CALORIES

Published

Harvey SE, et al. "Trial of the route of early nutritional support in critically ill adults". The New England Journal of Medicine. 2014. 371(18):1673-1684.
PubMed • Full text • PDF

Clinical Question

In critically ill patients, is early parenteral nutrition administration superior to early enteral feeding with respect to all-cause mortality?

Bottom Line

Among critically ill patients, there was no difference in 30-day mortality in a pragmatic RCT of early enteral vs. early parenteral feeding.

Major Points

In the 2000s, enteral nutritional was the guideline preferred route for nutritional supplementation among critically ill patients, due in large part to the widespread belief that it is physiologically superior and spares the patient the risks that are commonly associated with parenteral nutrition. However, enteral feeding is associated with its own unique profile of adverse effects and risks, most notably mechanical complications and associated underfeeding. In 2011, the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) trial did not demonstrate a decrease in ICU mortality but did demonstrate a decrease in number of ICU days and days until discharge from ICU in patients for whom parenteral support was delayed until hospital day 8. However, other randomized controls trials have demonstrated equivocal or even improved outcomes with early parenteral support with respect to nosocomial infection rate and mortality. There was need to compare early enteral vs early parenteral feeding among ICU patients to help clarify the ideal route.

Published in 2014, the CALORIES trial randomized approximately 2,400 adults in the ICU to early enteral vs early parenteral feeding. There was no statistical difference in the primary outcome of all-cause mortality at 30 days between the groups. Most secondary outcomes were similar between the groups, with the exceptions of incidences of vomiting and hypoglycemia which both occurred more frequently in patients fed enterally. Notably, parenteral support was not associated with an increased risk of infectious complications. It is important to note that while more calories were delivered to the parenteral arm of the trial, neither group met the study's pre-specified caloric goal of 25 kcal/kg/day. The results of this study suggest that early parenteral nutrition administration may not be harmful when compared to standard enteral feeding.

Guidelines

American Society for Parenteral and Enteral Nutrition/Society of Critical Care Medicine Guidelines (2016, adapted)

• Recommend initiation of enteral support in critically ill patient within 24-48 hours.
• Recommend use of enteral over parenteral nutrition in critically ill patients who can be fed with the former.
• For critically ill patients deemed low nutrition risk who cannot be fed enterally, recommend against use of parenteral support in first week.
• For critically ill patients deemed high nutrition risk who cannot be fed enterally, recommend initiation of parenteral support as soon as feasible.

European Society for Clinical Nutrition and Metabolism Guidelines (2018, adapted):

• Recommend initiation of enteral support in all eligible critically ill patients within 48 hours.
• In all critically ill patients with contraindications to enteral feeding, recommend initiation of parenteral support within three to seven days.

Design

• Multicenter, randomized, pragmatic, controlled trial
• N=2388
  • Parenteral therapy (n=1191)
  • Enteral therapy (n=1197)
• Setting: 33 English intensive care units
• Enrollment: 2011-2014
• Analysis: Intention-to-treat
• Follow-up: 30 days
• Primary outcome: All-cause mortality at 30 days

Population

Extended details of the design appears in the Protocol.

Inclusion Criteria

• Unplanned ICU admission
• Likely ICU stay ≥3 days; likely artificial nutritional ≥2 days
• Aged ≥18 years

Exclusion Criteria

• Nutritional support in prior 7 days
• Indwelling gastrostomy or jejunostomy
• Pregnancy
• In ICU for >36h prior to enrollment
• Admission for burn injuries or palliative care

Baseline Characteristics

From the parenteral group.

• Demographics: Aged 63 years, male sex 58%
• Coexisting disease: Liver 2%, renal 2%, resp 3%, CV 1%, immunodeficiency 7%
• Surgery in 24h prior to ICU admission: 14%
• APACHE II: Acute physiology score 15%, total score 20%
  • Median predicted risk of death: 0.34 WJC ed: Presumably this is 34% risk of death
• ICNARC: Physiology score 26%
  • Median predicted risk of death: 0.42
• Mechanical ventilation: 83%
• SOFA score: 9.5
• Assessed to have severe malnutrition: 13%
• Degree of malnutrition (based on BMI or weight loss thresholds described at the bottom of Table 1 on page 1678): None 93%, moderate 1%, high 6%
• BMI: 28 kg/m²

Interventions

• Within 36 hours of ICU admission, subjects were randomized to one of the following feeding strategies:
  • Parenteral therapy - nutrition via central venous catheter with dedicated lumen
  • Enteral therapy - feeding via nasogastric vs. nasojejunal tube
• Energy target was 25 kcal/kg for each arm, with aim to reach goal feeding within 48-72 hours of feeding initiation
• Patients were fed exclusively via pre-specified route for 5 days, or until these pre-determined end-points:
  • Discharge from ICU
  • Death
  • Transition to exclusive oral feeding
• Glycemic control goal for subjects was target blood glucose <180 mg/dL
• Choice of feeding formula/composition left to discretion of local Practitioners

Outcomes

Comparisons are parenteral therapy vs. enteral therapy except where specified.

Primary Outcomes

All-cause mortality at 30 days

33.1% vs. 34.2% (RR 0.97; 95% CI 0.86-1.08; P=0.57)

Secondary Outcomes

(Note: events counted up to 30 days unless otherwise specified)

Days free from advanced respiratory support (means)

14.3 vs. 14.3 (P=0.94)

Days free from advanced cardiovascular support (means)

18.9 vs. 18.5 (P=0.44)

Days free from renal support (means)

19.1 vs. 18.8 (P=0.66)

Days free from neurologic support (means)

19.2 vs. 18.9 (P=0.57)

Days free from gastrointestinal support (means)

13.0 vs. 13.2 (P=0.81)

Number of treated infectious complications per patient (means)

0.22 vs. 0.21 (P=0.72)

Hypoglycemic episodes

3.7% vs. 6.2% (P=0.006)

Elevated liver enzymes

17.8% vs. 15.0% (P=0.07)

Nausea requiring treatment

3.7% vs. 4.4% (P=0.41)

Abdominal distention

6.5% vs. 8.3% (P=0.12)

Vomiting

8.4% vs. 16.2% (P<0.001)

New or worsening pressure ulcers

15.2% vs. 15.0% (P=0.91)

Median number of ICU days

8.1 vs. 7.3 (P=0.15)

Median number of hospital days

17 vs. 16 (P=0.32)

All-cause mortality by setting

Within ICU: 26.6% vs. 29.4% (RR 0.91, 95% CI 0.80-1.03, P=0.13)

In acute care hospital: 36.4% vs. 37.9% (RR 0.96, 95% CI 0.86-1.06, P=0.44)

In any setting at 90 days: 37.3% vs. 39.1% (RR 0.96, 95% CI 0.86-1.06, P=0.40)

Adverse Events

Serious adverse events

5% vs. 5% (P=1.00)

See a complete list of adverse events in Table 2 on page 1679.

Other Outcomes

Nonadherence to nutritional support during intervention time

12.6% vs. 10.6%

Criticisms

• Few participants achieved the target intake of 25 kcal/kg
• Non-standardized feeding regimens
• Not blinded.
• Patients may not have needed nutritional support, low protein intake, low caloric intake, few patients in each center
• Only ~2% of participants received parenteral nutrition alone. Did not mention details about coexising diseases.

Funding

United Kingdom National Institute for Health Research. Multiple authors with financial conflicts.