2023 – March E-Journal Club

We are still working on getting ourselves back to a regular schedule of Journal Clubs after staffing changes, hospital expansions and re-organizations. Our article this month is likely to be one of the more controversial articles published in some time, but like most studies, there are important details to consider before accepting the abstract conclusions at face-value or putting the results into practice.

July Citation:
Heyland DK, Patel J, Compher C, et al. The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicentre, pragmatic, registry-based randomised trial. Lancet. 2023 Feb 18;401(10376):568-576.

This study was international, pragmatic, registry-based, single-blinded, randomized study which compared prescribing high-dose protein (≥2·2 g/kg per day) with usual dose protein (≤1·2 g/kg per day) started within 96 hours of ICU admission, in “nutritionally high risk adults” who required mechanical ventilation. The protein targets were based on pre-ICU actual dry weight, except for those with a BMI > 30 kg/m2 where an ideal body weight based on a BMI of 25 kg/m2 was used. Calorie provision was not controlled in either group, but clinicians were encouraged to avoid overfeeding “using published guidelines”.

Protein targets were allowed to be achieved via any combination of enteral or parenteral nutrition, intravenous amino acids, or enteral protein supplements in both groups. The interventions were administered for up to 28 days, until death, or until transition to full and permanent oral feeding. The primary outcome studied was time-to-discharge alive from hospital up to 60 days after ICU admission, and the secondary outcome was 60-day morality.

Inclusion and Exclusion Criteria:
Inclusion criteria:
Adult patients within 96 h of ICU admission who were expected to remain mechanically ventilated for at least 48 h from screening with one or more of the following nutritional risk factors:
1. Low (≤25 kg/m²) or high (≥35 kg/m²) BMI
2. Moderate to severe malnutrition, as defined by local assessment
3. Frailty, as defined by a Clinical Frailty Scale
4. Sarcopenia, as defined by a SARC-F score
5. Projected duration of mechanical ventilation of more than 4 days

Exclusion criteria:
Patients who had received > 96 continuous hours of mechanical ventilation before screening, those expected to die or undergo withdrawal of life-sustaining treatments within 7 days from screening, pregnant women, patients for whom the responsible clinician felt that the patient either needed low or high protein, and patients who required parenteral nutrition only and the site did not have products required to reach the high protein dose targets.

Major Results:
The researchers initially planned to enroll 4000 patients for adequate power (80% at 0.05) to detect a 4% absolute risk reduction in 60-day mortality. Due to limited enrolment during the COVID-19 pandemic, the sample size was decreased to 1200 patients and the primary outcome was changed to time to discharge alive from the hospital, with a secondary outcome of 60-day mortality. Ultimately, 1329 patients were randomized, with 28 patients excluded from the analysis due to early death, discharge or withdrawal of consent before receiving the assigned intervention. Analysis was completed on a modified intention-to-treat group of 1301 patients (645 high-dose protein and 656 usual dose protein). On study day 10 there were 463 patients remaining on the study protocol, on study day 11 there were 242 patients on protocol, and by study day 12 there were only 58 patients that remained on the study protocol.

Hospital admission category was “medical” in approximately 82% of the patients, with 13% of the participants having a surgical emergency. The most common cause of ICU diagnosis was “respiratory” (42%), followed by “neurological” (15%) and “sepsis” (13%) and just under 10% as “trauma”.

Patients in the high-dose protein group actually received a mean of 1.6 g/kg per day protein compared with 0.9 g/kg per day in the usual dose group. Both groups received a similar energy intake (14·7 kcal/kg per day vs 13·2 kcal/kg per day).

The cumulative incidence of alive hospital discharge at 60 days was 46.1% in the high-dose protein group compared with 50.2% in the usual dose protein group (HR 0.91, 95% CI 0.77–1.07; p=0.27). The 60-day mortality rate was 34.6% (222 of 642) in the high-dose protein group compared with 32.1% (208 of 648) in the usual dose protein group (RR 1.08, 95% CI 0.92–1.26). Hospital mortality, duration of mechanical ventilation, ICU stay, and hospital stay were similar between groups

Subgroup analysis suggested an interaction between protein dose and patients with acute kidney injury and high SOFA score (≥9) upon admission on both time-to-discharge-alive and 60-day mortality, favoring the usual protein dose.

During the study period, patients who received high-dose protein as compared with usual dose protein had a higher urea concentration by 2.1 mmol/L (5.88 mg/dL) (14.0 mmol/L vs 11.9 mmol/L). There were no clinically important differences in other metabolic parameters between groups

Author’s Conclusions:
“…Delivery of higher doses of protein to mechanically ventilated critically ill patients did not improve the time-to-discharge-alive from hospital and might have worsened outcomes for patients with acute kidney injury and high organ failure scores.”

