G Model

ARTICLE IN PRESS
Med Clin (Barc). 2017;xxx(xx):xxx–xxx

www.elsevier.es/medicinaclinica

Review

The refeeding syndrome. Importance of phosphorus夽

Marta Araujo Castro a,∗ , Clotilde Vázquez Martínez b
a
Servicio de Endocrinología y Nutrición, Hospital Universitario Rey Juan Carlos, Madrid, Spain
b
Servicio de Endocrinología y Nutrición, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Refeeding syndrome (RS) is a complex disease that occurs when nutritional support is initiated after a
Received 29 September 2017 period of starvation. The hallmark feature is the hypophosphataemia, however other biochemical abnor-
Accepted 2 December 2017 malities like hypokalaemia, hypomagnesaemia, thiamine deficiency and disorder of sodium and fluid
Available online xxx
balance are common.
The incidence of RS is unknown as no universally accepted definition exists, but it is frequently under-
Keywords: diagnosed.
Refeeding syndrome
RS is a potentially fatal, but preventable, disorder. The identification of patients at risk is crucial to
Hypophosphataemia
Starvation
improve their management.
Hypokalaemia If RS is diagnosed, there is one guideline (NICE 2006) in place to help its treatment (but it is based on
Hypomagnesaemia low quality of evidence).
Prevention The aims of this review are: highlight the importance of this problem in malnourished patients, discuss
the pathophysiology and clinical characteristics, with a final series of recommendations to reduce the
risk of the syndrome and facilitate the treatment.
© 2018 Elsevier España, S.L.U. All rights reserved.

El síndrome de realimentación. Importancia del fósforo

r e s u m e n

Palabras clave: El síndrome de realimentación es una enfermedad compleja que ocurre cuando se inicia el soporte nutri-
Síndrome de realimentación cional después de un periodo de ayuno. La característica principal es la hipofosfatemia, sin embargo,
Hipofosfatemia también son comunes otras alteraciones bioquímicas como la hipomagnesemia, el déficit de tiamina y
Ayuno
las alteraciones hídrico-electrolíticas.
Hipopotasemia
Su incidencia es desconocida, ya que no existe una definición universalmente aceptada, pero con
Hipomagnesemia
Prevención frecuencia está infradiagnosticado.
El síndrome de realimentación es un trastorno potencialmente fatal pero prevenible. Identificar a los
pacientes en riesgo es crucial para mejorar su manejo.
Si se diagnostica existen unas guías (NICE 2006) para orientar su tratamiento (pero basadas en un bajo
grado de evidencia).
Los objetivos de esta revisión son: destacar la importancia de este problema en pacientes desnutri-
dos, discutir su fisiopatología y características clínicas y dar una serie de recomendaciones finales para
disminuir el riesgo de desarrollarlo y facilitar su tratamiento.
© 2018 Elsevier España, S.L.U. Todos los derechos reservados.

Introduction and definition

The refeeding syndrome (RS) is a complex disorder, in which

the key event is the development of severe hypophosphataemia
夽 Please cite this article as: Araujo Castro M, Vázquez Martínez C. El sín- after reintroduction of nutrition, whether oral, enteral or parenteral
drome de realimentación. Importancia del fósforo. Med Clin (Barc). 2018. in malnourished or deprived patients. Anomalies also occur in the
https://doi.org/10.1016/j.medcli.2017.12.008 water balance and hydrocarbon metabolism, deficiency of vitamins
∗ Corresponding author.
(especially thiamine) and other electrolytes.1,2 All this translates
E-mail address: martaazul.2a@hotmail.com (M. Araujo Castro).

2387-0206/© 2018 Elsevier España, S.L.U. All rights reserved.

MEDCLE-4395; No. of Pages 7

G Model
ARTICLE IN PRESS
2 M. Araujo Castro, C. Vázquez Martínez / Med Clin (Barc). 2017;xxx(xx):xxx–xxx

Table 1
Causes of hypophosphataemia, hypokalaemia and hypomagnesaemia.

Hypophosphataemia Hypomagnesaemia Hypokalaemia

Increase extra-intracellular mobility Increase output to the extracellular space Increase intra-extracellular mobility
RS RS RS
Alkalosis Respiratory acidosis correction Alkalosis
Gram-negative sepsis Diabetic ketoacidosis correction Hypothermia
Salicylate toxicity Other: pancreatitis, transfusions, burns, sweating Theophylline intoxication
Drugs: insulin, intravenous glucose, adrenaline, Drugs: insulin, foscarnet, amphotericin B, tacrolimus
salbutamol, terbutaline, dopamine, etc.
Decreased intestinal absorption Decreased absorption or increase intestinal losses Increase extrarenal losses
Drugs: antacids with aluminium Malabsorption syndrome Profuse sweating
Vomiting, diarrhoea, fistulas Diarrhoea, vomiting
Drugs: laxatives
Increased renal excretion Increased renal excretion Increased renal excretion
Primary and secondary hyperparathyroidism Tubular disorders Hyperaldosteronism
Tubular disorders Hyperaldosteronism Diabetic ketoacidosis
Hyperaldosteronism SIADH Polyuria
Poorly controlled diabetes Diabetes mellitus Hypomagnesaemia
Alcoholism Hyperthyroidism Drugs: diuretics (loop, distal), penicillin, amphotericin
Hypercalcaemia Hypercalcaemia B, aminoglycosides
Hypomagnesaemia Alcoholism
Toxicity: iron, cadmium Drugs: diuretics (loop, thiazide, osmotic), cisplatin,
Drugs: diuretics, corticosteroids, bicarbonate, pentamidine, cyclosporine, aminoglycosides,
oestrogens at high doses, ifosfamide, cisplatin, foscarnet, amphotericin B, tacrolimus
foscarnet, pamidronate
Other: vomiting, diarrhoea and surgery

