Accepted Manuscript

Management and Prevention of Refeeding Syndrome in Medical Inpatients: An

evidence-based and consensus-supported algorithm

Natalie Friedli, Zeno Stanga, Alison Culkin, Martin Crook, Alessandro Laviano, Lubos
Sobotka, Reto W. Kressig, Jens Kondrup, Beat Mueller, Philipp Schuetz

PII: S0899-9007(17)30207-1
DOI: 10.1016/j.nut.2017.09.007
Reference: NUT 10040

To appear in: Nutrition

Received Date: 4 June 2017

Revised Date: 4 September 2017
Accepted Date: 12 September 2017

Please cite this article as: Friedli N, Stanga Z, Culkin A, Crook M, Laviano A, Sobotka L, Kressig RW,
Kondrup J, Mueller B, Schuetz P, Management and Prevention of Refeeding Syndrome in Medical
Inpatients: An evidence-based and consensus-supported algorithm, Nutrition (2017), doi: 10.1016/
j.nut.2017.09.007.

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 ACCEPTED MANUSCRIPT
1 Management and Prevention of Refeeding Syndrome in
2 Medical Inpatients:
3 An evidence-based and consensus-supported algorithm
4
5 Natalie Friedli1*, Zeno Stanga2*, Alison Culkin3, Martin Crook4, Alessandro Laviano5,
6 Lubos Sobotka6, Reto W. Kressig7, Jens Kondrup8, Beat Mueller1 and Philipp
7 Schuetz1

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9 Medical University Department, Clinic for Endocrinology, Metabolism and Clinical Nutrition,
10 Kantonsspital Aarau, Aarau and Medical Faculty of the University of Basel, Switzerland

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11 Department of Endocrinology, Diabetes and Clinical Nutrition, Bern University Hospital, and
12 University of Bern, Switzerland

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13 Department of Nutrition and Dietetics, St Mark's Hospital, Harrow, England
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14 Department of Clinical Biochemistry, Lewisham Hospital NHS Trust, London, United Kingdom

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15 Department of Clinical Medicine, Sapienza University, Rome, Italy
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16 Department of Medicine, Medical Faculty and Faculty Hospital Hradec Kralove, Charles University,
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17 Prague, Czech Republic
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18 University Center for Medicine of Aging, Felix Platter Hospital and University of Basel, Basel,
19 Switzerland
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20 Clinical Nutrition Unit, Rigshospitalet University Hospital, Copenhagen, Denmark
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22 *Contributed equally to the manuscript

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24 Corresponding author:
25 Prof. Philipp Schuetz, MD, MPH
26 Medical Faculty of the University of Basel
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27 University Department of Medicine, Kantonsspital Aarau

28 Tellstrasse, CH-5001 Aarau, Switzerland
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29 Phone: +41 (0)62 838 4141

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30 Fax: +41 (0)62 838 4100

31 E-mail: schuetzph@gmail.com
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33 Conflict of interest statement: All authors confirm that they do not have a conflict of
34 interest associated with this manuscript.
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36 Funding: This study was supported in part by the Swiss National Science
37 Foundation (SNSF Professorship, PP00P3_150531 / 1) and the Research Council of
38 the Kantonsspital Aarau (1410.000.044).

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39 Abstract
40 Introduction:
41 Refeeding Syndrome (RFS) can be a life-threatening metabolic condition following
42 nutritional replenishment if not recognised early and treated adequately. There is a
43 lack of evidence based treatment and monitoring algorithm for daily clinical practice.
44 Our aim was to propose an expert’s consensus guideline for RFS for the medical

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45 inpatient (not including anorexic patients) regarding risk factors, diagnostic criteria,
46 and preventive and therapeutic measures based on a previous systematic literature

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47 search.
48

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49 Methods:
50 Based on a recent qualitative systematic review on the topic, we developed clinically
51 relevant recommendations as well as a treatment and monitoring algorithm for the
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clinical management of inpatients regarding RFS. With international experts, these
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53 recommendations were discussed and agreement with the recommendation was
54 rated.
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56 Results:
Upon hospital admission, we recommend the use of specific screening criteria (i.e.,
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58 low BMI, high unintentional weight loss, little or no nutritional intake, history of alcohol
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59 or drug abuse) for risk assessment regarding the occurrence of RFS. According to
60 the individual risk of a patients for RFS, a careful start of nutritional therapy with a
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61 step-wise increase in energy and fluids goals, supplementation of electrolyte and

