Lilia Malcolm, Specialist Critical Care and Surgery Dietitian, Central Manchester University Hospitals NHS Foundation Trust, UK
Refeeding syndrome (RFS) was first described after the Second World War during reintroduction of nutrition in starved, undernourished prisoners. The prisoners exhibited cardiac and neurological abnormalities soon after feeding was started.1 Since then RFS has also been reported in patients with anorexia nervosa, chronic alcoholics and in people undertaking hunger strikes.2 Even though many clinicians may be aware of the condition, it is still poorly understood.
RFS is not a new phenomenon but despite this there is still no internationally agreed definition of this complex condition.3 It is often described as potentially fatal disturbances in fluid and electrolytes and can occur during refeeding of oral, enteral or parenteral nutrition.
The presence of hypophosphataemia has been labelled as the hallmark of RFS,4 but other biochemical shifts are recognised during the early stages of RFS, including low levels of potassium and magnesium. These biochemical shifts occur because of the reintroduction of glucose for energy, which initiates a rise in insulin causing an intracellular update of glucose, potassium, phosphate and magnesium. The reactivation of carbohydrate metabolism also requires thiamine as a cofactor, which is why current recommendations suggest supplementation of vitamin B1.5
As well as biochemical changes, clinical manifestations of RFS have been described, including oedema, as water is drawn in to the intracellular compartment by osmosis, as well as disturbances to organ function, primarily cardiac or respiratory failure.1
See Figure 1 for features of refeeding syndrome.
Figure 1: Refeeding Syndrome
There is however no clarity around what qualifies as a shift in electrolytes as no guideline states measurable cut-offs. Furthermore, it’s not specified whether an individual needs to have both biochemical changes and physical symptoms to have ‘true RFS’.6 Saying this, it’s debatable as to what symptoms should be expected as some are non-specific or may not develop at all, which adds to the struggle in formulating an agreed definition.7
Determining the incidence of RFS is not an easy matter because of the lack of an agreed definition. Therefore, the criteria used to define the syndrome differ across the studies looking into it, resulting in a considerable variation in the reported incidence rates.
A systematic review published in 2016 included 45 studies of mixed populations and explored reported incidence rates.8 The most common component of a definition across the studies included was hypophosphataemia, either as a cut-off or a drop from baseline. Still, there were wide variations in hypophosphataemia cut-offs to define RFS, from <1mmol/L to <0.32 mmol/L, and differences in the required drop from baseline by 30% or >0.16mmol/L.
In 34% of studies, there were no patients identified as displaying any sign or symptom of RFS. This may be due to the very rigorous definitions of RFS employed to include both biochemical and clinical manifestations. On the other extreme, RFS was reported up to 80% where definitions were more relaxed looking at electrolyte disturbances only, predominately hypophosphatemia.
It’s not unreasonable to think that the incidence of RFS may vary across different population groups. However, the heterogeneity of definitions used across studies makes it very difficult to form accurate comparisons across populations.8
Hypophosphataemia remains the most common component of definition and identification of RFS across current literature, and in some cases it has been the only defining element. It has been suggested that many reported cases of RFS in the literature could be more appropriately labelled as ‘refeeding hypophosphataemia’.7 The difficulty with having hypophosphataemia as the sole indictor of RFS is that there are many other clinical causes of low phosphate which have to be considered.
Most clinicians refer to the NICE guidance when identifying individuals at high risk of RFS (Table 1). These guidelines are a good starting point for all healthcare professionals to use and anyone working in the area of nutrition should be familiar with them. The NICE recommendations are best practice points based on the experience and expertise of the guideline development group (grade D), given the lack of any body of evidence supported by clinical studies.
Table 1: Individuals at High Risk of Refeeding Syndrome (NICE 2006)
|Patient has one or more of the following:||Patient has two or more of the following:||
Although the NICE recommendations are widely adopted in clinical practice, some studies have found them to have low sensitivity and specificity and propose that there may be other risk factors to take into account.8 The additional risk factors include older age, low albumin or pre-albumin, patients who are enterally fed, higher nutritional intake during feeding and low insulin-like growth factors. However, none of these have yet been included in national guidelines.
One study suggests that receiving intravenous glucose infusion prior to any nutrition support can precipitate RFS highlighting the importance of carefully selected intravenous fluids for those thought to be at high risk of developing the syndrome.2 The same study also identified low baseline serum levels of magnesium and starvation to be independent predictors of RFS.
However, since the most compelling risk factor for RFS agreed in literature is malnutrition, then the importance of adequate screening for this is paramount. Malnutrition is common within hospitals. The Nutrition Screening Survey has found that 34% of hospital adult inpatients are at risk of malnutrition.9
One emerging concept is that RFS is dependant on the extent of malnutrition at the start of refeeding and not on the amount of calories provided; as BMI reduces the severity of refeeding hypophosphataemia increases.9 The use of a validated, easy to use screening tool that takes into consideration BMI, such as the ‘Malnutrition Universal Screening Tool’ (‘MUST’), is an effective way to quickly identify those potentially at high RFS risk. BAPEN’s online e-learning package ‘Essentials of Clinical Nutrition’ is a free resource for NHS workers that teaches the basics of nutrition screening,’MUST’ and recognising malnutrition.
As they currently stand, the NICE guidelines require a detailed and accurate weight and diet history to truly identify at risk patients. Whilst calculating BMI is simple and can be captured by screening tools, to accurately ascertain ‘little or no nutritional intake’, and ‘percentage weight loss’, a detailed assessment by a dietitian or nutrition support team is warranted. Gathering this information requires accurate weight histories, which can be hard to ascertain, plus an assessment of diet recall which can be subjective. Could the difficulty in confidently gaining this information accurately lead us to being too cautious, and hence over-diagnosing RFS? Could over-diagnosing RFS mean that some patients are being unnecessarily underfed?
