Elsevier

Nutrition

Volume 35, March 2017, Pages 151-160
Nutrition

Review
Revisiting the refeeding syndrome: Results of a systematic review

https://doi.org/10.1016/j.nut.2016.05.016Get rights and content

Highlights

  • This is the first systematic review focusing on refeeding syndrome (RFS).

  • Definitions for RFS rely on electrolyte disturbances with or without clinical symptoms.

  • Incidence rates for RFS highly depend on the definition used.

  • Most of risk factors for RFS are in accordance with the National Institute for Health and Care Excellence guidelines.

  • No strong evidence for adverse outcomes and preventive measures in patients with RFS was found.

Abstract

Objective

Although described >70 y ago, the refeeding syndrome (RFS) remains understudied with lack of standardized definition and treatment recommendations. The aim of this systematic review was to gather evidence regarding standardized definition, incidence rate and time course of occurrence, association with adverse clinical outcomes, risk factors, and therapeutic strategies to prevent or treat this condition.

Methods

We searched MEDLINE and EMBASE for interventional and observational clinical trials focusing on RFS, excluding case reports and reviews. We extracted data based on a predefined case report form and assessed bias.

Results

Of 2207 potential abstracts, 45 records with a total of 6608 patients were included (3 interventional trials, 16 studies focusing on anorexic patients). Definitions for RFS were highly heterogenous with most studies relying on blood electrolyte disturbances only and others also including clinical symptoms. Incidence rates varied between 0% and 80%, depending on the definition and patient population studied. Occurrence was mostly within the first 72 h of start of nutritional therapy. Most of the risk factors were in accordance with National Institute for Health and Care Excellence guidelines, with older age and enteral feeding being additional factors. There was no strong evidence regarding association of RFS and adverse outcomes, as well as regarding preventive measures and treatment algorithms.

Conclusion

This systematic review focusing on RFS found consensus regarding risk factors and timing of occurrence, but wide variations regarding definition, reported incidence rates, preventive measures and treatment recommendations. Further research to fill this gap is urgently needed.

Introduction

Disease-related malnutrition is a common condition in medical and surgical inpatients and is associated with detrimental clinical outcomes including mortality, complications, and prolonged hospital stay [1], [2], [3]. Instigating nutritional therapy is commonly recommended in malnourished patients to prevent these adverse outcomes, although large clinical trials demonstrating benefit in the polymorbid inpatient population are largely lacking [4], [5], [6]. A potential risk for nutritional therapy in malnourished patients is the refeeding syndrome (RFS) with electrolyte disturbances leading to clinical deterioration and possible sudden cardiac death [7], [8]. Yet, as of today, the importance of the RFS in the polymorbid inpatient population is understudied, lacking a common definition and treatment recommendation.

For the first time, RFS was described in prisoners liberated from concentration camps at the end of World War II after a long period of starvation. Despite allegedly adequate nutritional support, these prisoners showed an unexpectedly high mortality rate of up to 20% [9], [10]. To date, the pathophysiology of RFS is still not completely understood. Proposed mechanisms include starvation and catabolic state-induced reduction in insulin and increased glucagon secretion [11] with resulting activated gluconeogenesis and proteolysis, as well as depletion of intracellular vitamin and electrolyte supplies [12], [13]. After the initial start of nutritional intake in patients in such a starved and catabolic state, glucose concentration and insulin secretion rises suddenly, leading to an overwhelming shift in electrolytes with increased sodium and water retention and extracellular volume expansion [11]. The potential clinical consequences are volume overload with risk for heart failure and peripheral edema [14], as well as transcellular shift and redistribution of phosphate, potassium, and magnesium [15] with life-threatening complications such as spasm, or cardiac arrhythmias [12], [15], [16], [17]. Additionally, the hypophosphatemia also affects the phosphate-dependent adenosine triphosphate production [18], [19], resulting in possible muscle weakness, rhabdomyolysis, and impaired hematopoiesis with symptoms of anemia and reduced oxygen supply [12].

Numerous reviews regarding RFS have been published focusing each on specific aspects of RFS. Yet, there is lack of a systematic literature search to better understand the current state of knowledge regarding RFS. The aim of this systematic review, which to our knowledge is the first, was to provide evidence regarding a standardized definition, incidence rate and time course of occurrence, association with adverse clinical outcome, risk factors, and therapeutic strategies to prevent or treat this condition in adult or adolescent patients.

Section snippets

Study objectives

This systematic review adheres to the PRISMA guidelines [20]. Our aim was to investigate the importance of the RFS in adult or adolescent patients. Particularly, we focused on the following six research questions:

  • 1.

    What are the definitions used for RFS?

  • 2.

    What is the incidence of RFS?

  • 3.

    When does RFS occur?

  • 4.

    Is RFS associated with an adverse clinical outcome?

  • 5.

    What are the risk factors for RFS?

  • 6.

    What are therapeutic strategies to prevent or treat RFS?

Eligibility criteria

Randomized clinical and observational studies

Trials identified through the search strategy

This systematic search identified 2910 titles and abstracts of potentially eligible studies through database searching. After duplicate removal, 2205 records were screened and 69 full texts were assessed for eligibility. Through two updated searches in mid-September and mid-December 2015 two additional studies were added. In all, 45 studies with a total of 6608 patients were included in the analysis including three interventional trials (Fig. 1). Sixteen studies focused on anorexic patients and

Summary of evidence

Although described >70 y ago, RFS is still not completely understood. The main findings of this systematic and comprehensive literature review are threefold. First, there is no well-accepted definition of RFS and no consensus whether the definition should only rely on laboratory parameters or also include clinical symptoms. Most studies, however, had a low or decreasing phosphate concentration as part of their definition. Depending on the definitions used, incidence rates showed wide

Conclusion

Although there is consensus with regard to risk factors and timely occurrence of RFS, there is still wide variation in definition, reported incidence rates and preventive measures, and treatment recommendations. This review is an important step toward a better understanding of the current state of knowledge regarding RFS and its clinical consequences. Further prospective high-quality research is warranted to fill this gap.

Acknowledgment

The authors acknowledge Heidrun Janka (Universitätsbibliothek Medizin Basel, Switzerland) for helping with the search. She did not receive any compensation for her help with this study.

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    This study was supported in part by the Swiss National Science Foundation (SNSF Professorship, PP00 P3_150531/1) and the Research Council of the Kantonsspital Aarau (1410.000.044). NF and PS wrote the initial protocol. NF performed the literature search and the data extraction. PS and ZS reviewed and commented on the final data extraction. NF drafted the manuscript. All authors amended and commented on the manuscript and approved the final version. PS and ZS oversaw the study and act as guarantors. The authors have no conflicts of interest to declare.

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