62 vitamins and a close clinical monitoring is recommended. We also propose criteria for
the diagnosis of imminent and manifest RFS with practical treatment
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64 recommendation with adaption of the nutritional therapy.
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66 Conclusion:
67 Based on the available evidence, we developed a practical algorithm for risk
68 assessment, treatment and monitoring of RFS in medical inpatients. In daily routine
69 clinical care, this may help to optimize and standardize the management of this
70 vulnerable patient population. We encourage future quality studies to further refine
71 these recommendations.
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73 Keywords: refeeding syndrome, nutritional therapy, hypophosphatemia, treatment
74 recommendation

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75 Introduction
76 The Refeeding Syndrome (RFS) is an anabolic reaction caused by nutritional therapy
77 and associated with serum electrolyte shifts and/or clinical symptoms resulting from
78 metabolic changes and a fluid dysbalance (e.g. peripheral oedema, heart or
79 respiratory failure). RFS is a potentially life-threatening physiologic condition that
80 occurs in seriously malnourished patients or in patients after overcoming severe

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81 catabolic diseases (e.g. sepsis, diabetic ketoacidosis) after start of nutritional therapy
82 [1, 2]. The main trigger for RFS is the switch from a catabolic to an anabolic state,

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83 which is a normal physiological reaction in the initial phase of replenishment. RFS is
84 thus not per se an abnormal metabolic reaction of nutritional replenishment and

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85 reported incidence rates depend on the patient population (e.g., 14% of geriatric
86 population, 25% of cancer patients and 28% of anorexia nervosa) [3-6]. In most
87 cases, RFS has been reported to occur within first three days of starting nutritional
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support [6]. It occurs commonly with all types of nutritional support, but the risk
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89 appears highest in patients fed with enteral or parenteral nutrition [4]. Clinically, RFS
90 may present with a full spectrum including mild forms of RFS with almost no clinical
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91 signs and no risks for the patient, but also severe forms of RFS leading to clinical
92 deterioration including sudden cardiac death [1]. In general, a higher mortality due to
severe RFS has been found for specific patient populations, particularly older
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94 patients, patient with HIV and critically ill patients among others [7-9].
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95 Historically, RFS was first described in prisoners liberated from concentration camps
96 in World War II [10, 11]. It is still understudied in the inpatient population even though
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97 nutritional therapy is one of the most commonly used inhospital treatments. Also
98 there is no standardized and evidence based guidelines with a common definition as
well as treatment recommendations for RFS. Optimal risk assessment, establishment
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100 of a nutritional care plan and monitoring of patients at risk for RFS has the potential
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101 to lower morbidity and mortality associated with RFS.

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103 Current Evidence on RFS
104 Recently, we conducted a systematic review about RFS aiming to find evidence–
105 based criteria regarding definition, incidence rates, time patterns of occurrence,
106 association with adverse clinical outcome, risk factors and therapeutic and preventive
107 strategies [12]. Randomized and observational clinical studies investigating RFS in
108 anorexic and non-anorexic adult or adolescent patients (medical and surgical), were

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109 considered eligible for this review. The initial systematic search identified 2910
110 potentially eligible titles and abstracts. After duplicate removal, 2205 records were
111 screened and 69 full texts were assessed for eligibility. Most studies were excluded
112 as RFS was not the main focus. Through two updated searches in mid-September
113 and mid-December 2015 two additional studies were added. The final review
114 included 45 studies with a total of 6608 patients. Of these, 16 focused on anorexia

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115 nervosa patients and three trials had an interventional design. We did not find any
116 differences among studies with and without anorexia nervosa patients regarding the

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117 main research questions. Nevertheless, anorexic patients are thought to be different
118 from a pathophysiological perspective and therefore we decided to only include

