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

Background: Equipoise exists regarding the benefits of restricting caloric intake during electrolyte replacement for refeeding syndrome, with half of intensive care specialists choosing to continue normal caloric intake. We aimed to assess whether energy restriction affects the duration of critical illness, and other measures of morbidity, compared with standard care. Methods: We did a randomised, multicentre, single-blind clinical trial in 13 hospital intensive care units (ICUs) in Australia (11 sites) and New Zealand (two sites). Adult critically ill patients who developed refeeding syndrome within 72 h of commencing nutritional support in the ICU were enrolled and allocated to receive continued standard nutritional support or protocolised caloric restriction. 1:1 computer-based randomisation was done in blocks of variable size, stratified by enrolment serum phosphate concentration (>0·32 mmol/L vs ≤0·32 mmol/L) and body-mass index (BMI; >18 kg/m vs ≤18 kg/m). The primary outcome was the number of days alive after ICU discharge, with 60 day follow-up, in a modified intention-to-treat population of all randomly allocated patients except those mistakenly enrolled. Days alive after ICU discharge was a composite outcome based on ICU length of stay, overall survival time, and mortality. The Refeeding Syndrome Trial was registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR number 12609001043224). Findings: Between Dec 3, 2010, and Aug 13, 2014, we enrolled 339 adult critically ill patients: 170 were randomly allocated to continued standard nutritional support and 169 to protocolised caloric restriction. During the 60 day follow-up, the mean number of days alive after ICU discharge in 165 assessable patients in the standard care group was 39·9 (95% CI 36·4-43·7) compared with 44·8 (95% CI 40·9-49·1) in 166 assessable patients in the caloric restriction group (difference 4·9 days, 95% CI -2·3 to 13·6, p=0·19). Nevertheless, protocolised caloric restriction improved key individual components of the primary outcome: more patients were alive at day 60 (128 [78%] of 163 vs 149 [91%] of 164, p=0·002) and overall survival time was increased (48·9 [SD 1·46] days vs 53·65 [0·97] days, log-rank p=0·002). Interpretation: Protocolised caloric restriction is a suitable therapeutic option for critically ill adults who develop refeeding syndrome. We did not identify any safety concerns associated with the use of protocolised caloric restriction. Funding: National Health and Medical Research Council of Australia

Intravenous amino acid therapy for kidney function in critically ill patients: a randomized controlled trial

Importance: Acute kidney injury (AKI) is characterized by severe loss of glomerular filtration rate (GFR) and is associated with a prolonged intensive care unit (ICU) stay and increased risk of death. No interventions have yet been shown to prevent AKI or preserve GFR in critically ill patients. Evidence from mammalian physiology and small clinical trials suggests higher amino acid intake may protect the kidney from ischemic insults and thus may preserve GFR during critical illness. Objective: To determine whether amino acid therapy, achieved through daily intravenous (IV) supplementation with standard amino acids, preserves kidney function in critically ill patients. Design, setting, and participants: Multicenter, phase II, randomized clinical trial conducted between December 2010 and February 2013 in the ICUs of 16 community and tertiary hospitals in Australia and New Zealand. Participants were adult critically ill patients expected to remain in the study ICU for longer than 2\ua0days. Interventions: Random allocation to receive a daily supplement of up to 100\ua0g of IV amino acids or standard care. Main outcomes and measures: Duration of renal dysfunction (primary outcome); estimated GFR (eGFR) derived from creatinine; eGFR derived from cystatin\ua0C; urinary output; renal replacement therapy (RRT) use; fluid balance and other measures of renal function. Results: 474 patients were enrolled and randomized (235 to standard care, 239 to IV amino acid therapy). At time of enrollment, patients allocated to receive amino acid therapy had higher APACHE\ua0II scores (20.2\ua0±\ua06.8 vs. 21.7\ua0±\ua07.6, P\ua0=\ua00.02) and more patients had pre-existing renal dysfunction (29/235 vs. 44/239, P\ua0=\ua00.07). Duration of renal dysfunction after enrollment did not differ between groups (mean difference 0.21\ua0AKI days per 10\ua0patient ICU days, 95\ua0% CI −0.27 to 1.04, P\ua0=\ua00.45). Amino acid therapy significantly improved eGFR (treatment group\ua0×\ua0time interaction, P\ua0=\ua00.004), with an early peak difference of 7.7\ua0mL/min/1.73\ua0m (95\ua0% CI 1.0–14.5\ua0mL/min/1.73\ua0m, P\ua0=\ua00.02) on study day\ua04. Daily urine output was also significantly increased (+300\ua0mL/day, 95\ua0% CI 145–455\ua0mL, P\ua0=\ua00.0002). There was a trend towards increased RRT use in patients receiving amino acid therapy (13/235 vs. 25/239, P\ua0=\ua00.062); however, this trend was not present after controlling for baseline imbalance (P\ua0=\ua00.21). Conclusion and relevance: Treatment with a daily IV supplement of standard amino acids did not alter our primary outcome, duration of renal dysfunction. Trial registration: anzctr.org.au Identifier: ACTRN12609001015235