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Critical Care Nutrition at the Clinical Evaluation Research Unit (CERU)

is dedicated to improving nutrition therapies in the critically ill through knowledge generation, synthesis, and translation. We engage in a broad range of research activities and promote a culture of best practices in critical care nutrition. Ultimately, this will result in improved clinical outcomes for critically ill patients and increased efficiencies to our health care systems.

The Effect of High versus Usual Protein Dosing in Critically Ill Patients:

A Multicenter Registry-based Randomized Trial

The EFFORT Trial

Principal Investigator

Dr. Daren Heyland
Queen’s University
Kingston General Hospital
Clinical Evaluation Research Unit
Watkins 5C, Room 4-5-308-0
76 Stuart Street
Kingston, ON   K7L 2V7
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.


Synopsis

In this project, we aim 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 usual care, 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 3000 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:

  1. Low (<25) and High BMI (>35)
  2. Traditional measures of malnutrition (Yes to one of questions below obtained by proxy or charts)
    1. Have you recently lost weight without trying?
    2. Have you been eating poorly because of reduced appetite?
    3. Hospital stay before ICU >3 days
  3. Frailty (Clinical Frailty Scale 5 or more from proxy)
  4. Sarcopenia- (SARC-F score of 4 or more from proxy)
  5. Projected duration of mechanical ventilation >4 days

We considered using the NUTRIC score as an entry criteria but it is difficult to use ‘real –time’ and would be a barrier to enrollment. Hence, we will collect the data to calculate a NUTRIC score retrospectively and conduct an a priori subgroup analysis on high vs. low NUTRIC. We considered whether to include or exclude various subgroups of patients who might have higher protein requirements (burns, trauma, for example) or lower requirements (liver disease, older patients, for example) but since the evidence for dosing these subpopulations is uncertain and provide beliefs on what is best are variable, we reasoned to no exclude them but to allow participating clinicians  to exclude any patient they feel would   be possible harmed if they were randomized to a high (or lower) dose of protein (in other words, where clinical equipoise does not exist). Additional exclusion criteria and the reason for them are outlined in the Table below.

Table 1.  Inclusion and Exclusion Criteria for Study Entry

Inclusion Criteria

Exclusion Criteria

Rationale for Exclusion

1. >18 years old 

2. Nutritionally ‘high-risk” 

3. Requiring mechanical ventilation with actual or expected total duration of mechanical ventilation >48 hours

 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. Acute or chronic renal failure requiring dialysis or expected to require dialysis in next 48 hrs

 Clinician would most likely not be comfortable randomizing to the low group.

 4.   Pregnant

 Unknown effects on fetus

 5.   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 >2.0 g/kg/day of protein using dry pre-ICU body weight. Usual Care group: Patients will be prescribed <1.2 g/kg/day of protein using dry pre-ICU 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). In both groups, ideal body weight will be used for patients with BMI >30. Moreover, 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 targets that are set. Similar efforts and products should be used to both groups to achieve at least 80% of these targets.

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 be measuring infectious complications except blood infections 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: 3000 patients from 80-100 sites over 2-3 years of enrolment (minimum of 30 patients per site). 

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 be randomizing eligible patients to usual care (<1.2 g/kg/d) or to a higher prescribed protein intake (>2.0 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 highlighted 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.

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