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119 patients without anorexia for the proposed algorithm [13].
120 When analysing all studies included in the systematic search, we found
121 heterogeneous definitions for RFS with some studies focusing only on serum
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electrolyte disturbances, while others also used clinical parameters to establish the
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123 diagnosis. There was also a high variation regarding incidence rates varying between
124 0% and 80%, depending on the patient population and definition criteria used in the
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125 studies. A total of 11 studies reported data regarding the time point of RFS onset.
126 Most cases of RFS occurred within the first 72 hours after start of nutritional
replenishment and risk for RFS decreased strongly thereafter.
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128 Most included studies also found the risk factors proposed by the NICE guidelines
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129 (National Collaborating Centre for Acute Care) to be associated with RFS [14]. Older
130 age, enteral feeding and higher malnutrition risk scores (i.e., Nutritional Risk
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131 Screening ≥3 points (NRS 2002) [15]) were additionally reported to identify patients
132 at risk. Little information with controversial conclusions was found regarding
associations of RFS and adverse outcomes and regarding the effect of preventive
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134 measures and treatment algorithms.
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135
136 Aims of this consensus paper
137 The results of the recent systematic review [12] are valuable to better understand
138 current evidence from clinical studies regarding RFS. However, in addition to a
139 profound pathophysiological understanding of the metabolic aspects, specific
140 recommendations and treatment algorithms are of utmost importance for clinicians
141 working with patients at risk for RFS. Herein, our aim was to propose an expert’s
142 consensus recommendation for RFS regarding pathophysiological aspects, clinical

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143 manifestations, risk factors, diagnostic criteria and preventive and therapeutic
144 measures. Specifically, we focused on clinically relevant questions for the
145 management of RFS in medical inpatients starting with risk assessment, diagnostic
146 criteria and management throughout the hospital.
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148 Pathophysiological aspects of RFS

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149 The membrane concentration gradients of all electrolytes between the intracellular
150 and extracellular compartments are the basic conditions of life of the eukaryote cells

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151 [16, 17]. The intracellular electrolytes are tightly connected with their metabolic
152 functions (Table 1). Inevitably, a consequence of catabolic processes (e.g., fasting,

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153 stress reaction, inflammation) is a cellular loss of intracellular ions (K, PO4, Mg),
154 which results in a very transient increase of circulating levels and is followed by a
155 bodily loss due to immediate urinary excretion in exchange with sodium, which is
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retained during all catabolic situations. Sodium retention is therefore a universal
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157 component of stress response, inflammation and starvation. The RFS is the result of
158 a feeding-induced disturbance of adapted homeostatic cell function, on the basis of
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159 sodium retention and low body stores of potassium, phosphate and magnesium,
160 possibly combined with an anabolism-induced interorgan shift, which forces already
depleted stores from some tissues to other tissues with a higher rate of metabolism.
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162 Too rapid refeeding with processed food, particularly with carbohydrates, may
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163 precipitate a number of metabolic and pathophysiological complications, which

164 adversely affect the cardiac, respiratory, haematological, hepatic, neurological and
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165 neuromuscular systems leading to clinical complications and even death [18]:
166 − Hypokalaemia due to rapid cellular uptake of potassium as glucose and amino
acids are taken up during cellular synthesis of glycogen and protein; potassium
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168 is the main intracellular cation balancing the negative charges on proteins.
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169 − Hypophosphataemia due to increased phosphorylation of glucose and other

170 high energy phosphorylated molecules (e.g. adenosine triphosphate – ATP,
171 creatin phosphate – PCr) -synthesis. Nutrition rich in carbohydrate and calcium
172 can reduce serum phosphate (calcium is a binder of phosphate; carbohydrate
173 lead to a intracellular shift of phosphate due to increased insulin levels), and
174 meals with high phosphate contents, such as dairy products, can increase
175 serum phosphate. Therefore, accurate phosphate concentration assessment in
176 serum should be performed before and during feeding. In addition,

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177 hypophosphataemia has been demonstrated to increase insulin resistance in a
178 considerable way, therefore the medical staff in charge should be aware of this
179 condition, because it can cause and maintain hyperglycaemia, a common
180 condition in starved patients [19].
181 − Hypomagnesaemia due to cellular uptake, also involved in adenosine
182 triphosphate synthesis.

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183 − Sodium and water retention leading to oedema and heart failure. This may be
184 aggravated in case of pre-existing pathology of the heart or thiamine deficiency.
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185 Thiamine pyrophosphate, the active form of thiamine (vitamin B1), is involved in
186 several enzyme functions associated with the metabolism of carbohydrates,

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187 branched-chain amino acids, and fatty acids.
188 In severe nutritional depletion, atrophy of the gut mucosa and impairment of
189 pancreatic function may predispose to severe diarrhoea following oral or enteral
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refeeding, precipitating further electrolyte and mineral imbalance [20].
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192 Clinical manifestations of RFS [14, 18, 21]
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193 Refeeding of patients after a time period of low food intake causes a shift in
194 metabolism from a catabolic to a anabolic state. The requirements of potassium,
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195 phosphate and magnesium in the cell increases during this time period. Ultimately,
196 RFS reflects uncovered requirements of unbalanced nutrition support with a depletion
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197 of electrolytes and vitamins causing clinical symptoms in patients. Severe

198 hypophosphataemia (<0.32 mmol·l-1) causes impaired neuromuscular function with
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199 paraesthesia, seizures, cramps or impaired musculo-skeletal function including

200 weakness and impaired muscular contractility. The disturbance of muscles of the
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201 ventilatory system causes hypoventilation and eventually respiratory failure.