This study is the largest controlled study of protein dose in critically ill patients to date. Unfortunately, due to the COVID pandemic, the investigators were unable to randomize the full number of subjects that they determined would be needed to fully evaluate the effect of protein dose on mortality. This study also highlights what other studies have demonstrated, that actual protein delivery is much less than the initial protein goal.

Our group noted that this study was conducted on patients who were mechanically ventilated patients who were expected to be at increased nutrition risk, but in so doing, excluded many ICU patients who were assessed, many of whom may require nutrition support. We also took note of the fact that any patient “whom the responsible clinician felt that the patient needed high protein” may not have been included into the study may have resulted in a study population that does not reflect the typical ICU nutrition support patient. This was primarily a study of medical and neurological ICU patients with a very small number of surgical and trauma patients represented. Despite the above mentioned factors that limit who the results of this study may apply, there will undoubtedly be a temptation for some to suggest that these results apply to all mechanically ventilated critically ill patients.

One potentially important aspect of this study that has thus far received very limited attention is the study protocol used for providing nutrition and the means used to provide additional protein in the study. Just under 1/3 of the study sites (32.9%) used modular protein supplements, and over ½ of the sites (56.1%) used volume-based feeding protocols. Several studies of volume-based feeding protocols have revealed negative consequences1-4, and the only study of volume-based feeding that met full calorie goals had to be stopped early due to increased mortality in the volume-based feeding group1. It is possible that any potential negative effects in this study that appeared to result from providing increased protein, may actually represent a negative effect of providing increased protein via volume-based feeding.

There were also very few patients in the study protocol after day 10, so this study also likely may not apply to patients who require ICU care and nutrition support for an extended period of time. Hospital acquired skin breakdown is a major liability and resource-consuming factor for healthcare facilities. Any recommendation to begin decreasing the standard protein dosing for critically ill patients before investigating the effect on skin breakdown seems very premature. There was a notable lack of any measure of muscle changes between the groups, measures of functional status in survivors, or any recording of potential differences in rehabilitation requirements among the survivors. It is notoriously difficult to demonstrate survival advantages of individual therapies in the ICU, and there may well be real nutritional advantages to additional protein not captured by this short term study.

The “associations” of increased protein and worse outcomes in the subgroups of AKI (312 patients) and SOFA score > 9 (672 patients) were done with a much smaller number of patients, which increases the likelihood of an association by chance alone (especially when a large number of subgroups were studied). It may also represent the possibility that more severely ill patients receiving increased protein with volume-based feeding may have been harmed. We did note that the statistically significant increase in blood urea in group receiving increased protein was less than 6 mg/dL average difference, which would be clinically unimportant. We noted that the investigators did not report if there were any differences in the number of patients who required renal replacement, or time on renal replacement between the groups.

Our Take Home Message(s):
1. There does not appear to be a survival benefit of increased protein dose in medical or neurological ICU patients at increased nutritional risk, who the clinician did not believe needed extra protein, with a length of ICU stay < 1 week, who receive volume-based feeding.
2. There would need to be a larger studies of more severely critically ill patients and those with AKI to determine if there are increased risks of providing increased protein while critically ill.
3. There is a need for additional study regarding the influence of protein dose on risk of skin breakdown, wound healing, muscle loss, functional status and rehabilitation needs before recommending decreasing protein goals for critically ill patients.

1. Braunschweig CA, Sheean PM, Peterson SJ, Gomez Perez S, et al. Intensive nutrition in acute lung injury: a clinical trial (INTACT). JPEN J Parenter Enteral Nutr. 2015 Jan;39(1):13-20

2. Lee JC, Williams GW, Kozar RA, et al., Multitargeted Feeding Strategies Improve Nutrition Outcome and Are Associated With Reduced Pneumonia in a Level 1 Trauma Intensive Care Unit. Journal of Parenteral and Enteral Nutrition. 2018 Mar;42(3):529-537.

3. Compher C, Chittams J, Sammarco T, et al. Greater Protein and Energy Intake May Be Associated With Improved Mortality in Higher Risk Critically Ill Patients: A Multicenter, Multinational Observational Study. Crit Care Med. 2017;45(2):156-163.

4. Taylor B, Brody, Denmark R, Southard R, Byham-Gray L. Improving Enteral Delivery Through the Adoption of the “Feed Early Enteral Diet Adequately for Maximum Effect (FEED ME)” Protocol in a Surgical Trauma ICU: A Quality Improvement Review. Nutr Clin Pract. 2014;29(5):639-648.

Joe Krenitsky MS, RDN

PS – Please feel free to forward on to friends and colleagues.