohort. METHODS: We determined GI hormone levels, time to achieve 50% of EN goal, and gastric emptying in critically ill children. Total amylin, active ghrelin, total glucagon-like peptide-1 (GLP-1), total gastric inhibitory polypeptide, glucagon, and total peptide-YY (PYY) were measured by multiplex assay and cholecystokinin by ELISA. Lower concentrations of acetaminophen at 1 hour (C1h, µg/mL) using the acetaminophen absorption test defined delayed gastric emptying. Correlation, regression analyses, and a principal component analysis were used to examine the association between GI hormones and time to 50% EN goal and C1h. RESULTS: GI hormones were measured in 14 of 21 patients with gastric emptying testing; median age of 11.2 years (6.74-16.3) and 50% male. Increasing hormone levels from GI hormone profile 1 (GLP-1, glucagon, and amylin) correlated with greater time to reach 50% EN goal (R2 = 0.296, P = 0.04). Decreasing hormone levels from GI hormone profile 2 (PYY and ghrelin) correlated with lower C1h and slower gastric emptying (R2 = 0.342, P = 0.02). CONCLUSION: GI hormone profiles are associated with time to achieve 50% of EN goal and gastric emptying in critically ill children. We have described a feasible model to study the role of GI hormones in this cohort, including the potential clinical applicability of GI hormone measurement in the management of delayed gastric emptying.