202 Rhabdomyolysis has also been described as result of severe hypophosphataemia
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203 [18]. Phosphate deficiency also causes thrombocytopaenia, impaired blood clotting
204 and deficiency in leukocyte function (impaired chemotactic, phagocytic and
205 bactericidal ability), because the metabolic rate of blood cell function is regulated by
206 serum phosphate [22, 23]. The red blood cells are indeed less flexible and show an
207 impaired ability to release oxygen to the target organs [24]. This acquired dysfunction
208 of the red and white blood cells can be improved with adequate phosphate
209 substitution [23, 24]. Other psychological effects of low phosphate include perturbed
210 mental state, confusion and eventually coma [18]. A moderate decrease in the

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211 plasma concentrations of magnesium (<0.50 mmol·l-1) and/or potassium (<2.5
212 mmol·l-1) in combination with possible other interorgan electrolyte shifts or medication
213 side effects (e.g. prolongation of QTc) can lead to cardiac arrhythmias and cardiac
214 arrest. Both hypomagnesaemia and hypokalaemia lead to neuromuscular and other
215 dysfunction such as weakness, paralysis, paraesthesia, confusion, rhabdomyolysis,
216 and respiratory depression [18].

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217 In severe and prolonged malnutrition, there may be cardiac atrophy as well as
218 electrolyte abnormalities, including sinus bradycardia and a prolonged QTc interval.

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219 These changes make the heart more vulnerable to hypophosphataemia and
220 hypokalaemia with ventricular arrhythmias and risk of sudden death, especially if the

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221 QTc interval exceeds 470 ms [25].
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223 Also, sodium retention due to starvation, stress and inflammation is further
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aggravated by the increased insulin release during refeeding and the resulting
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225 extracellular fluid expansion. Together with thiamine deficiency this leads to
226 accelerated heart rate, enlargement of the heart, severe oedema and ultimately to
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227 congestive cardiac failure with lung oedema (“wet beriberi”) [26]. This is more
228 pronounced in patients with reduced cardiac muscle mass due to malnutrition.
Thiamine is not stored in significant amounts in the body, so any acceleration of
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230 carbohydrate metabolism – for which Thiamine is an important cofactor - may
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231 precipitate acute deficiency [27]. Thiamine deficiency also leads to the typical
232 neurological sequelae within the syndrome of Wernicke’s encephalopathy (“cerebral
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233 beriberi”) [26]. The Wernicke-Korsakoff syndrome results in persistent alterations in

234 memory formation, along with encephalopathy-related symptoms. Beriberi was first
described as early as 2600 B.C. Thiamine deficiency also affects the peripheral
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236 nervous systems and results in neuropathy (“dry beriberi“) [26]. Typical symptoms
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237 are the “burning feet syndrome” and diminished sensation and weakness in legs and
238 arms. In addition, a decrease in the activity of thiamine-dependent enzymes limits the
239 conversion of pyruvate to acetyl-CoA and the utilization of the citric acid cycle (also
240 known as “Krebs cycle”) leading to accumulation of pyruvate and lactate. Lactic
241 acidosis, a condition resulting from the accumulation of lactate, is often associated
242 with nausea, vomiting, and severe abdominal pain (“gastrointestinal beriberi”) [28].
243 Most clinical symptoms that occur during a manifest RFS are unspecific. In daily
244 practice the main symptoms, which should be related to a manifest RFS are

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245 tachycardia, tachypnea and peripheral oedema [18, 29]. However, in medical
246 inpatients with different diseases, such symptoms may also be due to other
247 conditions, including pulmonary embolism, acute heart failure and others.
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249 Which medical inpatients are at risk for Refeeding Syndrome?
250 In table 2, the authors consensus on the different recommendations is summarized.

