Supplemental Parenteral Nutrition in Pediatric Respiratory Failure

Study Overview
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Brief Summary
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Optimal delivery of nutritional support during critical illness is central to appropriate intensive care unit management, and yet fundamental gaps in knowledge exist regarding timing, route, dose, and type of nutritional support for critically ill infants and children. Understanding how to optimize nutritional support during pediatric critical illness is important because even brief periods of malnutrition in infancy result in permanent negative effects on long-term neurocognitive development. Optimized nutrition support is a way to improve morbidity for survivors of pediatric critical illness. Parenteral nutrition (PN) supplementation could improve long-term neurocognitive outcome for pediatric critical illness by preventing acute malnutrition, but has unknown effects on intestinal barrier function; a proposed mechanism for late sepsis and infectious complications during critical illness. While randomized controlled trials (RCT) support early PN in premature infants and late PN in critically ill adults, the optimal time to begin PN is unknown for critically ill infants and children. Acute malnutrition may develop within 48 hours of admission in critically ill infants and children, and repleted energy stores are predictive of survival. And yet, due to concerns for PN-associated infectious morbidity, current PICU standard of care is to supplement with PN only in children who fail to enterally feed, as late as 7 days into their admission. Delays in nutrition may have long-term effects on cognitive outcome in older infants and children. In premature infants, PN begun within hours of birth results in improved 18-month neurocognitive outcome without an increase in infectious complications. An RCT is needed to determine if early PN in critically ill infants and children prevents acute malnutrition and improves short and long-term outcomes of PICU hospitalization. The central hypothesis of this proposal is that optimized early protein and calorie delivery will improve nutritional outcomes and intestinal barrier function for critically ill infants and children. The overall purpose of this study is to evaluate the efficacy and safety of early PN as a supplement to enteral nutrition to improve nutritional delivery, nutritional outcomes, and intestinal barrier function for infants and children with acute respiratory failure who are mechanically ventilated in the pediatric intensive care unit.

Official Title
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Supplemental Parenteral Nutrition in Pediatric Respiratory Failure

Conditions
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Acute Respiratory Failure With Hypoxia, Malnutrition

Intervention / Treatment
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* Drug: Parenteral Nutrition


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Admitted to study hospital pediatric intensive care unit (PICU), One month to 16 years of age, Exhibits Acute Hypoxemic Respiratory Failure as defined as: PaO2/FiO2 ≤ 300 or SpO2/FiO2 ≤ 260, No evidence of cardiac dysfunction, Mechanically ventilated, Require artificial nutrition, Anticipate placement of central venous line within 24 hours of admission Exclusion Criteria: Premature infants and neonates < 37 weeks corrected gestational age, Transfer patient on an established enteral or parenteral nutritional regimen, Known allergy to lactulose or mannitol, Pregnant, Admit BMI >30, Thoracic trauma, abdominal trauma, and/or active intracranial bleeding, Anuric renal failure, previous bowel surgery and/or short gut syndrome, Cannot be enterally fed within 24 hours of admission according to the admitting physician, On extracorporeal membrane oxygenation (ECMO), Expected survival <24 hours or limitations to aggressive ICU care (DNR), Receiving active CPR when admitted to the PICU, A pre-existing bronchopleural fistula, Previously enrolled and randomized into this protocol, Actively enrolled in another clinical trial which at the discretion of the PI would conflict with this study.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early Parenteral Nutrition<br>Patients receive supplemental parenteral nutrition within 12 hours of enrollment. Titrated with enteral nutrition to achieve target goal calories and protein. | Drug: Parenteral Nutrition<br> <br> |
| Active Comparator: Late Parenteral Nutrition<br>Patients receive supplemental parenteral nutrition 96 hours after enrollment. Titrated with enteral nutrition to achieve target goal calories and protein. | Drug: Parenteral Nutrition<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Prognostic Inflammatory and Nutritional Index (PINI) | The change day 0 to day 5 of the modified Prognostic Inflammatory and Nutritional Index (PINI) is a quantitative method to monitor the relation between markers of nutrition and acute phase proteins. It allows assessment of nutrition markers in the context of acute inflammation and in response to early enteral nutrition. A higher baseline PINI score indicates higher degree of inflammation. The modified PINI is calculated by the the ratio of (C-Reactive Protein(mg/dL) x Fibrinogen (mg/dL))/ (Transferrin (mg/dL) x Transthyretin (mg/dL)). The average change in the modified PINI from day 0 to day 5 critically ill children receiving early enteral nutrition is a decrease by 5.3 +/- 3.2 (mean +/- standard error of the mean) (Briassoulis et.al. Nutrition 2001). A larger negative number for the change from day 0 to day 5 indicates a greater degree of inflammation resolution. | Change in PINI from day 0 to day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Percent of Daily Goal Calories Achieved | Evaluate percentage of cumulative goal calories achieved through parenteral and enteral routes in both study arms until patient exits study participation. Measure is calculated by (sum of kcal delivered over days of study participation/number of days in study). | baseline and daily through day 7 | 
| Plasma Intestinal Fatty Acid Binding Protein (I-FABP) | The percent change in plasma Intestinal Fatty Acid Binding Protein from baseline to study day 5, prior to late PN initiation | baseline and day 5 | 
| Plasma Citrulline | Evaluates absolute plasma citrulline concentration as a measure of functional enterocyte mass. A higher citrulline concentration indicates a higher functional enterocyte mass. Healthy children have an average citrulline concentration of 25 +/- 9 uMol/L. Assessed on day 0 and day 5, results reported for day 0 and 5. Outcome analysis on difference between treatment groups on day 5. | baseline and day 5 | 
| Plasma Claudin 3 | As a measure of enterocyte tight junctions, calculate the percent change in plasma claudin 3 concentrations from baseline (day 0) and study day 5, prior to late PN administration. | baseline through hour 96 | 
| Gastrointestinal Permeability | Gastrointestinal permeability measured with the ratio of urinary recovery of lactulose and mannitol on day 5 of study participation. The range of values is generally reported as 0.02 to 2.2 with a higher value indicating greater gastrointestinal permeability. Values obtained on day 0 and day 5, day 5 reported. | day 5 |