Publication

• Title: Trial of the Route of Early Nutritional Support in Critically Ill Adults
• Acronym: CALORIES
• Year: 2014
• Journal published in: New England Journal of Medicine
• Citation: Harvey SE, Parrott F, Harrison DA, Bear DE, Segaran E, Beale R, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med. 2014;371(18):1673-1684.

Context & Rationale

• Background

  • Enteral nutrition (EN) had become the default early strategy in ICU because of biological plausibility (gut integrity, immunological effects) and prior evidence suggesting fewer infections compared with parenteral nutrition (PN).
  • However, EN delivery is commonly constrained by feed intolerance and interruptions, whereas PN can deliver more predictable energy/protein early but raises concerns about catheter-related infection, metabolic complications, and overfeeding.
  • By the early 2010s, ICU practice was shifting towards tighter glycaemic control avoidance and more conservative energy targets; whether “early route” (PN vs EN) materially changed outcomes under contemporary practice was uncertain.
• Research Question/Hypothesis

  In adult critically ill patients requiring early nutritional support, is early PN (initiated within 36 hours of ICU admission) superior to early EN in reducing 30-day all-cause mortality?
• Why This Matters

  • Route decisions are made daily in ICU and drive resource use (central venous access; dietetic/nursing workload) and complication risk profiles.
  • Guideline preferences for EN required robust confirmation in a modern, pragmatic ICU population where both EN and PN can be protocolised.
  • A large effectiveness trial could clarify whether “route” itself changes patient-centred outcomes or whether pragmatic focus should shift to adequacy, timing, and avoidance of iatrogenic harm.

Design & Methods

• Research Question: Among critically ill adults needing nutritional support early after ICU admission, does early PN (vs early EN) reduce 30-day all-cause mortality?
• Study Type: Pragmatic, multicentre, parallel-group, randomised controlled trial; open-label; conducted in 33 adult general critical care units in England; randomisation via a central telephone/web service using minimisation (with a random component).
• Population:
  • Setting: Adult general critical care units (unplanned ICU admissions).
  • Inclusion: Age ≥18 years; unplanned ICU admission; enrolled within 36 hours of ICU admission; clinician expected (a) ICU stay >3 days and (b) need for nutritional support for ≥2 days.
  • Key exclusions: unable to receive nutrition via either route; clinical contraindication to PN or EN at the time of enrolment; received nutritional support for >7 days before ICU admission; gastrostomy/jejunostomy in situ; pregnant; likely to be outside the UK within 6 months (follow-up feasibility).
• Intervention:
  • Early Parenteral Nutrition: PN started as soon as possible after randomisation (within 36 hours of ICU admission), delivered according to a trial protocol with a target of ~25 kcal/kg/day; approach to protein delivery followed local formulations but was protocolised within the study framework.
  • Intervention period: Up to 5 days (or until ICU discharge/death/establishment of oral intake), with route assignment guiding nutrition delivery during this phase.
• Comparison:
  • Early Enteral Nutrition: EN started as soon as possible after randomisation (within 36 hours of ICU admission), delivered by nasogastric/enteral tube feeding according to a structured protocol and similar energy target (~25 kcal/kg/day).
  • Usual co-interventions (vasopressors, ventilation strategies, glycaemic management) were clinician-directed and not standardised beyond trial nutrition protocols.
• Blinding: Open-label (route could not be blinded); primary outcome (30-day mortality) was objective, but management decisions and some secondary outcomes (e.g., recorded intolerance events) were potentially susceptible to performance/ascertainment bias.
• Statistics: Sample size 2400 patients required to detect a 6.4% absolute reduction in 30-day mortality (from 32.0% to 25.6%) with 90% power at a two-sided 5% significance level; primary analyses followed the intention-to-treat principle (excluding patients who withdrew permission for any data use).
• Follow-Up Period: Primary endpoint at 30 days; additional outcomes reported through ICU and acute hospital discharge and 90 days (protocol also planned longer-term follow-up for some outcomes).

Key Results

This trial was not stopped early. Recruitment reached the prespecified sample size target.

