Acute Respiratory Failure With Hypoxia, Malnutrition
Conditions
Brief summary
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.
Interventions
DRUGParenteral Nutrition
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Arizona
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Months to 16 Years
Healthy volunteers
No
Inclusion criteria
1. Admitted to study hospital pediatric intensive care unit (PICU), 2. One month to 16 years of age, 3. Exhibits Acute Hypoxemic Respiratory Failure as defined as: PaO2/FiO2 ≤ 300 or SpO2/FiO2 ≤ 260, No evidence of cardiac dysfunction, Mechanically ventilated, 4. Require artificial nutrition, 5. Anticipate placement of central venous line within 24 hours of admission
Exclusion criteria
1. Premature infants and neonates \< 37 weeks corrected gestational age, 2. Transfer patient on an established enteral or parenteral nutritional regimen, 3. Known allergy to lactulose or mannitol, 4. Pregnant, 5. Admit BMI \>30, 6. Thoracic trauma, abdominal trauma, and/or active intracranial bleeding, 7. Anuric renal failure, previous bowel surgery and/or short gut syndrome, 8. Cannot be enterally fed within 24 hours of admission according to the admitting physician, 9. On extracorporeal membrane oxygenation (ECMO), 10. Expected survival \<24 hours or limitations to aggressive ICU care (DNR), 11. Receiving active CPR when admitted to the PICU, 12. A pre-existing bronchopleural fistula, 13. Previously enrolled and randomized into this protocol, 14. Actively enrolled in another clinical trial which at the discretion of the PI would conflict with this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Prognostic Inflammatory and Nutritional Index (PINI) | Change in PINI from day 0 to day 5 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gastrointestinal Permeability | day 5 | 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. |
| Plasma Citrulline | baseline and day 5 | 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. |
| Plasma Claudin 3 | baseline through hour 96 | 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. |
| Cumulative Percent of Daily Goal Calories Achieved | baseline and daily through day 7 | 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). |
| Plasma Intestinal Fatty Acid Binding Protein (I-FABP) | baseline and day 5 | The percent change in plasma Intestinal Fatty Acid Binding Protein from baseline to study day 5, prior to late PN initiation |
Other
| Measure | Time frame | Description |
|---|---|---|
| 28-day Mortality | 28 days | Death of a study patient do to any cause measured up to 28 days after study enrollment. |
| Number of Participants With Hospital-Acquired Infections | until hospital discharge or day 28 if still hospitalized | Record any hospital-defined hospital acquired infections through day 28 in all study participants. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Early Parenteral Nutrition Patients receive supplemental parenteral nutrition within 12 hours of enrollment. Titrated with enteral nutrition to achieve target goal calories and protein over the one week study period. | 7 |
| Late Parenteral Nutrition Patients receive supplemental parenteral nutrition 96 hours after enrollment if meeting \< 80% of caloric goals with enteral nutrition alone. Titrated with enteral nutrition to achieve target goal calories and protein over the one week study period. | 11 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Late Parenteral Nutrition | Total | Early Parenteral Nutrition |
|---|---|---|---|
| Age, Continuous | 1.1 years | 1.3 years | 1.4 years |
| BMI z score | -.9 Z score | -0.9 Z score | -.73 Z score |
| PELOD-2 score | 7 units on a scale | 7.5 units on a scale | 8 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 15 Participants | 6 Participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 7 | 0 / 11 |
| other Total, other adverse events | 5 / 7 | 6 / 11 |
| serious Total, serious adverse events | 0 / 7 | 5 / 11 |
Outcome results
Primary
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.
Time frame: Change in PINI from day 0 to day 5
Population: Patients with central venous access and/or arterial access removed at study day 5 did not have blood drawn for PINI measurement. All patients with paired PINI values from day 0 and day 5 obtained are analyzed based on initial group assignment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Parenteral Nutrition | Modified Prognostic Inflammatory and Nutritional Index (PINI) | -1.6 score on a scale | Standard Error 1 |
| Late Parenteral Nutrition | Modified Prognostic Inflammatory and Nutritional Index (PINI) | -3.2 score on a scale | Standard Error 1.8 |
p-value: 0.57Wilcoxon (Mann-Whitney)
Secondary
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).
Time frame: baseline and daily through day 7
Population: All patients enrolled had daily nutrition data collected until end of study participation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Parenteral Nutrition | Cumulative Percent of Daily Goal Calories Achieved | 103.8 percent of goal kcal/day |
| Late Parenteral Nutrition | Cumulative Percent of Daily Goal Calories Achieved | 103.4 percent of goal kcal/day |
p-value: 0.68Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: day 5
Population: Analysis of lactulose and mannitol urinary concentrations performed on all patients who received the lactulose and mannitol study test and with urinary samples obtained on day 5.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Parenteral Nutrition | Gastrointestinal Permeability | 0.15 ratio |
| Late Parenteral Nutrition | Gastrointestinal Permeability | 0.17 ratio |
p-value: 0.88Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: baseline and day 5
Population: Citrulline concentrations obtained for patients with plasma samples available for analysis on study day 0 and 5
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Early Parenteral Nutrition | Plasma Citrulline | day 0 | 10 umoL per Liter |
| Early Parenteral Nutrition | Plasma Citrulline | day 5 | 19.4 umoL per Liter |
| Late Parenteral Nutrition | Plasma Citrulline | day 0 | 8 umoL per Liter |
| Late Parenteral Nutrition | Plasma Citrulline | day 5 | 14.5 umoL per Liter |
p-value: 0.04t-test, 2 sided
Secondary
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.
Time frame: baseline through hour 96
Population: Included all patients with claudin 3 plasma concentrations reported at hour zero and 96, analyzed in groups as initially assigned.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Parenteral Nutrition | Plasma Claudin 3 | 29.8 percent change |
| Late Parenteral Nutrition | Plasma Claudin 3 | 111.7 percent change |
p-value: 0.43t-test, 2 sided
Secondary
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
Time frame: baseline and day 5
Population: All patients enrolled in the study with IFABP results obtained at baseline and hour 96, analyzed in initial assigned groups.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Parenteral Nutrition | Plasma Intestinal Fatty Acid Binding Protein (I-FABP) | 2.11 percent change |
| Late Parenteral Nutrition | Plasma Intestinal Fatty Acid Binding Protein (I-FABP) | -25 percent change |
p-value: 0.27t-test, 2 sided
Other Pre-specified
28-day Mortality
Death of a study patient do to any cause measured up to 28 days after study enrollment.
Time frame: 28 days
Population: Determined for all study participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Parenteral Nutrition | 28-day Mortality | 2 Participants |
| Late Parenteral Nutrition | 28-day Mortality | 0 Participants |
p-value: 0.06Chi-squared
Other Pre-specified
Number of Participants With Hospital-Acquired Infections
Record any hospital-defined hospital acquired infections through day 28 in all study participants.
Time frame: until hospital discharge or day 28 if still hospitalized
Population: All study participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Early Parenteral Nutrition | Number of Participants With Hospital-Acquired Infections | 0 Participants |
| Late Parenteral Nutrition | Number of Participants With Hospital-Acquired Infections | 1 Participants |
p-value: 0.43Chi-squared