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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

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

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

MEDCLE-4395; No. of Pages 7

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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
manifestations, among others, which usually occur a few days after
the start of refeeding.3
The first description of RS was made in connection with prison-
ers of the Second World War who had suffered prolonged fasting;
a severe condition of congestive heart failure (CHF), seizures and
even death occurred when a normal diet was reintroduced. The
classic study that describes RS is the Minnesota experiment, in
which healthy volunteers are subjected to food restriction for 6
months and subsequent refeeding, observing a similar but milder
condition.4 In 1980, the hypothesis of hypophosphataemia sec-
ondary to refeeding was proposed as a key aspect of RS, which is
what is known today.5
The importance of RS lies in a significant associated morbidity
and mortality; however, death is currently unusual in this context.
In the hospitalized and severe patient there are multiple causes
of hypophosphataemia, hypomagnesaemia and hypokalaemia with
which a differential diagnosis must be made6 (Table 1).
Epidemiology
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
The incidence is very variable according to the definition used
and the different series, but it is usually underdiagnosed, especially
by non-nutritionists.2 Its true incidence is unknown, partly due to
the absence of a universally accepted definition and that most of
the studies are retrospective and do not evaluate all RS components,
but rather the presence of hypophosphataemia.1,8,9 It is estimated
that it develops in 20–40% of malnourished patients undergoing
NS.10
Patients with risk of RS are considered those with chronic mal-
nutrition, chronic exacerbated or acute who are going to receive NS.
The risk increases if there are long-standing nutritional deficiencies
(as in alcoholism or elderly patients).3 The morbidly obese with sig-
nificant weight loss after bariatric surgery, oncology patients with
total parenteral nutrition (PN) or patients undergoing prolonged
intravenous fluid therapy are also risk groups.3,8 Of special risk are
patients with head and neck tumours, since they present multiple
risk factors for a RS (fasting > 5 days in the context of dysphagia
due to tumour progression, tumour cachexia, prolonged fasting in
the postoperative period, previous history of alcohol abuse, among
others).11
There is the possibility of developing a RS with any type of NS,
even in patients undergoing oral nutrition at home. Some studies
document a higher incidence with enteral nutrition (EN) than with
PN (possible influence of incretin effect in EN that would produce
a higher insulin secretion and less predictable absorption than in
PN).12
Currently the main risk group is patients with anorexia nervosa
(AN), given its high prevalence and high risk of RS: 14% (0–38%)
of AN develop it.13,14 The guidelines of the National Institute for
Health and Care Excellence (NICE) 2006 establish a series of criteria
that help identify risk groups15 (Table 2).
On the other hand, hypophosphataemia is present in up to 40%
of hospitalized patients, and even a higher percentage in the case
of patients admitted to intensive care units and infectious disease
services.16 The RFs are basically the same as those of RS.17
Pathogeny
In normal conditions carbohydrates serve as the main energy
source for tissues (hepatic and muscular glycogen stores).
During fasting the body tries to compensate for the lack of energy
through changes in metabolism and hormonal regulation. The body
enters a catabolic state, in which glycogen reserves are used until
exhaustion. At that time, proteolysis (protein degradation in amino
acids) starts, followed by gluconeogenesis (obtaining glucose from
amino acids, lactate and glycerol). After 72 h of fasting other pro-
cesses are initiated to minimize the mobilization of amino acids
and decrease protein catabolism, including lipolysis, in which free
fatty acids are released that can be used for the synthesis of ketone
bodies. Ketoadaptation is one of the most important metabolic
phenomena in the response to fasting.1,6,8,18
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Table 2
Criteria of the NICE Guidelines to identify patients at risk of refeeding syndrome
(Recommendation Level D).
Patients with ≥1 of the following:
BMI < 16 kg/m2
Unintentional weight loss >15% in last 3–6 months
No or low intake >10 days
Low phosphorus, potassium, or magnesium levels before starting NS
Or patients with ≥2 of the following:
IMC < 18.5 kg/m2
Unintentional weight loss >10% in last 3–6 months
No or low intake >5 days
History of alcohol abuse or drug abuse such as insulin, chemotherapy,
antacids or diuretics
BMI: body mass index; NS: nutritional support.
