ReviewRevisiting the refeeding syndrome: Results of a systematic review
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.