The Augmented Versus Routine Approach to Giving Energy Trial

Study Overview
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Brief Summary
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Nutrition therapy is an essential standard of care for all critically ill patients who are mechanically ventilated and remain in the intensive care unit for more than a few days. The investigators plan to conduct a 4,000 patient, double-blind, randomised controlled trial to determine if augmentation of calorie delivery using energy dense enteral nutrition in mechanically ventilated patients improves 90 day survival when compared to routine care.

Detailed Description
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Each year around 130,000 Australians are admitted to ICU at a daily cost of approximately $4000 per patient. Their care consumes close to 3 billion dollars per year. These critically ill patients are the sickest in the hospital. They require substantial resources and multiple interventions. Some die and many of those who survive have delayed and compromised functional recovery which can persist for months or years. Nutrition therapy is an essential standard of care for all ICU patients who are mechanically ventilated and remain in ICU for more than a few days. Enteral nutrition (via a nasogastric tube) is usually initiated within 24 hours of ICU admission with a formula containing 1 kcal/ml and prescribed at an approximate rate of 1 ml/kg/hour. However, standard enteral nutrition practice typically results in the delivery of only  60% of the full-recommended calorie requirement. Although prescribed calories can reliably be delivered using the intravenous route, the enteral route is preferred for a number of reasons and is recommended by all nutrition guidelines as first-line therapy. In particular, enteral nutrition is more physiological, less costly and associated with fewer infective complications. Delivery of nutrient into the gut also has beneficial effects on subsequent gut function and may reduce ongoing sepsis which can be fuelled by the movement of gut flora through a permeable mucosa that has not been exposed to nutrient. Intravenous nutrition is accordingly, generally used only when enteral feeding is impossible, or persistently limited. Although supplementing enteral with intravenous nutrition can increase calorie delivery, this has not been shown to have a therapeutic benefit and may worsen important clinical outcomes. This may be because adverse effects associated with intravenous nutrition counteract the benefits of increased calorie delivery. Previous trials support the concept that optimising nutrition in the critically ill will improve outcome, however, the evidence is limited, inclusive and generally of low quality. It is extraordinary that there is not better (Level I) evidence to inform nutrition management in critically ill patients given the frequency of the intervention, the biologic rationale, the high mortality following ICU admission, the frequency of muscle wasting and the poor functional outcomes in survivors. This is especially true given the low cost of enteral nutrition ( $23/day). The investigators recently completed pilot study clearly achieved all the key criteria which, for a pharmaceutical product, would lead to a phase III trial, namely: 1. feasibility; 2. safety; 3. separation; 4. excellent recruitment rate; 5. successful blinding; 6. a signal for benefit. A definitive study must now be done to establish whether 90-day survival and functional outcomes following critical illness may be improved by increased calorie delivery.

Official Title
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The Augmented Versus Routine Approach to Giving Energy Trial: A Randomised Controlled Trial

Conditions
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Critical Illness

Intervention / Treatment
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* Dietary Supplement: TARGET protocol EN 1.5 kcal/mL
* Dietary Supplement: TARGET protocol EN 1.0 kcal/mL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Intubated and receiving mechanical ventilation About to commence enteral nutrition or enteral nutrition commenced within the previous12 hours Expected to be receiving enteral nutrition in ICU until at least the day after tomorrow Exclusion Criteria: Any Enteral Nutrition (EN) or Parenteral Nutrition (PN) received for >12 hours in this ICU admission Treating clinician considers the EN goal rate (i.e.1ml/kg of ideal body weight per hour) to be clinically contraindicated e.g. requirement for fluid restriction Requirement for specific nutritional therapy as determined by the treating doctor or dietitian i.e. TARGET protocol EN not considered to be in the best interest of the patient Death is deemed to be imminent or inevitable during this admission and either the attending physician, patient or substitute decision maker is not committed to active treatment The patient has an underlying disease that makes survival to 90 days unlikely ≥ 15% burns Previously enrolled in this study

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TARGET protocol EN 1.5 kcal/mL<br>Enteral (EN) feed 1.5 kcal/mL. The goal rate for administration of TARGET protocol EN is 1ml/kg/hr. To calculate the goal rate, weight is based on ideal body weight. | Dietary Supplement: TARGET protocol EN 1.5 kcal/mL<br>* Enteral feed 1.5 kcal/mL<br>|
| Active Comparator: TARGET protocol EN 1.0 kcal/mL<br>Enteral feed 1.0 kcal/mL The goal rate for administration of TARGET protocol EN is 1ml/kg/hr. To calculate the goal rate, weight is based on ideal body weight. | Dietary Supplement: TARGET protocol EN 1.0 kcal/mL<br>* Enteral feed 1.0 kcal/mL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause mortality | Mortality status | Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Mortality status | At hospital discharge an average of 28 days | 
| Mortality | Mortality status | Day 28 | 
| Time from randomisation until death | Mortality status | Day 180 | 
| Number of days alive and not in ICU | Mortality status | Day 28 | 
| Number of days alive and not in hospital | Mortality status | Day 28 | 
| Ventilator free days | Organ support status | Day 28 | 
| Proportion of patients receiving vasopressor support | Organ support proportion | Day 28 | 
| Vasopressor free days | Organ support status | Day 28 | 
| Proportion of patients receiving any renal replacement therapy | Organ support proportion | Day 28 | 
| Renal replacement therapy free days | Organ support status | Day 28 | 
| Proportion of patients with positive blood cultures | Blood stream infection proportion | Day 28 | 
| Proportion of patients requiring intravenous antimicrobials | Patients requiring intravenous antimicrobials | Day 28 | 
| Mortality | Mortality status | Day 180 | 
| Quality of life assessment | European Quality of Life 5 Dimensions | Day 180 | 
| Functional outcomes for patients under 65 years in the work force | Questions from the Australian Labour Force Survey | Day 180 | 
| Functional outcomes for patients under 65 years and not in the work force and patients 65 years and over living dependently | World Health Organization Disability Assessment Schedule 2.0 | Day 180 | 
| Functional outcomes for patients 65 years and over living independently | Adelaide Activities Profile | Day 180 | 
| Cause-specific mortality | Mortality status | Day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Enteral nutrition, randomised control trial, Critical care, Outcome