Synopsis: In this project, we aim to combine the International Nutrition Survey (INS) with the power of randomization to conduct a registry-based randomized clinical trial (RRCT). The specific purpose of the current proposal is to provide the rationale for a large clinical trial of 2 different protein doses that demonstrate the value of extra protein supplementation in critically ill, nutritionally high-risk patients using the INS as a type of RRCT.
Overall Hypothesis: Compared to a control group reflective of usual care prescribing practices, the administration of a higher dose protein/amino acids to nutritionally high-risk critically ill patients will be associated with improved survival and a quicker rate of recovery.
Study Design: A multicenter, pragmatic, volunteer-driven, registry-based, randomized, clinical trial.
Setting: ICUs from around the world will voluntarily participate and be screened for suitability. Participants must be knowledgeable about critical care nutrition, have Good Clinical Practice (or similar) training, and be committed to enrolling a minimum of 30 eligible patients in 2-3 years.
Study population: We plan to enroll 4000 critically ill mechanically ventilated adult patients (>18 years old) expected to remain mechanically ventilated for an additional 48 hours from screening and have one or more of the following risk factors that make them at high nutritional risk:
- Low (<25) or High BMI (>35)
- Moderate to severe malnutrition (as defined by local assessments). We will document the means by which sites are making this determination and capture the elements of the assessment (history of weight loss, history of reduced oral intake, etc.).
- Frailty (Clinical Frailty Scale 5 or more from proxy)
- Sarcopenia- (SARC-F score of 4 or more from proxy)
- From point of screening, projected duration of mechanical ventilation >4 days
Additional exclusion criteria and the reason for them are outlined in the table below.
|Table 1. Exclusion Criteria|
|Exclusion Criteria||Rationale for Exclusion|
|1. >96 continuous hours of mechanical ventilation before enrollment||Intervention most effective delivered early|
|2. Expected death or withdrawal of life-sustaining treatments within 7 days from enrollment||Patients unlikely to receive benefit|
|3. Pregnant||Unknown effects on fetus|
|4. The responsible clinician feels that the patient either needs low or high protein||Uncertainty doesn’t exist; patient safety issues|
|5. Requires parenteral nutrition only and site does not have products to reach the high protein dose group.|
Study Intervention: Eligible and enrolled patients will be randomized to one of 2 groups. High Dose group: Patients will be prescribed ≥2.2 g/kg/day of protein using dry pre-ICU actual body weight. Usual Care group: Patients will be prescribed ≤1.2 g/kg/day of protein using dry pre-ICU actual body weight. In both groups, targets will be achieved through any combination of enteral nutrition (high protein content if available), protein supplements, and parenteral nutrition or amino acids only (as clinically available). For patients with BMI >30, ideal body weight based on a BMI of 25 will be used. Although this trial is not about caloric dose, we want to encourage participating clinicians to be conservative in meeting energy targets and avoid overfeeding. We will endorse the guidelines for energy targets set forth by ASPEN/SCCM, especially as it pertains to the obese patient. The only difference between the 2 groups is the protein targets that are set. Similar efforts and products should be used in both groups to achieve at least 80% of these targets doses of protein while not exceeding 110% of caloric requirements.
Outcomes: Primary: 60-day mortality. Secondary: Time to discharge alive from hospital (time to event analysis), and ICU and hospital outcomes (mortality, length of stay and duration of mechanical ventilation). In this pragmatic trial, we will not measure infectious complications but our secondary endpoint, ‘time to discharge alive’ will capture the negative influence that all infections may have on both survival and length of stay.
Sample Size and Duration: 4000 patients from 100+ sites over 2-3 years of enrolment (minimum of 30 patients per site). Allowing for start-up and close out activities, total duration 5 years.
Ethics: This registry based RCT will be testing two practice standards of care. Currently, protein prescriptions for critically ill patients range from 0.5-3.8 g/kg/d. There is an insufficient evidentiary basis to establish which level of protein administration is right for which patient population. Some have argued that until one level of protein administration is proven to be beneficial, randomization is the most ethical approach that will provide the correct answer sooner compared to allowing current practice, with tremendous variability and uncertainty, to continue. We will take usual practices and create 2 groups randomizing eligible patients to a lower prescription (<1.2 g/kg/d) or to a higher prescribed protein intake (>2.2 g/kg/d). The remainder of care provided to eligible patient will be at the discretion of ICU providers. For this unfunded study using volunteer clinicians to conduct the research, to enhance the feasibility of the trial, we aim to apply for a waiver of informed consent from ethics boards at participating sites.
Funding: There is no specific funding associated with this trial. There will be no transfer of funds between sites, the coordinating center (CERU) or ASPEN. At CERU, Dr. Heyland will use existing resources to support the data collection/management infrastructure and analysis. Sites are expected to volunteer their time and use local resources to conduct the study. As with past INS projects, sites that enrol 30 or more patients in the RRCT will also receive a bench-marked report highlighting their nutrition performance compared to the performance in other sites in the database.
Significance: This study has both the potential to answer a high-priority clinical question but also transform the way we do research in clinical nutrition. It further represents a unique collaboration between ASPEN, its global partners, and the Clinical Evaluation Research Unit, a methodological support center based in Kingston, Ontario, Canada managed by Dr. Daren Heyland. Without the need for additional funding, CERU can coordinate this trial and by relying on motivated health care professionals around the world to contribute data, like they do in the INS, we have the potential to conduct a large scale pragmatic trial. If successful, this type of collaboration sets an important precedent for how our community may approach additional research questions related to clinical nutrition.
Insights from a recruiting site: View Article
EFFORT is open for registration! Interested ICUs should proceed to obtain local site and ethics approvals. Instructions and other support materials for these activities can be downloaded by clicking on the "Get Started" button below.
Dr. Daren Heyland
Dr. Charlene Compher
American Society for Parenteral and Enteral Nutrition (ASPEN) Representatives
|Dr. Charlene Compher|
|Dr. Todd Rice|
|Dr. Jayshil Patel|
|Jennifer Korol||Alfonso Ortiz|
|Office: +1-613-549-6666 ext. 4146|