PermiT

PermiT: Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults

Arabi. NEJM 2015; 372:2398-2408. doi:10.1056/NEJMoa1502826

Clinical Question

  • In critically ill adults, does restriction of non-protein calories (permissive underfeeding) compared to standard feeding reduce mortality at 90 days?

Design

  • Randomised, controlled trial
  • Computer-generated sealed opaque envelopes
  • Block randomisation with stratification according to medical centre
  • Non-blinded intervention but with objective end-point
  • Clinician-led management of non-nutrition elements of care
  • Powered at 80% to detect 8% absolute reduction in mortality from baseline of 25% with standard feeding if 892 patients recruited, allowing for 3% loss

Setting

  • 7 hospitals across Saudi Arabia and Canada
  • November 2009 to September 2014

Population

  • Inclusion: Enteral feeding commenced within 48 hours of ICU admission; expected to stay in ICU ≥ 72 hours; age 18–80 years
  • Exclusion: use of total parenteral nutrition; high-dose vasopressors (e.g. noradrenaline > 0.4 µg/kg/min); palliation or condition with expected 6-month mortality ≥ 50%; post cardiac arrest; pregnancy; liver transplant; burns
  • 894 patients randomised (14% of screened patients)
    • Demographic and physiological scores were similar between groups (intervention vs control as mean ± standard deviation)
      • Age: 50.2±19.5 vs 50.9±19.4
      • BMI: 29.0±8.2 vs 29.7±8.8
      • Medical: 75% vs 75%
      • Surgical: 4.2% vs 2.7%
      • Trauma: 21% vs 22%
      • APACHE 2: 21.0±7.9 vs 21.0±8.2
      • Mechanical ventilation: 97% vs 97%

Intervention

  • Permissive underfeeding
    • Caloric goal was 40–60% of caloric requirement
    • Protein was supplemented with Beneprotein, Nestle Nutrition
    • Supplemented fluid input with enteric 0.9% saline or water
    • Average caloric intake achieved was 835±297 kcal/day (46±14% caloric goal)

Control

  • Standard feeding
    • Caloric goal was 70–100% of caloric requirement
    • Average caloric intake achieved was 1299±467 kcal/day (71±22% caloric goal)

 Treatment common to both groups

  • Caloric requirements calculated using
    • Penn State equation 2003 if BMI < 30
    • Ireton-Jones equation 1992 if BMI ≥ 30 or spontaneously breathing
  • Protein goal was 1.2–1.5g per kg body weight per day
  • Continued for 14 days or until ICU discharge, oral feeding, death or palliation
  • Glucose goal was 4.4–10 mmol/l (80–180 mg/dl)
  • Enteric multivitamins
  • Under or over feeding on one day was balanced by targeted over or underfeeding the next day, respectively
  • Caloric intake calculations included propofol, intravenous dextrose and parenteral nutrition

Outcome

  • Primary outcome: there was no statistically significant difference in 90-day mortality
    • Permissive underfeeding: 27.2%
    • Standard feeding: 28.9%
    • Absolute risk reduction = 1.67% (95% CI -4.27 to 7.59%)
    • Relative risk reduction = 0.94 (95% CI 0.76 to 1.16; P-value = 0.58)
    • Cox proportional-hazard ratio (unadjusted) = 0.91 (95% CI 0.71 to 1.17; P-value = 0.48)
  • Secondary outcome: there were no statistically significant differences favouring either group
    • Mortality in ICU
    • 28-day mortality
    • In-hospital mortality
    • 180-day mortality
    • Serial SOFA scores
  • Tertiary data:
    • There were no significant differences in electrolytes
    • There was no difference in the calories provided by parental feeding
      • Permissive underfeeding: 3±32 kcal/day
      • Standard feeding: 5±59 kcal/day
      • P-value = 0.38
    • Blood glucose was higher in standard feeding group:
      • Permissive underfeeding: 9.1±5.3 mmol/l
      • Standard feeding: 9.4±5.0
      • P-value = 0.04
    • Insulin requirement was higher in standard feeding group
      • Permissive underfeeding: 15±27 units/day
      • Standard feeding: 22±40 units/day
      • P-value = 0.02
  • Post-hoc analysis
    • Incidence of renal replacement therapy
      • Permissive underfeeding: 7.1%
      • Standard feeding: 11.4%
      • Absolute risk reduction: 4.11% (95% CI 0.21 to 8.23%)
      • Number-needed-to-treat with permissive underfeeding to prevent one renal replacement therapy = 24

Authors’ Conclusions

  • Moderate caloric feeding with maintenance of full protein requirement, compared to standard full feeding, was not associated with reduced mortality

Strengths

  • Pragmatic and well designed trial
  • Appropriate statistical plan
  • Minimal biases present
  • Multi-centre including different ethnic populations
  • Highly generalisable given spread of medical, surgical and trauma patients

Weaknesses

  • Lack of blinding and clinician-led management of non-nutritional care may have introduced bias but the impact of this is unknown
  • Primary outcome of 90-days is a long-duration compared to just 14 days of intervention, such that a direct cause-and-effect link is unlikely to be observed
    • However, no difference was seen in shorter secondary outcomes either
  • Only powered to detect 8% absolute risk reduction
    • A smaller effect may still be clinically important
    • This study may have failed to show a true but small treatment effect (false negative)
  • 86% of screened patients were not randomised, which may have an impact upon the external validity (generalisability) of the results
  • The only notable positive outcome is the reduced incidence of renal replacement therapy
    • As a post-hoc analysis, this should be cautiously interpret and possibly used as theory-generating for future trials

The Bottom Line

  • This trial has not demonstrated a moderate survival benefit from permissive underfeeding with moderate caloric intake (around 50% of target calories) and maintenance of full protein requirement (1.2-1.5g per kg per day)
  • A small survival benefit may exist but this study was not large enough to detect one
  • Permissive underfeeding with full protein requirement appears safe in critically ill patients

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