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251 Most of the clinical trials focusing on risk factors for RFS are in agreement with
252 criteria proposed by the NICE guidelines [14, 30-35]. Still, Goyale [36] and Zeki [37]

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253 reported low sensitivity and specificity of these factors to predict RFS. NICE
254 guidelines were published in 2006 and deal with nutrition support, enteral tube

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255 feeding and parenteral nutrition in adults. These guidelines propose low BMI, high
256 unintentional weight loss in a short time period, little or no nutritional intake for
257 approximately 5 to 10 days or a history of alcohol or drug misuse (including insulin,
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chemotherapy, antacids or diuretics) to be risk factors for RFS in patients started on
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259 nutritional therapy.
260 Rio et al. [35] found starvation and low baseline serum magnesium concentration to
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261 be independent predictors for RFS, but no further study has yet validated these
262 findings. Furthermore low pre-albumin or albumin concentration [3, 38-40], use of
enteral nutrition [3, 37, 41] and higher amounts of nutritional intake during nutritional
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264 therapy [8, 32, 42] were found to be risk factors. Some studies did, however, not find
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265 that these factors predicted RFS, although some of the studies were small in size
266 with risk for type II error [38, 43, 44].
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267 Thus, based on the available evidence, risk criteria proposed by the NICE guidelines
268 seem to be adequate to identify patients at high risk for RFS with prolonged
starvation being the most important risk factor. Additionally there may be other risk
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270 factors such as high age, low baseline serum magnesium concentrations, high
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271 malnutrition risk scores (i.e., NRS 2002 ≥3 points) [15] or severe catabolic disease in
272 conjunction with the use of enteral or parenteral feeding . Also, because RFS is
273 potentially preventable and associated with life-threatening consequences, initial risk
274 assessment for RFS should be done in patients before start of nutritional
275 replenishment using the same risk factors (Figure 1 and table 1). In order to
276 differentiate between no risk, low risk, high risk and very high risk for RFS we
277 adapted the NICE guidelines and added additional criteria for the very high risk
278 category.

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279
280
281 How should high risk patients be treated in order to prevent RFS
282 Several trials [30, 33] found prophylactic administration of phosphate and thiamine in
283 patients at risk for RFS to be effective in order to prevent hypophosphatemia, RFS
284 and also mortality and adverse outcome during nutritional replenishment. Only three

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285 studies showed no such effect . This is in agreement with a pathophysiological view
286 where intracellular electrolytes and vitamins are depleted in patients with

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287 deteriorating nutritional status and after the start of nutritional therapy the sudden flux
288 into the cells leads to a drop of plasma levels. Especially phosphate is the result of

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289 restarting metabolism with the initiation of nutritional replenishment in starved
290 patients. Therefore, preventive supplementation of phosphate in patients at high and
291 very high RFS risk should be considered, even if the phosphate concentration is still
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in the low normal range. Of note, during starvation there is phosphate outflow from
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293 the cells into the blood and thus plasma phosphate levels are often still in the normal
294 range before start of feeding despite deficiencies in storage levels. In patients with
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295 renal failure phosphate supplementation should be administered carefully. Thiamine

296 should also be preventive administrated before initiation of nutritional therapy
independent of blood levels. Also, deficiencies of other electrolytes such as
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298 potassium and magnesium should corrected, if levels are below the normal range. In
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299 order to prevent fluid overload, sodium and fluid should be restricted to the minimum
300 necessary for restoring sodium and water balance.
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301 Regarding nutritional therapy, there is evidence from several studies and guidelines
302 supporting the concept of lowering energy intake in patients at risk for RFS during the
initial phase of nutritional support [14, 21, 30, 45]. Still, Rio et al. [35] found in their
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304 prospective observational trial no preventive effect of hypocaloric feeding in regard to
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305 RFS, but risk for RFS was generally low and the study was thus underpowered. In
306 fact, only 3 out of 243 patients were diagnosed with RFS defined by clinical criteria
307 and laboratory abnormalities. Also, the study was not randomized, making causal
308 inference impossible. Importantly, a recent high-quality randomized trial authored by
309 Doig et al [9] in 339 critically ill adults admitted to intensive care found caloric
310 restriction to be an effective measure to prevent RFS. Mortality on day 60 after study
311 inclusion was significant lower in the intervention group where hypocaloric treatment
312 was used during the initial phase of nutrition support. Although this study was not