• Early PN was not superior to early EN for 30-day mortality (RR 0.97; 95% CI 0.86–1.08; P=0.57), with concordant null effects across ICU, hospital, and 90-day mortality.
• Route mainly shifted tolerance/metabolic profiles: vomiting and severe hypoglycaemia were lower with PN, while constipation was higher with PN; infections and organ-support–free days were similar.
• Prespecified subgroup analyses did not show credible effect modification (interaction tests not significant), limiting arguments for a mortality benefit confined to a particular clinical subgroup.

Internal Validity

• Randomisation and allocation: Central telephone/web randomisation with minimisation (ICU, age, sex, severe malnutrition, oncological/haematological cancer), supporting allocation concealment and baseline balance.
• Attrition / exclusions: 2400 randomised; 12 patients withdrew permission for any data use post-randomisation and were excluded from analyses; primary outcome unavailable for 5 patients at day 30 (2 PN; 3 EN); loss to follow-up was very low.
• Performance/detection bias: Open-label design; objective endpoints (mortality) robust; subjective/process outcomes (e.g., vomiting, feeding intolerance events) potentially influenced by awareness of assigned route and local documentation practices.
• Protocol adherence: Nonadherence occurred in 150/1191 (12.6%) PN vs 127/1197 (10.6%) EN during the 5-day intervention; common reasons included clinical changes that prompted switching route or temporary cessation.
• Crossover: Route crossover reported as 12 PN-assigned patients receiving EN and 4 EN-assigned receiving PN during the intervention; additional patients received no nutrition during some or all of the intervention period (27 PN vs 18 EN).
• Baseline characteristics: Groups were well matched (median age 61 vs 61 years; APACHE II 19.0 vs 18.8; ≈70% mechanically ventilated at baseline; ≈25% on vasoactive drugs), supporting comparability and adequate illness severity for potential nutrition-related effects.
• Separation of the variable of interest (route and delivery):
  • Calories from nutrition during intervention: 89 ± 44 kcal/kg (PN) vs 74 ± 44 kcal/kg (EN).
  • Non-nutritional calories: 6.0 ± 8.1 kcal/kg (PN) vs 8.5 ± 9.6 kcal/kg (EN).
  • Protein from nutrition: 3.0 ± 2.0 g/kg (PN) vs 3.0 ± 2.1 g/kg (EN) (similar total protein exposure).
  • Enteral exposure (days receiving EN): 0.9 ± 1.5 days (PN) vs 3.3 ± 1.8 days (EN).
  • Support for intolerance (any prokinetic use): 26/1191 (2.2%) PN vs 426/1197 (35.6%) EN.
• Timing: Nutrition commenced early in both groups (median time from ICU admission to starting assigned support 24.0 hours PN vs 22.5 hours EN), consistent with the “early route” hypothesis.
• Statistical rigour: Prespecified primary endpoint, appropriate large-sample design, and consistent primary/secondary mortality results; the observed mortality difference was far smaller than the effect size assumed for power.

Conclusion on Internal Validity: Overall, internal validity is strong for the primary outcome: randomisation and follow-up were robust, and mortality is objective; limitations relate mainly to open-label delivery and modest nonadherence/crossover that may have diluted small route effects.

External Validity

• Population representativeness: Pragmatic enrolment of unplanned UK ICU admissions expected to require prolonged critical care and nutritional support; baseline severity and high rates of ventilation/vasopressors reflect typical general ICU case-mix.
• Important exclusions: Patients with contraindication to either route, those already receiving prolonged pre-ICU nutrition (>7 days), and those with existing enteral access devices were excluded; elective post-operative admissions were not the primary target population.
• Applicability: Findings generalise best to high-income ICUs able to deliver protocolised PN and EN with contemporary infection prevention and conservative energy targets; applicability to resource-limited settings or populations with markedly different nutrition delivery capability is less certain.

Conclusion on External Validity: External validity is moderate-to-strong for general adult ICUs in similar systems, but may be limited where PN formulations, line-care bundles, or EN intolerance management differ substantially.

Strengths & Limitations

• Strengths: Large pragmatic RCT (n=2400) across 33 ICUs; early randomisation with objective primary endpoint; prespecified SAP; very low loss to follow-up; clinically meaningful secondary outcomes and safety reporting.
• Limitations: Open-label design; modest route separation for key nutritional exposures (notably protein) and overall calorie delivery below the nominal target in both groups; nonadherence/crossover within the intervention window; restricted to unplanned admissions in one national health system; outcomes beyond 90 days not reported in the main publication.