SIADH: Syndrome of Inappropriate ADH Secretion; RS: refeeding syndrome.

Source: Fernández López et al.6

into cardiovascular, respiratory, neurological and haematological intravenous fluid therapy are also risk groups.3,8 Of special risk are
manifestations, among others, which usually occur a few days after patients with head and neck tumours, since they present multiple
the start of refeeding.3 risk factors for a RS (fasting > 5 days in the context of dysphagia
The first description of RS was made in connection with prison- due to tumour progression, tumour cachexia, prolonged fasting in
ers of the Second World War who had suffered prolonged fasting; the postoperative period, previous history of alcohol abuse, among
a severe condition of congestive heart failure (CHF), seizures and others).11
even death occurred when a normal diet was reintroduced. The There is the possibility of developing a RS with any type of NS,
classic study that describes RS is the Minnesota experiment, in even in patients undergoing oral nutrition at home. Some studies
which healthy volunteers are subjected to food restriction for 6 document a higher incidence with enteral nutrition (EN) than with
months and subsequent refeeding, observing a similar but milder PN (possible influence of incretin effect in EN that would produce
condition.4 In 1980, the hypothesis of hypophosphataemia sec- a higher insulin secretion and less predictable absorption than in
ondary to refeeding was proposed as a key aspect of RS, which is PN).12
what is known today.5 Currently the main risk group is patients with anorexia nervosa
The importance of RS lies in a significant associated morbidity (AN), given its high prevalence and high risk of RS: 14% (0–38%)
and mortality; however, death is currently unusual in this context. of AN develop it.13,14 The guidelines of the National Institute for
In the hospitalized and severe patient there are multiple causes Health and Care Excellence (NICE) 2006 establish a series of criteria
of hypophosphataemia, hypomagnesaemia and hypokalaemia with that help identify risk groups15 (Table 2).
which a differential diagnosis must be made6 (Table 1). On the other hand, hypophosphataemia is present in up to 40%
of hospitalized patients, and even a higher percentage in the case
Epidemiology of patients admitted to intensive care units and infectious disease
services.16 The RFs are basically the same as those of RS.17
It is a relatively common problem in malnourished patients,
which is important, since 30–50% of hospitalized patients have
malnutrition or are at risk of developing it.7 Pathogeny
The incidence is very variable according to the definition used
and the different series, but it is usually underdiagnosed, especially In normal conditions carbohydrates serve as the main energy
by non-nutritionists.2 Its true incidence is unknown, partly due to source for tissues (hepatic and muscular glycogen stores).
the absence of a universally accepted definition and that most of During fasting the body tries to compensate for the lack of energy
the studies are retrospective and do not evaluate all RS components, through changes in metabolism and hormonal regulation. The body
but rather the presence of hypophosphataemia.1,8,9 It is estimated enters a catabolic state, in which glycogen reserves are used until
that it develops in 20–40% of malnourished patients undergoing exhaustion. At that time, proteolysis (protein degradation in amino
NS.10 acids) starts, followed by gluconeogenesis (obtaining glucose from
Patients with risk of RS are considered those with chronic mal- amino acids, lactate and glycerol). After 72 h of fasting other pro-
nutrition, chronic exacerbated or acute who are going to receive NS. cesses are initiated to minimize the mobilization of amino acids
The risk increases if there are long-standing nutritional deficiencies and decrease protein catabolism, including lipolysis, in which free
(as in alcoholism or elderly patients).3 The morbidly obese with sig- fatty acids are released that can be used for the synthesis of ketone
nificant weight loss after bariatric surgery, oncology patients with bodies. Ketoadaptation is one of the most important metabolic
total parenteral nutrition (PN) or patients undergoing prolonged phenomena in the response to fasting.1,6,8,18
G Model
ARTICLE IN PRESS
M. Araujo Castro, C. Vázquez Martínez / Med Clin (Barc). 2017;xxx(xx):xxx–xxx 3

