Enriched ICU Nutrition Strategy Spoiled in Randomized Trial

Higher protein doses did not improve critically ill patient outcomes, and may even be detrimental to patients with high organ failure and acute kidney injury, the EFFORT trial found.

In nutritionally high-risk adults undergoing mechanical ventilation, alive hospital discharge for those who received higher doses of protein reached 46.1% by 60 days after randomization,

compared with the 50.2% rate in peers receiving standard protein (HR 0.91, 95% CI 0.77-1.07), according to the randomized trial published in The Lancet.

Moreover, mortality at 60 days was 34.6% in the high-protein group and 32.1% in the control group (RR 1.08, 95% CI 0.92-1.26), reported Daren Heyland, MD, of Queen's University and Kingston

General Hospital in Ontario, and coauthors.

They noted that in critically ill patients with obesity, observational and "sparse" randomized trial data have resulted in critical care nutrition guidelines that recommend higher protein

dose.

"Despite an overall null finding, our trial results will affect practice guidelines worldwide. Our findings do not support the prevailing notion that mechanically ventilated patients who are

older, obese, more severely ill, frail, malnourished, or sarcopenic benefit from a higher protein dose. In contrast, higher protein dosing could be harmful in patients with greater severity

of illness," the group wrote.

Subgroup analysis revealed patients with high organ failure scores and acute kidney injury had particularly bad outcomes as a result of receiving higher protein dose treatment, Heyland and

colleagues found.

"They are just not able to tolerate the utilization or metabolism of the increased protein load," Heyland told MedPage Today. "In the setting of kidneys that don't work properly, toxins

accumulate and they experience harm."

Yet the optimal protein dose for an individual during critical illness remains unknown, the investigators acknowledged. "Labelled isotope studies suggest that exogenous amino acids could

stimulate an anabolic response, yet other observational studies suggest benefits with both lower and higher protein doses in critically ill patients," the group wrote.

For the EFFORT trial, Heyland's group included 1,301 patients receiving mechanical ventilation from 85 ICUs across 16 countries from 2018 to 2021. Participants were roughly split between

those randomized to higher-dose protein (an average 2.2 g/kg protein per day) and those to usual protein (1.2 g/kg protein per day).

"This is one of the most common and important clinical decisions nutrition practitioners in the ICU make every day. Yet, we have such little evidence from randomized trials to guide us and

the observational studies have conflicting findings -- some saying that more is better, others saying that usual doses (or less) are better," said Heyland. "Hence, it was considered a top

priority for our community to answer this question. The fact that so many sites engaged and we enrolled over 1,300 patients was a testament to the collaborative nature of our community and

the importance of the question."

In order to participate in the study, all patients had to have at least one risk factor such as moderate to severe malnutrition, frailty, sarcopenia, a predicted need for ventilation lasting

at least 4 days, and a body mass index (BMI) in the range of 25-35.

Protein targets were determined by using the patient's actual dry weight prior to the ICU. Enteral protein supplements, intravenous amino acids, or combinations of enteral and parenteral

supplements were used. Both assigned protein dose treatments began within 96 hours of the patient's admission to the ICU and was measured until the patient was able to transition to oral

feeding, 28 days had passed, or if the patient died.

Study authors reported that ICU and hospital stay, hospital mortality, and the length of time a patient experienced mechanical ventilation were similar between groups.

Among the trial's limitations, however, is the single-blinded design that left clinicians unblinded to treatment. Additionally, energy dose administered to the patient could not be

controlled for in the study, though overfeeding was discouraged.

Heyland's team acknowledged that the primary and secondary outcomes of EFFORT had been switched due to enrollment troubles during the COVID-19 pandemic. Investigators were unable to achieve

the originally planned sample size of 4,000 patients.

The group maintained that their findings warrant further research among important subgroups (e.g., trauma, surgical, and/or burn patients).

"In conclusion, prescribing 1.2 g/kg per day (lower end of the American Society for Parenteral and Enteral Nutrition 2022 guidelines or 1.3 g/kg per day to be consistent with the European

Society of Parenteral and Enteral Nutrition 2019 guidelines) and striving to achieve 80% of what was prescribed seems like a reasonable and safe approach for all critically ill patients,"

the authors wrote.

The results of the study also indicate that the guidelines for nutrition intervention need to change in order to meet the unique needs of patients, according to Emma Ridley, MD, of Monash

University in Melbourne, and Lee-anne Chapple, PhD, of the University of Adelaide in Australia.

"Studies have observed impaired protein metabolism early in critical illness, which could explain the signal for harm with high-dose protein delivered within 38 h of ICU admission in more

susceptible patient cohorts," the duo wrote in an accompanying editorial.

"The signal for harm in specific patient groups also suggests that a one-size-fits-all approach for nutrition interventions should be reassessed, with consideration that not all patients

will respond to an intervention in the same manner and that timing might be as important as dose," Ridley and Chapple commented.

The study received support from Nutrinovo, Stanningley Pharma, and Nutricia.

Ridley has received honoraria from Baxter Healthcare, Nestlé, Nutricia, Avanos, and Fresenius Kabi. Ridley and Chapple are chief investigators on a project grant from the National Health and

Medical Research Council of Australia.