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Foundational Trials

PRECISe

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Publication

  • Title: Effect of high versus standard protein provision on functional recovery in people with critical illness (PRECISe): an investigator-initiated, double-blinded, multicentre, parallel-group, randomised controlled trial in Belgium and the Netherlands
  • Acronym: PRECISe
  • Year: 2024
  • Journal published in: The Lancet
  • Citation: Bels JLM, Thiessen S, van Gassel RJJ, Beishuizen A, De Bie Dekker A, Fraipont V, et al. Effect of high versus standard protein provision on functional recovery in people with critical illness (PRECISe): an investigator-initiated, double-blinded, multicentre, parallel-group, randomised controlled trial in Belgium and the Netherlands. Lancet. 2024 Aug 17;404:659-669.

Context & Rationale

  • Background
    • Critical illness is characterised by early catabolism, rapid loss of lean body mass, and ICU-acquired weakness—key contributors to long-term disability and reduced health-related quality of life (HRQoL).
    • Protein dosing is a modifiable ICU therapy, but recommended targets vary and certainty is limited (e.g., ~1.3 g/kg/day in ESPEN; 1.2–2.0 g/kg/day in ASPEN). 12
    • Randomised trials of higher protein delivery have been heterogeneous (timing, achieved separation, and energy co-delivery), and a large pragmatic registry-based RCT (EFFORT Protein) did not demonstrate benefit on time-to-discharge alive. 3
    • Contemporary meta-analyses highlight ongoing uncertainty about benefit on patient-important outcomes and raise concerns about harm in specific subgroups (e.g., acute kidney injury), while emphasising between-trial heterogeneity. 4
    • Many prior interventions increased protein by increasing calories, confounding causal attribution; isolating protein dose requires isocaloric (energy-matched) strategies.
  • Research Question/Hypothesis
    • In invasively ventilated adults expected to require ≥3 days of mechanical ventilation, does a higher protein target (2.0 g/kg/day) delivered via isocaloric enteral feeds improve functional recovery (HRQoL) over 6 months versus standard protein delivery (1.3 g/kg/day)?
    • Hypothesis: higher protein would improve functional recovery without increasing clinically important harms.
  • Why This Matters
    • Protein targets are widely implemented in ICU nutrition protocols; small relative changes may affect large patient populations.
    • PRECISe used isocaloric feeds and double blinding to test protein dose as the isolated exposure—addressing a key limitation of earlier nutrition trials.
    • By prioritising survivorship outcomes (HRQoL and physical function) rather than mortality alone, the trial aligns with modern critical care priorities.

Design & Methods

  • Research Question: Among invasively ventilated ICU adults, does higher-protein isocaloric enteral feeding (target 2.0 g/kg/day) versus standard-protein isocaloric enteral feeding (target 1.3 g/kg/day) improve functional recovery (EQ-5D-5L health utility score over 180 days)?
  • Study Type: Investigator-initiated, multicentre, parallel-group, randomised (1:1), double-blinded controlled trial in adult ICUs in Belgium and the Netherlands; protocol published a priori. 5
  • Population:
    • Inclusion
    • Adult ICU patients receiving invasive mechanical ventilation within 24 h of ICU admission.
    • Expected duration of invasive mechanical ventilation ≥3 days.
    • Enteral nutrition initiated within 48 h of ICU admission.
    • Key exclusions
    • Contraindication to enteral nutrition.
    • Moribund or decision to withhold life-sustaining treatment.
    • Body-mass index <18 kg/m².
    • Transferred from a non-participating ICU after >24 h.
    • Kidney failure with a “no-dialysis” code.
    • Hepatic encephalopathy (West Haven grade 3–4).
  • Intervention:
    • Isocaloric high-protein enteral feed (1.3 kcal/mL; 0.10 g protein/mL; Nutrison Protein Intense).
    • Energy target 25 kcal/kg/day, based on admission actual bodyweight (BMI >27 adjusted to weight equivalent to BMI 27); feeds started at 25% of target and increased by 25% per day to reach 100% by day 4.
    • Protein exposure intended to approximate 2.0 g/kg/day at full energy target (with identical caloric density to control).
    • Study feeds continued until ICU discharge, cessation of enteral nutrition, or day 90 (whichever occurred first).
    • Supplemental parenteral nutrition permitted from day 8 at clinician discretion.
  • Comparison:
    • Isocaloric standard-protein enteral feed (1.3 kcal/mL; 0.06 g protein/mL; Nutrison Protein Plus).
    • Identical energy targets, ramp-up strategy, duration rules, and allowance for supplemental parenteral nutrition from day 8.
  • Blinding: Double-blinded (participants/proxies, clinicians, investigators, outcome assessors, and analysts); feeds were labelled and indistinguishable in caloric density, with group assignment revealed only after database lock and analysis.
  • Statistics: Initial sample size 824 to detect a standardised effect size of 0.2 in EQ-5D-5L health utility score (≈0.06 absolute difference assuming SD 0.3) with 80% power at two-sided α=0.05, allowing 5% loss to follow-up; increased to 935 after interim sample size re-estimation due to higher-than-anticipated mortality and SD inflation; primary analyses were intention-to-treat (mixed-effects modelling for repeated HRQoL measures and time-to-event models for survival/discharge outcomes).
  • Follow-Up Period: 180 days (questionnaires and functional assessments at 30, 90, and 180 days where feasible).