Table 2 The hypophosphataemia in RS normally develops in the 1st

Criteria of the NICE Guidelines to identify patients at risk of refeeding syndrome
week after starting NS, usually after the third day. Its occurrence is
(Recommendation Level D).
mainly related to the glucose content of the diet: glucose increases
Patients with ≥1 of the following: insulin secretion, which promotes the intracellular reuptake of
BMI < 16 kg/m2
phosphorus, being this the key determinant of hypophosphataemia
Unintentional weight loss >15% in last 3–6 months
No or low intake >10 days
in RS. The reduction of intake (fasting), the alteration of absorption
Low phosphorus, potassium, or magnesium levels before starting NS (intestinal villous atrophy due to prolonged fasting) and an increase
Or patients with ≥2 of the following: in renal and extrarenal losses also contribute.25,26,29
IMC < 18.5 kg/m2 There are 3 grades: mild 2.3–2.5 mg/dl, moderate 1.5–2.2 mg/dl
Unintentional weight loss >10% in last 3–6 months
and severe <1–1.5 mg/dl. Mortality in severe hypophosphataemia
No or low intake >5 days
History of alcohol abuse or drug abuse such as insulin, chemotherapy, is 30%.28
antacids or diuretics Symptomatology develops with levels <1.5 mg/dl (may develop
BMI: body mass index; NS: nutritional support. with higher figures if the decrease is rapid) and is evident with
<1 mg/dl. There are mainly cardiovascular, respiratory, neurologi-
cal and haematological manifestations.26,30
Other adaptive changes are produced with the aim of pre- The cardiovascular manifestations usually appear in the first
serving vital functions: the secretion of insulin, triiodothyronine, week of NS.17 Fluid replacement and sodium and water retention
gonadotropins and leptin decreases, among others. All this, in asso- induced by hyperinsulinism, associated with myocardial dysfunc-
ciation with a decrease in the tone of the sympathetic nervous tion due to pre-existing cardiac atrophy (due to malnutrition)
system, results in a 20–25% decrease in basal metabolism.19–21 and severe hypophosphataemia, predispose to CHF.31,32 Severe
There is also loss of weight and cell mass, and therefore a hypophosphataemia can cause hypotension, pericardial effusion,
decrease in the size of organs, being more significant in some of shock, arrhythmias and even sudden death. Ventricular arrhyth-
them, such as in the heart (myocardial atrophy that can cause mias appear in up to 20% of patients without structural heart
CHF). disease, increasing the risk in case of coexistence with hypomag-
Potassium, magnesium and phosphorus deposits are depleted, nesaemia and hypokalaemia.5
however, their serum levels may be normal (especially in the initial The decrease of intraerythrocytic ATP in the haematological
phases of refeeding), since they are mainly intracellular ions.3 system alters the flexibility of the erythrocyte membrane, deter-
An anabolic state occurs during refeeding. Insulin secretion mining a reversible spherocytosis (with the administration of
increases (especially with diets rich in carbohydrates), this gener- phosphorus) that predisposes to the development of haemolytic
ates the introduction of phosphorus, potassium and magnesium in anaemia. Severe hypophosphataemia is associated with throm-
the cell (decrease in plasma levels) and an increase in the synthe- bocytopenia and leucocyte dysfunction, which predispose to the
sis of proteins, lipids and glycogen.22 For the synthesis of these, development of secondary haemorrhages and serious infections,
cofactors are needed (of phosphorus, magnesium and thiamine, respectively.8,18,32,33
among others), their demand increases, and their deficiency can Severe hypophosphataemia can lead to acute respiratory fail-
be exacerbated. Hyperinsulinism exerts an antinatriuretic effect in ure or difficulties in disconnecting mechanical ventilation in the
the renal tubule: water and sodium are retained (risk of CHF) and respiratory system (it would be advisable to wait until reach-
there is an increase in energy expenditure (increased conversion of ing a normal phosphataemia before disconnecting the patient
T4 to T3).23–25 from ventilation). All this is related to the decrease of ATP in
the intercostal muscles and diaphragm, and the decrease of 2,3-
DPG.18,34,35
Biochemical abnormalities and clinical manifestations
The neurological manifestations range from paraesthesia, con-
fusion and weakness to seizures and even coma. Occasionally,
The clinical manifestations of RS occur mainly as a consequence
acute areflexic paralysis symptomatology simulating a Guilläin-
of hypophosphataemia, hypokalaemia and hypomagnesaemia and
Barré syndrome may occur.36 These abnormalities are infrequent
the rapid change in metabolic rate (Table 3).
with phosphate levels >1 mg/dl and, although its aetiology is not
clear, they seem to be related to cellular hypoxia secondary to the
Hypophosphataemia decrease of 2,3-DPG and ATP.3
Muscle-skeletal involvement is the most common manifes-
Phosphate is the main intracellular anion. Its organic deposits tation of hypophosphataemia (30%). It is characterized by
are 500–800 mg: 80% is found in the bone and the rest in the muscle weakness, myalgias, rhabdomyolysis (more common in alco-
and soft tissues. Inorganic (extracellular) phosphate accounts for holics), diaphragmatic weakness or symptomatology of proximal
1% of the total body reserves (TBR). Its deficiency in a normal diet myopathy.3,32,35
is rare, with its excess being more normal.26 Hypophosphataemia
occurs in up to 50% of patients with chronic alcoholism, and the Hypokalaemia
prolonged intake of antacid drugs also promotes its development.10
Its normal levels range from 2.5 to 4.5 mg/dl. Short-term reg- K is the main intracellular monovalent cation (98% intracellu-
ulation depends on the intracellular-extracellular flow dependent lar). It is essential for the maintenance of membrane potential and
on the intake of carbohydrates and lipids and modifications of the the regulation of glycogen and protein synthesis.37 In addition, it
acid–base balance, and kidney in the long-term.27 participates in water, osmotic and acid-base balance.
Phosphate is essential for all intracellular processes and for the Clinical manifestations range from mild gastrointestinal
integrity of cell membranes. It allows the activation of multiple symptoms and muscle weakness in case of mild-moderate
enzymes and second messengers, it is necessary for the storage of hypokalaemia, to more severe clinical symptoms with serum
energy in the form of ATP and regulates the affinity of haemoglobin levels <2.5 mEq/l: areflexic paralysis, paraesthesias, rhabdomy-
for oxygen (it is a cofactor of glyceraldehyde phosphate dehydro- olysis, muscle necrosis, respiratory distress or confusion. Elec-
genase – 2,3-diphosphoglycerate [2,3-DPG] and ATP decreases in trocardiographic changes (ST segment depression, flattened
hypophosphataemia19,28 ). or inverted T-waves, U waves) are also observed; increased
G Model
ARTICLE IN PRESS
4 M. Araujo Castro, C. Vázquez Martínez / Med Clin (Barc). 2017;xxx(xx):xxx–xxx

