The Refeeding Syndrome Trial


Restricted versus continued standard caloric intake during the management of refeeding syndrome in critically ill adults: a randomised, parallel-group, multicentre, single-blind controlled trial

Doig. Lancet Resp Med 2015;3:943-52. doi: 10.1016/S2213-2600(15)00418-X

Clinical Question

  • In critically ill patients with refeeding syndrome, does restricting caloric intake compared with unrestricted caloric feeding, reduce the composite outcome of ICU length of stay, overall survival time and mortality at day 60?


  • Randomised, parallel-group, multicentre study
  • Single-blinded
  • Assignment based on 1:1 ratio
  • Computerised random blocks of variable size for stratification within study sites by enrolment serum phosphate concentration and body mass index
  • Modified intention to treat analysis
  • 60 day follow up
  • 336 patients were required to provide 90% power to detect to detect a 6.4 day difference in number of days alive after ICU discharge. This was based on findings from a database of 209 critically ill patients who developed re-feeding associated hypophosphataemia


  • 13 ICUs in Australia and New Zealand
  • December 2010 – August 2014


  • Inclusion: critically ill adults, serum phosphate concentration decreased to below 0.65mmol/L within 72 hours after starting nutritional support. This change needed to be > 0.16mmol/L decrease from any concentration previously recorded during the patient’s ICU stay
  • Exclusion: other causes of hypophosphataemia e.g dialysis, recent parathyroidectomy or treatment for hyperphosphataemia
  • 339 patients randomised
  • Group baseline characteristics were well matched for: age; APACHE II score; diagnosis; admission source; requirement for mechanical ventilation; body mass index; subjective nutritional assessment; chronic health states; and risk factors for refeeding


  • Restricted caloric management group
    • 20 kcal/h for at least 2 days and then a gradual return to normal intake protocol over the following 2-3 days
      • 40 kcal/hr for 24 hours, then increased to 60 kcal/h for 24 hours, followed by 80% of calculated energy goals for 24 hours, with 100% of goals achieved by day 4
      • If serum phosphate dropped below 0.71mmol/L at any time during the gradual return to normal intake protocol, energy intake was reduced to 20kcal/h and the patient was returned to day 2 of the study caloric management protocol


  • Standard group: No calorific restriction


  • Primary outcome: no statistical difference in the composite outcome of mean number of days alive after ICU discharge
    • ‘number of days alive’ was a composite outcome consisting of ICU length of stay, overall survival time and mortality at day 60
    • 39·9 (95% CI 36·4-43·7) in the standard group vs 44·8 (95% CI 40·9-49·1) in the caloric restriction group
    • difference 4·9 days, 95% CI -2·3 to 13·6, p=0·19
  • Secondary outcome:
    • protocolised caloric restriction resulted in the following statistically significant improved outcomes:
      • number of patients alive at day 60: (128 [79%] of 163 vs 149 [91%] of 164, p=0·002). NNT 9, fragility index 6 patients
      • overall survival time (48·9 [SD 1·46] days vs 53·65 [0·97] days, log-rank p=0·002)
      • % alive at 90 days. 128 [79%] of 163 vs 143 [87%] of 164, P=0·041). NNT 21, fragility index 1 patient
      • fewer airway or lung infections: 21% vs 32% P=0.0342. NNT 10, fragility index 1 patient
      • reduced mean hospital length of stay: 21.7 vs 27.9 P=0.003
    • protocolised caloric restriction resulted in a worse RAND-35 general health score
      • 46·0 (26·0 n=136/143) vs 53·4 (22·6; n=124/128)
      • Risk difference 95% CI: –7·5 (–13·4 to –1·5); P=0·014
    • no statistical difference between groups in:
      • ICU length of stay
      • quality of life and physical function scores (RAND-36 physical function and ECOG)
      • non-airway or lung infections
      • new pulmonary infiltrates
      • witnessed aspiration
      • organ system dysfunction & need for concomitant therapies including:
        • days of mechanical ventilation or RRT
        • antibiotic course length
      • daily phosphate replacement requirements
    •  No difference in adverse events

Authors’ Conclusions

  • Protocolised caloric restriction is a suitable therapeutic option for critically ill adults who develop refeeding syndrome


  • Relevant clinical question and outcome measures
  • Statistical analysis was published a priori
  • Allocation concealment
  • Written chest radiograph reports were obtained from radiologists who were unaware of the patient’s assigned study treatment groups
  • Severity of infections were graded across all sites
  • Adherence with the study caloric management protocol was high


  • Composite outcome measure

The Bottom Line

  • Restrictive caloric intake for refeeding syndrome did not statistically increase the number of days alive after ICU. However it did increase two clinically important components of this composite measure, survival time and 60-day mortality. In addition there were fewer respiratory infections. I will continue to use a restrictive caloric feeding regimen whilst treating refeeding syndrome

External Links


Summary author: Steve Mathieu
Summary date: 20th April 2016
Peer-review editor: Dave Slessor


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  • The Improved RAND-35 general health score paradoxically was actually WORSE for the protocolised feeding group (not better, as implied by the outcomes in this summary)

    RAND-36 general health:
    standard care: 53·4 (22·6; n=124/128)
    protocolised care: 46·0 (26·0 n=136/143)
    Risk difference 95%CI: –7·5 (–13·4 to –1·5)
    p-value: 0·014

    This is counter to the mortality outcomes.

    Was it that similarly sick patients in the control group died earlier?



    • Duncan Chambler

      Thanks for spotting this Chris! I’ll double check the paper and with Steve (who summarised it for TBL), and I’ll make amendments if needed.

      This paper is fascinating. I can see why Paul Young included it in his Top 10 for 2015/2016. It challenges a lot of held beliefs and gives some contradicting results. Why do people die with standard care, yet those with reduced caloric feeding have poorer health? Lots of questions requiring further thought and research.

  • Steve Mathieu

    Thanks for the post publication peer review Chris
    You are quite right and I have now updated the outcomes section
    Many thanks

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