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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

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Summary

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/m2 vs ≤18 kg/m2). 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.

Introduction

Unexpected deaths arising from the rapid reinstitution of nutritional support in people who were severely malnourished were first reported in medical literature during the mid-1940s.1 Nowadays, the so-called refeeding syndrome is known to occur in patients who are apparently well nourished after only a short period of fasting.2

The “hallmark clinical sign” of refeeding syndrome is serum hypophosphataemia,3 but patients often present with additional metabolic disturbances including hypokalaemia, fluid overload, and thiamine deficiency.4 In patients who are accepted to have refeeding syndrome, the clinical sequelae of extreme metabolic disturbances might include respiratory failure, cardiac failure, delirium, rhabdomyolysis, haemolytic anaemia, seizures, coma, excess infections, and death.4, 5

Correction of phosphate and other electrolyte imbalances, plus thiamine supplementation, are accepted as the first steps in the appropriate treatment for refeeding syndrome.2, 4, 5, 6 However, expert recommendations regarding other aspects of medical care for such patients differ. For example, healthy patients' serum phosphate concentrations can decrease after the ingestion or intravenous infusion of glucose.7 Thus, some nutritional experts recommend that nutritional support should be stopped or restricted during phosphate and electrolyte replacement for refeeding syndrome.2, 5 With an absence of evidence from clinical trials5 and outcome studies,8 other experts recommend that “feeding can be continued” during electrolyte replacement.5 This discordance in expert recommendations is mirrored by clinical practice. In a survey undertaken in 33 intensive care units (ICUs) throughout Australia and New Zealand, about half (52%) of the ICU clinicians interviewed reported that they restrict energy intake during the treatment of refeeding syndrome, whereas the other half reported that they continue feeding without energy restriction.9

Research in context

Evidence before this study

We searched MEDLINE and Embase, without language restrictions, between Jan 1, 1945, and Aug 20, 2015, to identify clinical trials that evaluated competing approaches for the treatment of refeeding syndrome in any population of patients. We used the search term “refeeding” in combination with “malnou*” or “starv*”. Although case reports and case series were identified, we could not find any clinical trial that objectively evaluated the effects of competing approaches to the treatment of refeeding syndrome, in any patient population. All randomised and pseudo-randomised interventional studies done in any patient population with refeeding syndrome were eligible for inclusion. Observational studies, opinion papers, animal studies, and case reports were not eligible.

Added value of this study

The Refeeding Syndrome Trial is, to our knowledge, the first reported randomised clinical trial undertaken in any patient population with refeeding syndrome. Our results provide important evidence to guide treatment choices for the management of critically ill patients with this condition.

Implications of all the available evidence

Many health-care professionals, patients, and families might now judge caloric restriction during treatment for refeeding syndrome in critically ill adults preferable to continued standard caloric intake. Future research is needed to objectively assess the effects of caloric restriction in other patient populations and to investigate how appropriate the other aspects of care are for patients with refeeding syndrome (eg, thiamine dose, electrolyte replacement triggers, and doses).

We aimed to address the equipoise surrounding the decision to restrict or continue the provision of nutritional support during electrolyte replacement in adult critically ill patients who developed refeeding syndrome; and assess whether energy restriction affects the duration of critical illness compared with standard care.

Section snippets

Study design and participants

We did a randomised, parallel-group, multicentre, single-blind clinical trial in 13 tertiary care and community hospitals across Australia (11 sites) and New Zealand (two sites). The Human Research Ethics Committee at each participating site reviewed and approved the study. The study protocol is available online.

We screened critically ill adults (aged ≥18 years) for eligibility and enrolled them if their serum phosphate concentration decreased to below 0·65 mmol/L within 72 h after starting

Results

Between Dec 3, 2010, and Aug 13, 2014, we enrolled 339 adult critically ill patients from 13 participating hospitals in Australia and New Zealand: 170 patients were randomly allocated to standard care and 169 patients to protocolised caloric management (figure 1). Seven patients (four in standard care, three in caloric management) subsequently withdrew consent. Primary outcomes were available for all 332 consenting enrolled patients.

One patient was inappropriately enrolled based on a sample

Discussion

Caloric restriction during treatment for refeeding syndrome did not increase the number of days alive after ICU discharge, although it did result in significant improvements in its two main components: overall survival time and mortality at day 60 follow-up. Moreover, caloric restriction significantly reduced incidence of major infections and incidence of airway or lung infections.

In view of our understanding of the physiology in refeeding syndrome and the association between caloric intake and

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