Table 3
Biochemical abnormalities and clinical manifestations of RS.

Hypophosphataemia Hypokalaemia Hypomagnesaemia Thiamine Excess sodium Hyperglycaemia

deficiency

Cardiac Hypotension Arrhythmias Arrhythmias CHF Hypotension

Myocardial
function
depression
Respiratory Diaphragmatic Respiratory failure Weakness, shaking, Acute pulmonary Hypercapnia
weakness tetany, oedema Respiratory failure
Dyspnoea convulsions,
Respiratory failure altered level of
consciousness and
coma
Neurological Paraesthesias, Weakness Encephalopathy Coma
and/or muscular weakness, Paralysis
confusion, Rhabdomyolysis,
disorientation, muscle necrosis
lethargy
Areflexic paralysis
Convulsions, coma
haematological Leucocyte Nausea, vomiting, Nausea, vomiting
and/or GI dysfunction, constipation, and diarrhoea
haemolysis,
thrombocytopenia
Other Death Death Hypokalaemia and Lactic acidosis and Ketoacidosis
refractory death Dehydration
hypocalcaemia Immune alteration
Death

CHF: congestive heart failure; GI: gastrointestinal.

Source: Fuentebella and Kerner.19

risk of arrhythmia and other abnormalities such as a carbo- Chronic alcoholics, those with malabsorption syndrome and
hydrate intolerance, metabolic alkalosis and digitalic toxicity pregnant women with significant vomiting are considered to be
potentiation.37,38 at risk for thiamine deficiency.
Its decrease in RS is due to its intracellular use as a cofactor
of several enzymes (mainly for the synthesis of glycogen). In thi-
Hypomagnesaemia amine deficiency, CHF symptomatology may appear (wet beriberi),
Wernicke encephalopathy (dry beriberi) (eye disorders, confusion,
Magnesium is the second most abundant intracellular cation ataxia and coma) or a Korsakov syndrome (antegrade and retro-
(99% intracellular). It acts as a cofactor of numerous enzymes: grade amnesia and confabulation).35,41–43
it participates in the regulation of various biochemical reactions
(oxidative phosphorylation, ATP production) and also requires ade-
Sodium and water retention and lipid and hydrocarbon
quate levels of magnesium for the active form of vitamin B1.39
metabolism disorders
Their normal levels are 1.8–2.5 mg/dl. Hypomagnesaemia is
common in critical patients, alcoholics, with diabetes, digestive
Changes in the metabolism of carbohydrates have an important
diseases or regular users of diuretics and aminoglycosides. It is
effect on the balance of water and sodium: the intake of hydrates
associated with an increase in morbidity and mortality.39
in the diet leads to a decrease in renal elimination of sodium and
During refeeding it increases its passage to the intracellular
water, which favours the development of CHF.
space, favouring its deficiency. Evident symptoms are normally
Glucose ingestion in malnutrition suppresses gluconeogenesis,
absent in mild-moderate hypomagnesaemia (1–1.5 mg/dl), but
with a decrease in the use of amino acids (especially alanine),
with levels <1 mg/dl, neuromuscular dysfunction, electrocardio-
however if the administration of glucose is excessive, hypergly-
graphic changes (prolonged PR, widening of the QRS, prolonged
caemia may appear, with the risk of hyperosmolar decompensation
QT, peaked or flattened T waves), arrhythmia or even sudden death
and ketoacidosis. On the other hand, excess glucose can be
may occur. In addition, hypomagnesaemia favours hypocalcaemia
used for the synthesis of lipids and predispose to the devel-
(produces a resistance to vitamin D and abnormalities in the secre-
opment of hypertriglyceridemia, fatty liver and liver function
tion and action of PTH on bone and kidney) and hypokalaemia
abnormalities.1,3,8,26,44
(produces an alteration of the Na+ /K+ -ATPase, leading to an increase
in renal losses of potassium).40
Prevention