Interpretation & Why It Matters

• Route is not a mortality lever (here)

  Within early, protocolised nutrition delivery (median ~23–24 hours from ICU admission), PN did not reduce 30-day mortality versus EN; the null effect persisted through ICU/hospital discharge and 90 days.
• Expect trade-offs in tolerance/metabolism

  PN reduced vomiting and severe hypoglycaemia but increased constipation; these are clinically actionable differences that influence comfort, nursing workload, and escalation decisions (e.g., prokinetics, post-pyloric feeding) rather than survival.
• Pragmatic lesson for practice

  When EN is not feasible or is poorly tolerated early, protocolised PN appears a reasonable alternative without clear excess infection or mortality risk—shifting the emphasis towards timely, safe delivery and avoidance of overfeeding rather than route dogma.

Controversies & Subsequent Evidence

• Does CALORIES truly test “route”, or mostly test tolerance management? The editorial accompanying CALORIES emphasised that pragmatic delivery and modest differences in achieved macronutrient exposure can limit inference that “route” itself is causal for outcomes, and argued for focusing on deliverability and avoiding iatrogenic harm rather than assuming superiority of either approach.¹
• Withdrawal of permission and modified ITT: Exclusion of 12 post-randomisation withdrawals (data removal requests) represents an unavoidable ethical constraint in UK research; critics noted that strict ITT is compromised in principle, but the small number makes material bias unlikely.²
• Route interacts with haemodynamic context: NUTRIREA-2 (shock, mechanically ventilated) also found no mortality difference between early EN and early PN, but reported more gastrointestinal complications with EN, supporting the view that route choice may matter more for harm profiles in specific physiological states than for survival.³
• How CALORIES fits with “timing of PN” debates: EPaNIC demonstrated that early supplemental PN (when EN insufficient) can worsen some outcomes compared with late PN, highlighting that timing, dose, and metabolic context may dominate route effects; CALORIES differs by comparing early PN vs early EN under contemporary targets and in a pragmatic UK population.⁴
• Systematic reviews after CALORIES: Updated analyses incorporating CALORIES (and later trials) generally show no consistent mortality advantage for EN vs PN, with infection differences attenuated compared with older literature and heterogeneity driven by trial era, caloric dose, and co-interventions.⁵⁶
• Guideline evolution: Post-CALORIES guidelines generally recommend early EN when feasible, but accept early PN when EN is contraindicated or clearly inadequate—framing PN as an alternative or supplement rather than an inherently inferior route.⁷⁸⁹

Summary

• In 2400 critically ill adults, early PN did not reduce 30-day mortality compared with early EN (33.1% vs 34.2%; RR 0.97; 95% CI 0.86–1.08).
• Mortality remained similar at ICU discharge, hospital discharge, and 90 days; organ-support–free days were also similar.
• Route mainly altered complication profiles: PN reduced vomiting and severe hypoglycaemia but increased constipation.
• Protocol adherence was high, but nonadherence/crossover occurred (~11–13%), and achieved nutritional separation—especially for protein—was modest.
• CALORIES reframed “EN vs PN” as a question of safety, feasibility, and context, rather than a universal mortality-determining choice.

Further Reading

Other Trials

• 2011Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365(6):506-517.
• 2013Doig GS, Simpson F, Sweetman EA, et al. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA. 2013;309(20):2130-2138.
• 2013Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial. Lancet. 2013;381(9864):385-393.
• 2018Reignier J, Boisramé-Helms J, Brisard L, et al. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomized controlled trial. Lancet. 2018;391(10116):133-143.
• 2018Ridley EJ, Davies AR, Parke R, et al. Supplemental parenteral nutrition versus usual care in critically ill adults: a pilot randomized controlled study. Crit Care. 2018;22(1):12.

Systematic Review & Meta Analysis

• 2016Elke G, van Zanten ARH, Lemieux M, et al. Enteral versus parenteral nutrition in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials. Crit Care. 2016;20:117.
• 2018Lewis SR, Andersen HK, Thomas S. Enteral nutrition versus parenteral nutrition in critically ill adults. Cochrane Database Syst Rev. 2018;Issue 6:CD012276.
• 2023Talebi S, Zeraattalab-Motlagh S, Vajdi M, et al. Early vs delayed enteral nutrition or parenteral nutrition in hospitalized patients: an umbrella review of systematic reviews and meta-analyses of randomized trials. Nutr Clin Pract. 2023;38(3):564-579.
• 2025Baik HW, Moshavero S, Alabdulaziz H, et al. Comparison of early enteral nutrition vs early parenteral nutrition in critically ill patients: a systematic review and meta-analysis. Nutrients. 2025;17(1):10.
• 2005Simpson F, Doig GS. Parenteral vs. enteral nutrition in the critically ill patient: a meta-analysis of trials using the intention-to-treat principle. Intensive Care Med. 2005;31(1):12-23.