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313 done in medical ward patients, it is considered the best quality evidence today
314 regarding treatment of patients with evidence of RFS.
315 Today, the most widely used guideline for RFS is the recommendations published by
316 NICE. Those guidelines recommend starting with hypocaloric feeding in patients at
317 high risk for RFS. Based on this and the recent evidence from the study by Doig et
318 al. [9] we recommend to use a risk-adjusted low caloric target in patients at risk for

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319 RFS. The recommended initial energy intake is based on the four risk categories (no
320 risk, low risk, high risk, very high risk) with a gradual increase to the full caloric

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321 amount within 5 - 10 days (Figure 1). Because current evidence points to beneficial
322 effects of nutritional therapy in medical inpatients [46-48], RFS risk should not lead to

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323 suboptimal nutritional care in patients. Thus, we recommend to use individual clinical
324 judgement in deciding the best rate to increase nutrition support to reach targets in
325 the different phases of replenishment (Figure 1). Specifically, we decided to lower
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the amount of calories in the high risk group to 10 kcal/kg despite the lack of research
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327 studies documenting that such a measure would be beneficial to the patient. Yet,
328 there was no strong consensus about this measure within the group and some
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329 centers have reported good clinical experience with using higher targets (i.e., 20
330 kcal/kg) for the high risk group. Also, in patients who are initially not at increased risk
for RFS but later develop RFS during nutritional replenishment, energy targets should
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332 be reduced and the feeding algorithm adapted. In addition we recommend a careful
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333 fluid management to avoid fluid overload (Table 1).

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335 How should we monitor patients at risk for Refeeding Syndrome?

336 In a study on malnourished cancer patients started on artificial nutritional support, the
incidence of the RFS defined by a phosphate concentration <0.40 mmol l-1, was
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338 found to be 24.5%, with a higher incidence in patient with enteral (37.5%) compared
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339 to parenteral (18.5%) nutrition [4]. In that study, 61.5% of patients developed the RFS
340 within the first three days after start of feeding. In line with this, most studies reported
341 that the RFS occurs within the first 72h after start of nutritional therapy. This period
342 seems to be the most vulnerable phase, as metabolism changes from a catabolic to
343 an anabolic state and electrolytes as well as fluids shifts are most likely to occur.
344 Thus, we recommend that during this initial phase, electrolytes should be monitored
345 and clinical examination performed at least daily in order to detect signs and
346 symptoms of fluid overload or impaired organ function associated with RFS. If critical

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347 electrolytes drop significantly during the refeeding period, an adequate substitution
348 should be started preferably by oral route. In patients with gastrointestinal failure
349 (e.g., Ileus, short bowel, malabsorption), parenteral routes are preferable.
350 Furthermore, monitoring of the cardiac rhythm is advisable by electrocardiogram in
351 the initial refeeding phase in high risk patients. This helps to early detect
352 abnormalities caused by electrolyte shifts (e.g., QT prolongation) which potentially

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353 causes severe arrhythmias (e.g. torsades de pointes).
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355 Which diagnostic criteria should be used for Refeeding Syndrome?
356 During starvation (catabolic state) the organism switches from carbohydrates/

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357 glycogen to body protein (gluconeogenesis) and fat (free fatty acids, ketogenesis)
358 metabolism as the main source of energy. During replenishment, the sudden glucose
359 supply results in an overwhelming increase in insulin concentrations (anabolic state)
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stimulating the production of glycogen, fat and protein. Importantly, high
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361 concentrations of insulin lead to renal sodium retention with potential fluid overload.
362 For those processes electrolytes and minerals are needed which cause a depletion of
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363 the serum concentrations of potassium, phosphate, magnesium and thiamine.

364 Considering these physiological changes, a shift in electrolytes is the hallmark of
RFS and often considered a main diagnostic criterion for RFS. Clinical symptoms
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366 such as peripheral oedema, respiratory insufficiency or heart failure resulting from
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367 these electrolyte and fluid shifts may occur in severe cases. Manifest RFS is defined
368 as electrolyte changes and clinical symptoms, while imminent RFS is defined by
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369 electrolyte shifts only. A majority of studies use hypophosphatemia as the main
370 criterion for RFS [21]. In fact, in our recent systematic review 20 out of 38 studies
based their RFS definition on hypophosphatemia. We therefore see a shift of serum
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372 phosphate as the main diagnostic criteria of RFS, although shifts in other electrolyte
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373 may also occur and point to RFS. If during the first 72h after the start of nutrition
374 therapy phosphate decreases >30% from baseline or below 0.6 mmol l-1, or any two
375 other electrolyte shifts below the normal range occur, imminent RFS is highly likely.
376 If clinical symptoms occur, manifest RFS should be considered.
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378 How should we treat imminent or manifest Refeeding Syndrome?
379 Out of 45 studies included in the systematic review [12], only three reported on
380 therapeutic strategies to treat RFS. Two of them reported phosphate