Thiamine deficiency The RS is a potentially fatal, but preventable condition. Iden-

tifying patients at risk is crucial to improve their management.
Thiamine or vitamin B1 is a water-soluble vitamin, with a short There are some key steps to avoid its development, however, some
half-life (9.5–18.5 days), resulting in a rapid depletion of its deposits cases of RS have been reported despite its correct application. It is
in case of malnutrition. It acts as a cofactor of pyruvate dehy- also important to request an assessment by the nutrition depart-
drogenase and transketolases, its presence being necessary for ment at an early stage. The points considered most important
carbohydrate metabolism.41 are1–6,14,16,19,26,29,33,34 (Table 4):
G Model
ARTICLE IN PRESS
M. Araujo Castro, C. Vázquez Martínez / Med Clin (Barc). 2017;xxx(xx):xxx–xxx 5

Table 4 some cases, as in malnutrition secondary to chronic alcoholism,

Preventive measures in refeeding syndrome. 2006 NICE Guidelines.
in addition to thiamine, a multivitamin supplementation must
1. Patient at risk be administered to avoid other associated deficiencies.
2. Determination of potassium, calcium, phosphorus and magnesium 9. Daily monitoring of heart rate (HR) and respiratory rate, blood
3. Before starting NS: administer 200–300 mg/day of oral thiamine,
® pressure and pulse oximetry. Elevation of HR is considered an
vitamins B group complex (example: vitamin B co strong 3–6 tablets/day,
or the total dose intravenously) and multivitamin and trace elements
early sign of development of RS and in patients with AN even a
supplement 1/day HR of 70–80 bpm should alert us to its possible development.46
4. Start NS with 10 kcal/kg/daya
Slow increase of NS in 4–7 days
5. Careful rehydration and supplement and/or correct the levels of
Treatment
potassium (2–4 mmol/kg/day), phosphorus (0.3–0.6 mmol/kg/day),
calcium and magnesium (0.2 mmol/kg/day intravenous or
0.4 mmol/kg/day oral) Once RS has been diagnosed, a series of general measures must
6 Monitor potassium, phosphorus, calcium and magnesium in the first 2 be carried out together with an aggressive correction of the elec-
weeks and treat when necessary
trolyte disorder.1–6,13,18,27,44,47,48
NS: nutritional support. Regarding general measures, the first is to diminish, or even dis-
Source: management guidelines, adapted from the NICE Guidelines and the British continue, the supply of nutrients immediately.32,34 In addition, the
Association of Parenteral and Enteral Nutrition.15
a
necessary support measures should be established to manage its
In severe malnutrition (for example BMI < 14) or low intake >2 weeks start NS
with a maximum of 5 kcal/kg/day; 1 mg/dl = 0.32 mmol/l. complications and administer 100 mg of intravenous thiamine if
neurological changes occur.6 NS can be reintroduced after verify-
ing that the patient is stable and asymptomatic. It must be restarted
1. Identify patients with RS risk through a complete medical and at a low rate (50% of the initial NS) and perform a slow progression.
nutritional assessment before initiating NS. The criteria pro- Adequate supplementation of electrolytes and vitamins should also
posed by the 2006 NICE Guidelines must be taken into account be carried out together with a strict monitoring of the patient.
(Table 2). When treating hypophosphataemia phosphate levels, the pres-
2. Request a complete blood count and biochemistry before and ence of symptoms and the available route of administration must
during refeeding. It should be taken into account that serum be taken into account.29,30,35,49
levels of phosphorus, potassium and magnesium do not always In the case of mild–moderate hypophosphataemia, absence
reflect TBR reliably. Daily monitoring of phosphorus, potassium, of symptoms and functioning digestive tract, the usual is oral
magnesium and sodium should be carried out during the first treatment, taking into account the common development of
week and then at least 3 times a week. diarrhoea with oral preparations. In severe hypophosphataemia,
3. Ensure haemodynamic stability and correct electrolyte anoma- symptomatic or non-functioning digestive tract, its intravenous