Observational Studies

• 2010Cahill NE, Dhaliwal R, Day AG, Jiang X, Heyland DK. Nutrition therapy in the critical care setting: what is “best achievable” practice? An international multicenter observational study. Crit Care Med. 2010;38(2):395-401.
• 2014Weijs PJM, Looijaard WGPM, Beishuizen A, Girbes ARJ, Oudemans-van Straaten HM. Early high protein intake is associated with low mortality and energy overfeeding with high mortality in non-septic mechanically ventilated critically ill patients. Crit Care. 2014;18:701.
• 2016Nicolo M, Heyland DK, Chittams J, et al. Clinical outcomes related to protein delivery in a critically ill population: a multicenter, multinational observational study. JPEN J Parenter Enteral Nutr. 2016;40(1):45-51.
• 2022Slingerland-Boot R, Bischoff SC, Meijers JMM, et al. Reached protein and energy intake during the post-ICU hospitalization period: a prospective observational cohort study (PROSPECT-I). Clin Nutr. 2022;41(12):2736-2746.
• 2023Zou H, Meng H, Yan X, et al. Effect of early nutrition and feeding route on clinical outcomes of neurocritically ill patients: a retrospective cohort study. Ann Transl Med. 2023;11(5):219.

Guidelines

• 2016McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: SCCM and A.S.P.E.N. JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.
• 2017Reintam Blaser A, Starkopf J, Alhazzani W, et al. Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Intensive Care Med. 2017;43(3):380-398.
• 2019Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38(1):48-79.
• 2022Compher C, Bingham AL, McCall M, et al. Guidelines for the provision of nutrition support therapy in the adult critically ill patient: the ASPEN update. JPEN J Parenter Enteral Nutr. 2022;46(1):12-41.
• 2023Singer P, Blaser AR, Berger MM, et al. ESPEN practical guideline: clinical nutrition in the intensive care unit. Clin Nutr. 2023;42(9):1671-1711.

Notes

• CALORIES tested early route in a pragmatic UK ICU population with protocolised targets (~25 kcal/kg/day), but achieved calorie and (especially) protein separation between groups was modest—an important lens for interpretation.

Overall Takeaway

CALORIES is a landmark pragmatic ICU nutrition trial because it dismantled the assumption that early enteral feeding is intrinsically superior to early parenteral feeding for survival under contemporary practice. Instead, it suggests that the route decision should be driven by feasibility and safety trade-offs (tolerance, metabolic stability, and context such as shock), while broader outcome gains—if any—may depend more on timing, dose, and avoidance of overfeeding than on route alone.

Bibliography

• 1Cook D. The route of early nutrition in critical illness. N Engl J Med. 2014;371(18):1683-1685.
• 2Harvey SE, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med. 2015;372(5):488-489.
• 3Reignier J, Boisramé-Helms J, Brisard L, et al. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomized controlled trial. Lancet. 2018;391(10116):133-143.
• 4Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365(6):506-517.
• 5Elke G, van Zanten ARH, Lemieux M, et al. Enteral versus parenteral nutrition in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials. Crit Care. 2016;20:117.
• 6Lewis SR, Andersen HK, Thomas S. Enteral nutrition versus parenteral nutrition in critically ill adults. Cochrane Database Syst Rev. 2018;Issue 6:CD012276.
• 7McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: SCCM and A.S.P.E.N. JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.
• 8Compher C, Bingham AL, McCall M, et al. Guidelines for the provision of nutrition support therapy in the adult critically ill patient: the ASPEN update. JPEN J Parenter Enteral Nutr. 2022;46(1):12-41.
• 9Singer P, Blaser AR, Berger MM, et al. ESPEN practical guideline: clinical nutrition in the intensive care unit. Clin Nutr. 2023;42(9):1671-1711.