The recommended management for the initiation of nutrition in patients at high risk of RFS is a gradual increase of calories starting at 10 kcals/kg/day and aiming to meet or exceed nutritional needs within 4-7 days. In extremely high risk patients it is recommended to start at 5 kcal/kg/day.5
Despite these recommendations, refeeding practices do vary. One emerging idea is that the overall amount of nutrition provided at the start of refeeding may not be quite as important as initially thought.
A systematic review of the feeding practices in adolescents with anorexia nervosa (AN) show varying energy intakes at the start of feeding (125-1900 kcals/day) and, interestingly, incidence of refeeding hypophosphatemia did not appear to be influenced by total energy intake but rather by the degree of malnutrition, i.e. lower BMI.10 A similar theory was proposed by a study in a non-anorexia population where hypocaloric feeding did not prevent the development of RFS in a small number (n=3) of at risk patients.2
In contrast, a recent RCT carried out in intensive care patients showed that caloric restriction in patients who developed RFS (as defined by phosphate <0.65 mmol/L) improved survival, reduced infectious complications and reduced hospital length of stay.11
You could conclude that refeeding practices should be tailored for different clinical areas. The main apprehension surrounding strict adherence to the NICE guidelines is the risk of unnecessarily underfeeding, delaying nutrition and having a negative impact on patients that are already malnourished.
Rather than the total amount of nutrition provided to high RFS risk patients, should we be looking at where the calories are coming from? One suggestion is that RFS may be more likely to manifest when the nutrition provided is predominately from carbohydrates.7 Whether nutrition mainly composed of fats and proteins and less carbohydrates, e.g. less than 40%, would minimise RFS is an area that needs further quality research.
NICE guidelines recommend supplementation of potassium, phosphate and magnesium, unless baseline levels are high. Moreover, low baseline electrolytes should not delay commencement of nutrition.5 When phosphate was supplemented prophylactically in AN patients, who received calories above current NICE guidance, there wasn’t any reported incidences of hypophosphataemia.12 Should we be prophylactically supplementing electrolytes as common practice in RFS risk patients, as suggested by NICE guidelines?
As clinicians the NICE recommendations offer us guidelines to identify high risk RFS patients and how to manage them. They do, however, require information that can be difficult to accurately measure, and thus warrant the need for detailed assessments by a dietitian or nutrition specialist. Even then there is the potential to misdiagnose the condition. Although these guidelines are based on expert opinion rather than robust clinical studies, they are a good starting point, but we eagerly await updated recommendations to take into account some of the newer concepts emerging from more recent literature.
BAPEN Media Panel member Lilia Malcolm is a Specialist Critical Care and Surgery Dietitian at Central Manchester University Hospitals NHS Foundation Trust. You can follow her on Twitter: @LiliaMalcolm
References 1. Brozek J, Chapman CB, Keys A. Drastic Food Restriction; effect on cardiovascular dynamics in normotensive and hypertensive conditions. JAMA 1948; 137: 1569-74. 2. Rio A, Whelan K, Golf L, Reidlinger P, Smeetin N. Occurrence of refeeding syndrome in adults started on artificial nutrition support: prospective cohort study. BMJ 2013; 3. 3. Mehanna H, Nankivell PC, Moledina J, Travis J, “Refeeding syndrome—awareness, prevention and management,” Head and Neck Oncology, 2009; 1(1): 4. 4. Mehanna H, Moledina J, Travis J. Refeeding Syndrome: What is it, and how to prevent and treat it. BMJ 2008; 336. 5. National Institute for Heath and Clinical Excellence (NICE). Nutrition Support in Adult: Oral Nutritional Support, Enteral Tube Feeding and Parenteral Nutrition Clinical Guidance (CG32) 2006. 6. Stanga Z, Brunner A, Leuenberger M, Grimble RF, Shenkin A, Allison SP, Lobo DN. Nutrition in clinical practice – the refeeding syndrome: illustrative cases and guidelines for prevention and treatment. European Journal of Clinical Nutrition, 2008; 62: 687-694 7. Crook MA. Refeeding Syndrome: Problems with definition and management. Nutrition, 2014; 30: 1448-1455 8. Friedli N, Stanga Z, Sobotka L, Culkin A, Kondrup J, Laviano A, Mueller B, Schuetz P. Revisiting the refeeding syndrome: Results of a systematic review. Nutrition, 2016; 35: 151-160 9. Russell CA, Elia M. Nutrition Screening Surveys in Hospitals in England, 2007-2011: A report based on the amalgamated data from the four Nutrition Screening Week surveys undertaken by BAPEN in 2007, 2008, 2010 and 2011: BAPEN, 2014. 10. O’Connor G and Nicholls D. Refeeding Hypophosphatemia in Adolescents with Anorexia Nervosa: A systematic Review. ASPEN 2013; 28(3): 358-364. 11. Doig GS, Simpson F, Heighes PT, Bellomo R, Chesher D, Caterson ID, Restricted Versus continued standard caloric intake during the management of refeeding syndrome in critically ill patients: a randomised, parallel-group, multicentre, single-blind controlled trial. Lancet, 2015; 3: 943-52. 12. Madden S, Miskovic-Wheatley J, Clarke S, Touyz S, Hay P, Kohn M. Outcomes of a rapid refeeding protocol in adolescent anorexia nervosa. Journal of Eating Disorders 2015; 3: 8.
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