Key Results

This trial was not stopped early. 935 patients were randomised (standard protein n=465; high protein n=470) with outcomes assessed to 180 days.

Outcome High protein Standard protein Effect p value / 95% CI Notes
Primary: EQ-5D-5L health utility score (HUS) over 180 days (death assigned HUS=0) Day 30: 0.29 (0.32)
Day 90: 0.34 (0.38)
Day 180: 0.36 (0.40) 		Day 30: 0.33 (0.33)
Day 90: 0.38 (0.38)
Day 180: 0.39 (0.39) 		Mean difference -0.05 95% CI -0.10 to -0.01; P=0.031 Analysed n=419 (high) vs 430 (standard) with ≥1 follow-up measure; baseline HUS collected in 391 vs 394.
All-cause mortality to 180 days 0.42 (SE 0.02) 0.38 (SE 0.02) HR 1.14 95% CI 0.92 to 1.40; P=0.22 Mortality probability from Kaplan–Meier curves; hazard ratio from time-to-event modelling.
Time-to-discharge alive (to 180 days) Not reported Not reported HR 0.91 95% CI 0.80 to 1.04; P=0.17 Post-hoc generalised Wilcoxon test P=0.043 (signal towards longer time-to-discharge alive in high protein).
Gastrointestinal intolerance or symptoms 43/469 (9%) 26/465 (6%) OR 1.76 95% CI 1.06 to 2.92; P=0.030 Symptoms included vomiting, ischaemia, diarrhoea, abdominal distension, gastric paresis, or bleeding.
6-minute walking distance (% predicted) Day 30: 61.6 (24.2)
Day 90: 73.9 (25.8)
Day 180: 81.8 (23.4) 		Day 30: 60.6 (23.9)
Day 90: 68.0 (28.3)
Day 180: 72.6 (24.9) 		Mean difference 5.55 95% CI 0.04 to 11.07; P=0.048 Secondary outcome (n=201 high vs 221 standard); no multiplicity adjustment across multiple secondary endpoints.
Serious adverse event: pneumatosis intestinalis 1/470 (<1%) 0/465 (<1%) Not reported Not reported Rare event; other adverse event rates (infection, VAP, AKI) were similar between groups.
  • Protein separation was achieved with similar caloric density: median protein intake 1.87 g/kg/day (IQR 0.96–2.00) in high protein vs 1.19 g/kg/day (0.63–1.26) in standard protein; median study-nutrition duration 10 days (IQR 5–21) vs 9 days (4–19).
  • High protein was associated with worse HRQoL (primary endpoint) and a signal towards longer time-to-discharge alive, without a statistically significant difference in mortality.
  • Exploratory subgroups (appendix): larger negative primary outcome effect in females (mean difference -0.10; 95% CI -0.17 to -0.03; P=0.0072) and medical admissions (mean difference -0.07; 95% CI -0.13 to -0.02; P=0.0095); mortality hazard ratio in medical admissions 1.34; 95% CI 1.04 to 1.71; P=0.021 (interaction P=0.038). 6

