Early Parenteral Nutrition in Critically Ill Patients With Short-term Relative Contraindications to Early Enteral Nutrition

Doig. JAMA. 2013;309(20):2130-2138. doi:10.1001/jama.2013.5124

Clinical Question

• In critically ill patients with relative contraindications to early enteral nutrition (EN), does providing early parenteral nutrition (PN), improve mortality?

Design

• Randomised controlled trial
• Block randomisation with variable block sizes
• Stratified by site, age and BMI
• Single-blind
• Intention to treat analysis
• Power calculation: with baseline mortality of 29.7%, a sample size of 1470 patients required to detect a 7.7% risk difference between groups, with 90% power

Setting

• 31 community and tertiary hospitals in Australasia
• October 2006 – June 2011

Population

• Inclusion criteria
  • Adult patients admitted to ICU
  • Considered ineligible for EN by the attending clinician due to a short-term relative contraindication
  • Expected to remain in ICU for >2 days
• Exclusion criteria
  • Not expected to survive 24 hours, or receiving palliative care
  • Licensing contraindication to PN e.g. pregnancy, allergy
• 1372 patients randomised
  • 46% Emergency Surgery
  • 20% Elective Surgery
  • Mean APACHE II score 21

Intervention

• Early PN (Kabiven G19%, Fresenius Kabi Australia)
  • ‘Early’ defined as within 24 hours of ICU admission
  • Mean time from ICU admission to randomisation was 13.8 hours
  • Mean time from randomisation to PN was 44 minutes
• Energy target
  • set by Harris-Benedict equation
  • capped at 35kcal/kg/day
  • If BMI 30+ then fed to ideal body weight (BMI = 21)

Control

• Standard care
  • Not defined by protocol
    • 278 (40.8%) never received EN or PN during their 3.72 (95% C.I. 2.65-5.2) ICU stay
    • 199 (29.2%) started EN after 2 days (95% C.I. 1.43-2.78), of whom 48 eventually received supplemental PN
    • 186 (27.3%) started PN after 2 days (95% C.I. 1.45-2.7)
    • 19 (2.8%) started both EN + PN at the same time after 5.58 days (95% C,I, 3.9-7.96)
    • 13 (1.9%) patients received EN, PN, or oral feed within 24 hours of ICU admission
  • Overall remained unfed for mean 2.8 days  (95% C.I. 2.3-3.4)
  • Of note in Australasia it is NOT accepted practice to infuse isolated glucose solutions to provide caloric intake prior to initiating feeding

Outcome

• Primary Outcome
  • 60 day mortality – no significant difference
• Secondary outcomes
  • Quality of life and physical function
    •  RAND-36 General Health Status –  significant improvement in early PN group, however, magnitude of difference did not exceed one-half the standard deviation, which was defined a priori as clinically meaningful
    • ECOG performance status –  no significant difference
    • RAND 36 physical function – no significant difference
• Tertiary Outcomes
  • Length of mechanical ventilation – significantly shorter in early PN group
  • ICU stay – no significant difference
  • Hospital stay – no significant difference
  • No differences in any types of infection
• Subgroup analysis
  • No significant differences in 60 day mortality based on BMI, age or chronic insulin treated DM

Authors’ Conclusions

• The use of early PN did not result in significant differences in 60 day mortality or infection rates

Strengths

• Randomised
• Intention to treat analysis
• Multi-centre
• Early enrollement of patients (mean time from ICU admission to enrolment 13.8hrs)
• Patients treated with early PN received >90% of target feed
• Pragmatic study – comparing early parenteral nutrition with standard treatment. However, the downside of this is that standard treatment varies and this trial therefore compares it against all of these.
• Minimal exclusion criteria leading to high external validity. The downside of this is that in the control group 41% discharged from ICU within 3.72 days (95% CI, 2.65-5.20) without feeding. In these patients it may have been optimistic to hope to find a large mortality benefit. It may be that patients with more prolonged critical illness would be more likely to benefit from early PN.

Weaknesses

• Non-blinding of study intervention and outcome assessment
• In the standard care group nearly 40% of patients received parenteral nutrition, the majority within a few days. Therefore it is not surprising that there was no difference in infectious complications found