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381 supplementation to be effective [49, 50]. Doig et al. [9] reduced energy intake for
382 critically ill patients suffering from RFS (defined by hypophosphataemia) and showed
383 that this measure was successful. We therefore recommend intensifying or starting
384 electrolyte supplementation in case of an imminent or manifest RFS. If patients suffer
385 from evident RFS with clinical symptoms (oedema, lung or heart failure, other organ
386 deterioration), both the energy content of nutritional replenishment should be reduced

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387 and a careful fluid management should be used in high risk patients, in addition an
388 adequate treatment for clinical symptoms is mandatory.

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389
390 Limitations of current evidence and outlook

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391 Based on a recent systematic review on RFS [12] and pathophysiological
392 considerations, we developed a treatment algorithm for the nutritional care of
393 malnourished medical inpatients in order to prevent RFS. Current evidence is in line
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with former NICE guidelines and updated with recent trial data. Most of trial data
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395 used for this guidelines was observational but not interventional making strong
396 recommendations difficult. There are unanswered questions regarding why patients
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397 develop RFS and whether it is rather a physiological biological response or

398 maladaptation [47]. Also, it is unknown whether there is a difference between RFS
and refeeding hypophosphataemia. In addition, it remains unclear what the optimal
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400 calorie replacement rate is and whether it differs between patient populations (e.g.,
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401 critically ill vs medical ward patients)[51]. Finally, it remains still unclear whether
402 hypo- or hyperglycaemia plays a role in the manifestation of RFS and if treatment
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403 with insulin may interact with the risk for RFS.
404 Although several blood markers have been proposed as malnutrition biomarkers [52],
there are only few reports about markers predicting the later occurrence of RFS.
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406 Some studies state that increased IGF-1 in combination with an increased leptin
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407 concentration would be associated with a 30% decrease in phosphate concentration

408 within 12-36 hours after starting parenteral nutrition therapy [43]. Other markers such
409 as cytokines may also play an important role here. Finally, several reports [26-28]
410 have shown that thiamine substitution is important to prevent Wernicke’s and
411 Korsakoff psychosis, but little is known about the potential of other vitamin and trace
412 elements.
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414

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415
416 Conclusion
417 The RFS is a life-threatening metabolic condition due to a rapid, inadequate
418 nutritional support in malnourished catabolic patients. High morbidity and mortality
419 can be reduced by early diagnosis of RFS and appropriate measures taken [18].
420 Therefore, in-depth knowledge of this metabolic condition is essential for its

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421 prevention, recognition and treatment. Based on a recent systematic literature review
422 [12], we developed a practical algorithm for risk assessment, treatment and

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423 monitoring of RFS in medical inpatients, which may help to optimize and standardize
424 the RFS management. Still, many aspects and pathophysiological pathways of RFS

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425 remain unclear. We therefore encourage future quality studies to further refine our
426 recommendations.

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427 TABLE 1: Metabolic functions of intracellular electrolytes

Phosphate

Phosphate (PO4) is important for intracellular metabolism of proteins, lipids and

carbohydrates and it is a major component in phospholipid membranes, RNAs, nicotinamide
diphosphate (an enzymatic cofactor), cyclic adenine and guanine nucleotides (second
messengers), and phosphoproteins. It is involved in cellular regulatory processes like

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protein phosphorylation/de-phosphorylation, mitochondrial energy production and energy
transfer (e.g. generation of adenosine triphosphate (ATP), creatine phosphate). Phosphate

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is a component of 2,3-diphosphoglycerate (2,3-DPG), which regulates the release of oxygen
from haemoglobin to tissues. Furthermore, phosphate has a regulatory role in the glycolysis

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and hydroxylation of cholecalciferol. It is also an important acid base buffer.
Note: Phosphor (P) is present as phosphate (PO4) in biologic systems; it is the concentration
of elemental (or inorganic) phosphorus that is measured in the clinical laboratory, although

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the terms phosphorus and phosphate tend to be used interchangeably. As long as molar
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concentrations are used, the phosphorous and phosphate concentration can be used
interchangeably as they refer to the same (molar) amount of phosphate in a given volume.
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Magnesium

Magnesium has a widespread physiological role in maintaining neuromuscular functions and

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enzymatic functions. It is an essential component for ATP stabilization, acting as a cofactor

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for phosphorylation of ATP from adenosine diphosphates (ADP) and for many enzymatic
processes.