lies before initiating NS. The 2006 NICE Guidelines indicate that administration is recommended.29,30,50,51
their correction can be made during refeeding, thus avoiding a In moderate hypophosphataemia, sodium or potassium phos-
delay in the start of NS (prolonging malnutrition even further). phate is recommended orally (depending on electrolyte status and
Give some recommendations on the amounts of electrolytes to renal function) in divided doses (2–3 daily doses), not exceed-
be administered (Table 4). However, it is important to individu- ing 2 g/day, monitoring phosphataemia every 24 h. Supplements
alize the dose in each particular case to avoid under or overdose. should be discontinued with values > 2.5 mg/dl.
4. Perform an adequate distribution of the macronutrients. An ini- In severe hypophosphataemia, intravenous administration is
tial contribution of 150–200 g/day of glucose, 1.2–1.5 g/kg/day recommended. The recommended doses are 0.08–0.16 mmol/kg
of proteins (their needs being highly variable depending on to be administered in 6 h, and in severe cases the infusion can
the degree of stress) and a maximum of 1.5 g/kg/day of fats be increased to 0.25–0.5 mmol/kg in 8–12 h. For the intravenous
(adjusting their intake according to the level of triglycerides) is route, sodium phosphate is preferable to potassium phosphate.
considered an appropriate guideline. Do not exceed 0.81 mmol/kg in 6 h, phosphataemia should be
5. Start caloric repletion with caution (start low, advance slow) in checked every 6 h, making a transition to the oral route with levels
patients with RS risk, especially in the first week of NS. There is >1.5 mg/dl.46,50,52,53
no consensus about the number of kilocalories with which one In the treatment of hypokalaemia, replacement can be oral
should start. Generally, in adults it is recommended to start with or intravenous, depending on the clinical features, severity of
20 kcal/kg/day or 1000 kcal/day and gradually increase per week hypokalaemia and available route of administration. In case of
until the patient is metabolically stable. The 2006 NICE Guide- severe deficiency, symptomatic patients or non-functioning diges-
lines recommend a more cautious start (Table 4). In patients tive tract, the intravenous route is preferable. The side effects of oral
with AN, they consider a weight gain of 0.5–1 kg/week as a safe and intravenous potassium should be taken into account: diarrhoea
therapeutic goal.44 and abdominal discomfort (oral) and phlebitis (intravenous).37,38,53
6. Empirical electrolyte supplementation before and during NS, The recommended initial doses are 1.2–1.5 mEq/kg, with doses
with a minimum contribution of 10–15 mmol of phosphorus per up to 2.5 mEq/kg in severe hypokalaemia. The administration
non-protein 1,000 kcal, taking into account that in case of severe should be slow, with a maximum allowed of 40 mEq/h and, in case
malnutrition, critical illnesses, trauma or burns the requirements of administering >10 mEq/h, a central line administration is rec-
will be higher.45 ommended, with electrocardiographic monitoring due to the risk
7. Individualize the administration of water and sodium, monitor of arrhythmia. Its concentration should not exceed 80 mEq/l by
the inputs and outputs, in order to avoid volume overload. Any peripheral route and 120 by central line.53
increase >1 kg of weekly weight should be attributed to water Treatment of hypomagnesaemia can be done with oral sup-
retention. plements (preferably prolonged-release preparations, such as
8. The general recommendation regarding vitamin supplemen- chloride or magnesium lactate). Their low absorption and com-
tation is the administration of thiamine empirically before mon gastrointestinal side effects is a disadvantage, therefore in
starting NS (at least 30 min before), and during the first 10 days severe, symptomatic hypomagnesaemia, or intolerance to oral
in patients with RS risk. The doses recommended by the NICE magnesium, parenteral administration should be chosen, with
Guidelines are 200–300 mg/day orally or intravenously.25,45 In magnesium sulfate being the drug of choice.39
G Model
ARTICLE IN PRESS
6 M. Araujo Castro, C. Vázquez Martínez / Med Clin (Barc). 2017;xxx(xx):xxx–xxx

