COMMENT|ONLINE FIRST
Nutrition in critical illness—research is worth the EFFORT
Emma J Ridley, Lee-anne S Chapple
Lancet Published:January 25, 2023
DOI:https://doi.org/10.1016/S0140-6736(23)00091-0
Multiple high-quality randomised controlled trials conducted over the past decade in critical care nutrition have shown no difference between interventions and routine care.1, 2, 3, 4 These findings have led to the assumption that nutrition in critical illness is an innocuous, supportive therapy only.
Due to a shortage of definitive evidence for many aspects of critical care nutrition, principles from health are often extrapolated, and protein provision is one such extrapolation. In health, a protein intake of 0·8–1·0 g/kg per day is recommended (depending on sex and age) for muscle maintenance and essential body functions. In acute illness, physiological studies have shown patients experience negative nitrogen balance and muscle loss, hence the assumption that higher protein doses could counteract these issues.5, 6 Consequently, clinical practice guidelines for critical illness recommend achieving protein doses of 1·2–2·0 g/kg per day.7, 8
In The Lancet, Heyland and colleagues9 describe the EFFORT Protein Trial, which is the largest randomised controlled trial to date investigating augmented protein in critical illness and is the first known registry-based randomised controlled trial in the area. This trial included 1301 patients in the primary modified intention-to-treat analysis from 85 intensive care units (ICUs) across 16 countries.9 The hypothesis was that high-dose protein (prescribed ≥2·2 g/kg per day) in patients who were mechanically ventilated with an indication of nutritional risk (defined according to one or more of the following nutritional risk factors: low or high BMI, malnutrition based on local assessment, frailty, sarcopenia, or predicted mechanical ventilation of more than 4 days) would reduce time to discharge alive from hospital compared with usual dose protein (prescribed ≤1·2 g/kg per day).9 The population was predominately male, mean BMI was 28 kg/m2, mean age was 57 years, and represented a significantly unwell population (around 40% on vasopressors, mean APACHE II score of 21, a Sequential Organ Failure Assessment (SOFA) of 9, and around 25% with acute kidney injury).9 Clinically relevant separation in protein dose was achieved (high-dose protein group 1·6 [SD 0·5] g/kg per day vs 0·9 [0·3] g/kg per day in the usual dose group).9 The cumulative incidence of alive hospital discharge to day 60 was 46·1% in the high-dose protein group compared with 50·2% in the usual dose protein group (Hazard Ratio 0·91, 95% CI 0·77–1·07; p=0·27), with no differences in secondary outcomes.9 Of note, a subgroup effect was observed with high-dose protein associated with harm in patients with acute kidney infection and worse organ failure (SOFA score >9) at baseline.9
There are several considerations in the interpretation of this trial. Methodologically, a registry-based trial was a bold choice, resulting in a pragmatic study reflective of real-world care, but one that likely led to several limitations including poor protocol compliance. Clinicians were advised to meet protein targets using local standards of care; however, it is known that global standard care achieves just 0·6 g protein/kg per day.10 A waiver of consent is one of the key advantages to a registry-based randomised controlled trial, facilitating rapid recruitment (even within a pandemic study); yet, in this instance, 54 (63·5%) of 85 sites required previous consent, probably affecting recruitment potential and introducing recruitment bias of participants whom clinicians believed could benefit from high-dose protein. Unfortunately, the COVID-19 pandemic and low recruitment resulted in a reduction in sample size from 4000 to 1200 and a change in the primary outcome from 60-day mortality to time to discharge alive (which was previously a secondary outcome).
Although a concept only, it is plausible that the effect of nutrition could change according to the phase of illness. In past trials predominately investigating calorie delivery of varying amounts, short-duration interventions have been provided with no signal for benefit identified; yet, in non-critically ill hospitalised patients, long-term enhanced energy and protein interventions have reduced mortality and adverse outcomes.11 Moreover, studies5, 6 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 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.
Although there were challenges, the authors should be congratulated for completing this large, pragmatic, international randomised controlled trial during a pandemic. Benefit for high-dose protein was not found but the indication for harm in some subgroups should be scrutinised. We must determine which patients are most likely to benefit from nutrition, but equally, we must understand potential harm. Future trials should consider the effect of nutrition during phase of illness (including recovery) and in specific patient subgroups.
The authors would like to declare that EJR has received honorarium from Baxter Healthcare (USA and Australia), Nestlé, and Nutricia (Australia) for work unrelated to this comment. EJR is supported by a National Health and Medical Research Council (NHMRC) Emerging Leadership Fellowship. LSC is supported by an NHMRC Early Career Fellowship and has received honorarium from Nutricia (Australia and global), and Avanos and Fresenius Kabi for work unrelated to this comment. Both EJR and LSC are chief investigators on an NHMRC project grant investigating an augmented protein intervention, which is currently recruiting (ANZCTR.org.au: ACTRN12621001484831).