Potassium and Sodium

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The sodium - potassium membrane gradient is an indispensable condition for membrane

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excitation, signal transduction and for transport processes. This is partly due to the larger
hydration shell of sodium, which prevents spontaneous membrane transport and ideally
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keeps the extracellular volume. In contrast, the smaller hydration shell of potassium allows
free exchange and potassium shift to cells during growth and anabolism. Importantly, while
the amount of sodium in natural food is low with at the same time higher amounts of
potassium, magnesium and phosphate, the opposite is true for processed foods. This may
explain why the metabolic changes during refeeding were safe in our ancestors, but is now
more problematic with the high salt intake of common modern diets.
428
429

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430 TABLE 2: Consensus opinion on management of RFS in medical inpatients

Topic Recommendations Agreement

RFS can occur in medical inpatients and is associated with adverse

outcome if left untreated. Risk assessment, establishment of a care plan
General
and monitoring of patients during nutritional therapy are important to Strong
reduce RFS-related morbidity.
Which medical inpatients are at risk for RFS?

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NICE guidelines criteria seem to be accurate for identification of patients
at high risk for RFS with starvation being the most important risk factor.
Patients at Other criteria such as high age, low baseline serum magnesium

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risk for RFS concentrations, high malnutrition risk scores (i.e., NRS 2002 ≥3 points) Strong
or overcoming severe catabolic disease together with aggressive use of
enteral or parenteral feeding maybe considered as additional risk factors

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for development of RFS.
How should high risk patients be treated to prevent RFS?
Patients at high risk for RFS should receive substitution of lower-than-

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normal electrolytes (Mg <0.70-0.75mmol/l, PO4 <0.80mmol/l, K
Initial <3.5mmol/l). Additionally, patients should be treated with vitamin B1
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treatment of (thiamine) and multivitamins. In those patients nutritional therapy should
high risk be started with reduced caloric targets and a slow increase to the full
patients and caloric amount over 5-10 days according to the individual risk category Moderate
prophylactic for RFS. Fluid overload should be prevented by restricted use of fluid
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measures to and sodium restricted diet within the first 7 days. We recommend
prevent RFS prophylactic supplementation of electrolytes, thiamine and minerals
before initiation of nutritional support in patients at risk for RFS. No iron
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substitution within the first 7 days even when patients have iron
deficiency.
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How should we monitor patients at risk for RFS?

RFS Electrolyte concentrations should be monitored daily during the first 72h
Monitoring of nutritional therapy with additional clinical examination to detect signs Strong
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and symptoms of fluid overload in patients at risk for RFS.

Which diagnostic criteria should be used for RFS?

Based on electrolyte concentrations and clinical symptoms, imminent
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Diagnostic and manifest RFS may be distinguished. Imminent RFS is present if shift
criteria for in electrolytes (decrease of phosphate from baseline >30% or below
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0.6mmol/l or any two other electrolyte shifts below normal range) occurs Strong
RFS
within 72 hours after start of nutrition therapy, while manifest RFS is
considered if any electrolyte shifts occur in conjunction with typical
clinical symptoms.

How should we treat imminent or manifest RFS?

In case of an imminent or manifest RFS, electrolyte supplementation
Treatment of should be started or adapted. If patients suffer from manifest RFS with
RFS oedema, lung or heart failure, the caloric target should be reduced as in Strong
high risk patients and adequate treatment for those conditions is
needed.
431
432

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433 FIGURE 1: Guidelines for management and prevention of RFS in medical
434 inpatients receiving nutritional therapy
435
436

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Highlights

• Refeeding Syndrome is a dangerous metabolic condition following nutritional

replenishment if not recognised early and treated adequately
• Refeeding Syndrome is most critical in the first 72 hrs period upon refeeding.

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Therefore, special attention has to be given upon initiation of food replenishment
• According to the individual risk of a patients, a careful start of nutritional therapy

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with a step-wise increase in energy and fluids goals, supplementation of
electrolyte and vitamins is recommended.
•

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We propose criteria for the diagnosis of imminent and manifest Refeeding
Syndrome
• An evidence-based algorithm to manage RFS in clinical practice is provided

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