A possible regimen is to administer 8–32 mEq of magnesium, 14. O’Connor G, Nicholls D. Refeeding hypophosphatemia in adolescents with
with a maximum dose of 1 mEq/kg/day, and in severe cases anorexia nervosa. A systematic review. Nutr Clin Pract. 2013;28:358–64.
15. Stroud M. Nutrition support for adults: oral nutrition support, enteral tube feed-
between 32–64 mEq, with a maximum of 1.5 mEq/kg. The infusion ing and parenteral nutrition. NICE clinical guideline 32; 2006.
should be slow, with a maximum rate of 1 g/h of magnesium sulfate 16. Halevy J, Bulvik S. Severe hyphosphatemia in hospitalized patients. Arch Intern.
and a maximum dose of 12 g (1 g of magnesium sulfate contains 1988;148:153–5.
17. Katzman DK, Garber AK, Kohn M, Golden NH. Refeeding hypophosphatemia
8 mEq of magnesium).54 Magnesaemia should be monitored and in hospitalized adolescents with anorexia nervosa: a position statement of
signs of toxicity should be sought. In cases of toxicity, the antidote the society for adolescent health and medicine. J Adolesc Heal. 2014;55:
is calcium chloride or intravenous calcium gluconate.39 455–7.
18. Ferreras JLT, Lesmes IB, de Cuerda C, Álvarez MC. Revisión síndrome de reali-
In the replacement of phosphorus, potassium and/or magne-
mentación. Rev Clin Esp. 2005;2:79–86.
sium, doses are indicative, they should always be individualized in 19. Fuentebella J, Kerner JA. Refeeding syndrome. Pediatr Clin. 2009;56:1201–10.
each case, since there is a lack of correlation between serum lev- 20. Marliss EB, Aoki TT, Unger RH, Soeldner JS, Cahill GF. Glucagon levels and
metabolic effects in fasting man. J Clin Invest. 1970;49:2256–70.
els and TBR. In patients with impaired renal function (creatinine
21. Klein S, Horowitz JF, Landt M, Goodrick SJ, Mohamed-Ali V, Coppack SW. Lep-
clearance < 50 ml/min, plasma creatinine > 2 mg/dl or oligoanuria tin production during early starvation in lean and obese women. Am J Physiol
that are not in renal replacement therapy) the initial administration Endocrinol Metab. 2000;278:E280–4.
should be <50% of the recommended empirical doses.45 22. O’Connor G, Goldin J. The refeeding syndrome and glucose load. Int J Eat Disord.
2011;44:182–5.
23. DeFronzo RA, Cooke CR, Andres R, Faloona GR, Davis PJ. The effect of insulin
on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin
Conclusions Invest. 1975;55:845–55.
24. Danforth E Jr, Horton ES, O’Connell M, Sims EA, Burger AG, Ingbar SHE, et al.
RS is a potentially fatal situation, caused by a rapid initiation Dietary-induced alterations in thyroid hormone metabolism during overnutri-
tion. J Clin Invest. 1979;64:1336–47.
of refeeding after a period of malnutrition. The most important
25. Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome. Nutri-
symptom is the presence of hypophosphataemia, which is associ- tion. 2001;17:632–7.
ated with other abnormalities in electrolyte balance and different 26. Dwyer K, Barone JE, Rogers JF. Severe hypophosphatemia in postoperative
patients. Nutr Clin Pract. 1992;7:279–83.
clinical and metabolic complications.
27. Viana LA, Burgos MG, Silva R. Reefeding syndrome: clinical and nutritional rel-
The identification of patients at risk is key in the prevention of evance. ABCD Arq Bras Cir Dig. 2012;25:56–9.
RS as well as to consider the potential complications associated 28. Shiber JR, Mattu A. Serum phosphate abnormalities in the emergency depart-
with the reintroduction of feeding in malnourished patients. The ment. J Emerg Med. 2002;23:395–400.
29. Skipper A. Refeeding syndrome or refeeding hypophosphatemia: a systematic
main risk groups are patients with chronic malnutrition and fasting review of cases. Nutr Clin Pract. 2012;27:34–40.
longer than 10 days. 30. Morón IB. Hipofosfatemia e hiperfosfatemia: concepto, fisiopatología, etiopato-
NS should be reinitiated with a low energy intake, with thiamine genia, clínica, diagnóstico y tratamiento. Medicine (Baltimore). 2004;9:
1063–9.
supplementation from the beginning and for at least 10 days. If 31. Huang YL, Fang CT, Tseng MC, Lee YJ, Lee MB. Life-threatening refeeding syn-
diagnosed, NS should be reduced or even discontinued immedi- drome in a severely malnourished anorexia nervosa patient. J Formos Med Assoc.
ately, and any electrolyte disorder should be corrected, together 2001;100:343–6.
32. Mallet M. Refeeding syndrome. Age Ageing. 2002;31:65–6.
with the specific treatment of the associated complications 33. Adams LG, Hardy RM, Weiss DJ, Bartges JW. Hypophosphatemia and hemolytic
of RS. anemia associated with diabetes mellitus and hepatic lipidosis in cats. J Vet
Intern Med. 1993;7:266–71.
34. Marik PE, Bedigian MK. Refeeding hypophosphatemia in critically ill patients
Conflict of interest in an intensive care unit. A prospective study. Arch Surg. 1996;131:
1043–7.
35. Marinella MA. The refeeding syndrome and hypophosphatemia. Nutr Rev.