Internal Validity

  • Randomisation and allocation concealment
    • Web-based randomisation (1:1), stratified by centre, with variable block sizes (8 and 12).
    • Allocation concealment supported by identical caloric density feeds and blinded labelling.
  • Drop-out, exclusions, and missingness
    • Study nutrition received: 461/470 (98.1%) high protein vs 463/465 (99.6%) standard protein.
    • Primary outcome missingness: EQ-5D-5L HUS analysed in 419/470 (89.1%) high protein vs 430/465 (92.5%) standard protein; lost to follow-up for the primary outcome 51 vs 35.
    • Follow-up-dependent secondary outcomes (physical tests) were available in smaller subsets (e.g., 6-min walk n=201 vs 221), increasing imprecision and susceptibility to informative missingness.
  • Performance and detection bias
    • Double blinding reduces co-intervention and ascertainment bias for subjective outcomes (HRQoL, symptom reporting).
    • However, higher gastrointestinal intolerance in the intervention arm could drive downstream management differences (e.g., interruptions, prokinetics), potentially mediating outcomes.
  • Protocol adherence and exposure separation
    • Median protein intake: 1.87 (0.96–2.00) g/kg/day vs 1.19 (0.63–1.26) g/kg/day (high vs standard), indicating clear exposure separation.
    • Energy targets were protocolised and feeds were isocaloric by design; supplemental parenteral nutrition was permitted from day 8 (use by group not reported in the main manuscript).
    • Protocol deviations were reported (48 high protein vs 36 standard protein), but ITT analysis mitigates bias from such deviations.
  • Baseline comparability
    • Groups were broadly similar in demographics and severity (median age 62–63 years; median APACHE II 21–22; median SOFA 9–10), suggesting adequate randomisation.
    • There were modest imbalances (e.g., more females and more surgical admissions in the high-protein arm), relevant given exploratory subgroup signals.
  • Timing and dose
    • Enteral nutrition was initiated within 48 h with stepwise escalation to full energy/protein targets by day 4.
    • High-protein dosing was delivered in the early acute phase; this timing is mechanistically contentious (potential interaction with autophagy and urea burden) and may not represent the optimal window for aggressive protein provision.
  • Outcome assessment and statistical rigour
    • Primary outcome used a validated HRQoL instrument (EQ-5D-5L); assigning death a HUS of 0 integrates mortality into the HRQoL estimand but can amplify sensitivity to differential mortality/missingness patterns.
    • Primary analysis was prespecified, intention-to-treat, and appropriately modelled repeated measures with baseline adjustment; sample size re-estimation was performed without stopping early.
    • Multiple secondary endpoints were tested without multiplicity adjustment, increasing the likelihood of chance findings (e.g., the borderline 6-min walk signal).

Conclusion on Internal Validity: Overall, internal validity is moderate-to-strong given concealed randomisation, rigorous blinding, and clear protein separation, but is tempered by differential loss to follow-up for HRQoL and the multiplicity/availability limitations of secondary functional outcomes.

External Validity

  • Population representativeness
    • Participants were typical of higher-acuity ICU practice: invasively ventilated adults expected to require prolonged ventilation and enteral feeding early in ICU admission.
    • Important exclusions (underweight, severe hepatic encephalopathy, enteral contraindications, and “no-dialysis” kidney failure codes) limit applicability to these subgroups.
  • Intervention feasibility and health-system transferability
    • The intervention is implementable where enteral formula composition can be adjusted independently of calories; however, replicability depends on local formularies and dietetic infrastructure.
    • Findings should translate best to similar high-resource ICUs with protocolised feeding and early enteral nutrition; extrapolation to resource-limited settings or markedly different case-mix should be cautious.

Conclusion on External Validity: Generalisability is moderate for adult, mechanically ventilated ICU populations managed with early enteral nutrition in high-resource settings, but is limited for excluded nutritional extremes and specific hepatic/renal contraindication groups.

Strengths & Limitations

  • Strengths:
    • Large, investigator-initiated multicentre RCT with concealed allocation and double blinding.
    • Isocaloric feed design provides unusually strong isolation of protein dose from energy delivery.
    • Patient-centred primary outcome with 6-month follow-up, alongside multiple functional and psychological secondary outcomes.
    • Protocol published before trial completion, supporting transparency in outcome selection and analysis planning. 5
  • Limitations:
    • Non-trivial differential missingness for the primary HRQoL endpoint (lost to follow-up 51 vs 35), with potential for informative attrition.
    • Achieved protein in the high-protein arm (median 1.87 g/kg/day) remained below the nominal target of 2.0 g/kg/day; conversely, standard-protein delivery was below 1.3 g/kg/day (median 1.19 g/kg/day).
    • Secondary outcomes were measured in subsets and multiple comparisons were not multiplicity-adjusted, increasing risk of chance findings.
    • Exploratory subgroup effects (sex, admission type) risk false discovery and require prospective confirmation. 6

Interpretation & Why It Matters

  • Clinical practice
    • Routine escalation to very high early protein targets (~2.0 g/kg/day) in mechanically ventilated ICU patients is not supported by PRECISe and may worsen patient-centred recovery.
    • Clinicians should prioritise achieving adequate (rather than maximal) protein delivery, monitor for gastrointestinal intolerance, and individualise dosing (e.g., by phase of illness and tolerance).
  • Mechanistic implications
    • The direction of effect (worse HRQoL; longer time-to-discharge alive) is consistent with concerns that aggressive early protein may be maladaptive in the acute catabolic phase (e.g., urea burden, metabolic stress, interference with cellular repair pathways).
  • Research implications
    • Future trials should focus on timing (acute vs recovery phase), patient selection (including sex and admission phenotype), and mechanistic endpoints that connect protein exposure to functional recovery.

Controversies & Other Evidence