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|
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.