The authors declare no conflict of interest. 2003;61:320–3.
36. Silvis SE, Dibaryolomeo AG, Aaker HM. Hypophosphatemia and neurological
changes secondary to oral caloric intake: a variant of hyperalimentation syn-
References drome. Am J Gastroenterol. 1980;73:215–22.
37. Kogika MM, de Morais HA. Hypokalemia: a quick reference. Vet Clin North Am
1. Mehanna HM, Moledina J, Travis J. Refeeding syndrome: what it is, and how to Small Anim Pract. 2008;38:481–4.
prevent and treat it. BMJ. 2008;336:1495–8. 38. Tejada Cifuentes F. Alteraciones del equilibrio del potasio: hipopotasemia. Rev
2. Perreault MM, Ostrop NJ, Tierney MG. Efficacy and safety of intravenous Clín Med Fam. 2008;2:129–33.
phosphate replacement in critically ill patients. Ann Pharmacother. 1997;31: 39. González EP, Rodríguez FS, García EC. Homeostasis del magnesio. Etiopatogenia,
683–8. clínica y tratamiento de la hipomagnesemia. A propósito de un caso. Nefrologia.
3. Solomon SM, Kirby DF. The refeeding syndrome: a review. JPEN J Parenter Enter 2009;29:518–24.
Nutr. 1990;14:90–7. 40. Schenck PA, Chew DJ. Hypocalcemia: a quick reference. Vet Clin North Am Small
4. Keys A, Brozek J, Henschel A, Mickelsen O. Experimental starvation in man. Bull Anim Pract. 2008;38:455–8.
Chic Med Soc. 1945;49:42–6. 41. Abdou E, Hazell AS. Thiamine deficiency: an update of pathophysiologic
5. Weinsier RL, Krumdieck CL. Death resulting from overzealous total par- mechanisms and future therapeutic considerations. Neurochem Res. 2014;40:
enteral nutrition: the refeeding syndrome revisited. Am J Clin Nutr. 1981;34: 353–61.
393–9. 42. Latt N, Dore G. Thiamine in the treatment of Wernicke encephalopathy in
6. Fernández López MT, López Otero MJ, Alvarez Vázquez P, Arias Delgado J, Varela patients with alcohol use disorders. Intern Med J. 2014;44:911–5.
Correa JJ. Síndrome de realimentación. Farm Hosp. 2009;33:183–93. 43. Agabio R. Thiamine administration in alcohol-dependent patients. Alcohol Alco-
7. Álvarez-Hernández J, Planas Vila M, León-Sanz M, García de Lorenzo A, Celaya- hol. 2005;40:155–6.
Pérez S, García-Lorda P, et al. Prevalencia y costes de la malnutrición en pacientes 44. Marzola E, Nasser JA, Hashim SA, Betty Shih P, Kaye WH. Nutritional rehabilita-
hospitalizados; estudio PREDyCES. Nutr Hosp. 2012;27:1049–59. tion in anorexia nervosa: review of the literature and implications for treatment.
8. Bellido D, Martínez-Olmos YM. Síndrome de realimentación. Endocrinol Nutr. BMC Psychiatr. 2013;13:1–13.
2004;51:336–42. 45. Kraft MD, Btaiche IF, Sacks GS. Review of the refeeding syndrome. Nutr Clin
9. Weinsier RL, Bacon J, Butterworth CE Jr. Central venous alimentation: a prospec- Pract. 2005;20:625–33.
tive study of the frequency of metabolic abnormalities among medical and 46. Garber AK, Michihata N, Hetnal NK, Shafer MA, Moscicki AB. A prospective exam-
surgical patients. JPEN J Parenter Enter Nutr. 1982;6:421–5. ination of weight gain in hospitalized adolescents with anorexia nervosa on a
10. Thompson JS, Hodges RE. Preventing hypophosphatemia during total parenteral recommended refeeding protocol. J Adolesc Health. 2012;50:24–9.
nutrition. JPEN J Parenter Enteral Nutr. 1984;8:137–9. 47. Boateng AA, Sriram K, Meguid MM, Crook M. Refeeding syndrome: treatment
11. Mehanna H, Nankivell PC, Moledina J, Travis J. Refeeding syndrome: awareness, considerations based on collective analysis of literature case reports. Nutrition.
prevention and management. Head Neck Oncol. 2009;1:1–5. 2010;26:156–67.
12. Zeki S, Culkin A, Gabe SM, Nightingale JM. Refeeding hypophosphataemia is 48. Friedli N, Stanga Z, Sobotka L, Culkin A, Kondrup J, Laviano A, et al. Revisit-
more common in enteral than parenteral feeding in adult in patients. Clin Nutr. ing the refeeding syndrome: results of a systematic review. Nutrition. 2017;35:
2011;30:365–8. 151–60.
13. Fisher M, Simpser E, Schneider M. Hypophosphatemia secondary to oral refeed- 49. Martinez Nunez ME, Hernandez Muniesa B. Prevention of the refeeding syn-
ing in anorexia nervosa. Int J Eat Disord. 2000;28:181–7. drome. Nutr Hosp. 2010;25:1045–8.
G Model
ARTICLE IN PRESS
M. Araujo Castro, C. Vázquez Martínez / Med Clin (Barc). 2017;xxx(xx):xxx–xxx 7

50. Martinez MJ, Martinez MA, Montero M, Campelo E, Castro I, Inaraja MT. 52. Gaasbeek A, Meinders AE. Hypophosphatemia: an update on its etiology and
Hypophosphatemia in postoperative patients with total parenteral nutrition: treatment. Am J Med. 2005;118:1094–101.
influence of nutritional support teams. Nutr Hosp. 2006;21:657–60. 53. Ariyoshi N, Nogi M, Ando A, Watanabe H, Umekawa S. Hypophosphatemia-
51. Amanzadeh J, Reilly RF Jr. Hypophosphatemia: an evidence-based approach induced cardiomyopathy. Am J Med Sci. 2016;352:317–23.
to its clinical consequences and management. Nat Clin Pr Nephrol. 2006;2: 54. Oster JR, Epstein M. Management of magnesium depletion. Am J Nephrol.
136–48. 1988;8:349–54.