Other adaptive changes are produced with the aim of pre-
serving vital functions: the secretion of insulin, triiodothyronine,
gonadotropins and leptin decreases, among others. All this, in asso-
ciation with a decrease in the tone of the sympathetic nervous
system, results in a 20–25% decrease in basal metabolism.19–21
There is also loss of weight and cell mass, and therefore a
decrease in the size of organs, being more significant in some of
them, such as in the heart (myocardial atrophy that can cause
CHF).
Potassium, magnesium and phosphorus deposits are depleted,
however, their serum levels may be normal (especially in the initial
phases of refeeding), since they are mainly intracellular ions.3
An anabolic state occurs during refeeding. Insulin secretion
increases (especially with diets rich in carbohydrates), this gener-
ates the introduction of phosphorus, potassium and magnesium in
the cell (decrease in plasma levels) and an increase in the synthe-
sis of proteins, lipids and glycogen.22 For the synthesis of these,
cofactors are needed (of phosphorus, magnesium and thiamine,
among others), their demand increases, and their deficiency can
be exacerbated. Hyperinsulinism exerts an antinatriuretic effect in
the renal tubule: water and sodium are retained (risk of CHF) and
there is an increase in energy expenditure (increased conversion of
T4 to T3).23–25
Biochemical abnormalities and clinical manifestations
The clinical manifestations of RS occur mainly as a consequence
of hypophosphataemia, hypokalaemia and hypomagnesaemia and
the rapid change in metabolic rate (Table 3).
Hypophosphataemia
Phosphate is the main intracellular anion. Its organic deposits
are 500–800 mg: 80% is found in the bone and the rest in the muscle
and soft tissues. Inorganic (extracellular) phosphate accounts for
1% of the total body reserves (TBR). Its deficiency in a normal diet
is rare, with its excess being more normal.26 Hypophosphataemia
occurs in up to 50% of patients with chronic alcoholism, and the
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-
ulation depends on the intracellular-extracellular flow dependent
on the intake of carbohydrates and lipids and modifications of the
acid–base balance, and kidney in the long-term.27
Phosphate is essential for all intracellular processes and for the
integrity of cell membranes. It allows the activation of multiple
enzymes and second messengers, it is necessary for the storage of
energy in the form of ATP and regulates the affinity of haemoglobin
for oxygen (it is a cofactor of glyceraldehyde phosphate dehydro-
genase – 2,3-diphosphoglycerate [2,3-DPG] and ATP decreases in
hypophosphataemia19,28 ).
3
The hypophosphataemia in RS normally develops in the 1st
week after starting NS, usually after the third day. Its occurrence is
mainly related to the glucose content of the diet: glucose increases
insulin secretion, which promotes the intracellular reuptake of
phosphorus, being this the key determinant of hypophosphataemia
in RS. The reduction of intake (fasting), the alteration of absorption
(intestinal villous atrophy due to prolonged fasting) and an increase
in renal and extrarenal losses also contribute.25,26,29
There are 3 grades: mild 2.3–2.5 mg/dl, moderate 1.5–2.2 mg/dl
and severe <1–1.5 mg/dl. Mortality in severe hypophosphataemia
is 30%.28
Symptomatology develops with levels <1.5 mg/dl (may develop
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
The cardiovascular manifestations usually appear in the first
week of NS.17 Fluid replacement and sodium and water retention
induced by hyperinsulinism, associated with myocardial dysfunc-
tion due to pre-existing cardiac atrophy (due to malnutrition)
and severe hypophosphataemia, predispose to CHF.31,32 Severe
hypophosphataemia can cause hypotension, pericardial effusion,
shock, arrhythmias and even sudden death. Ventricular arrhyth-
mias appear in up to 20% of patients without structural heart
disease, increasing the risk in case of coexistence with hypomag-
nesaemia and hypokalaemia.5
The decrease of intraerythrocytic ATP in the haematological
system alters the flexibility of the erythrocyte membrane, deter-
mining a reversible spherocytosis (with the administration of
phosphorus) that predisposes to the development of haemolytic
anaemia. Severe hypophosphataemia is associated with throm-
bocytopenia and leucocyte dysfunction, which predispose to the
development of secondary haemorrhages and serious infections,
respectively.8,18,32,33
Severe hypophosphataemia can lead to acute respiratory fail-
ure or difficulties in disconnecting mechanical ventilation in the
respiratory system (it would be advisable to wait until reach-
ing a normal phosphataemia before disconnecting the patient
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
The neurological manifestations range from paraesthesia, con-
fusion and weakness to seizures and even coma. Occasionally,
acute areflexic paralysis symptomatology simulating a Guilläin-
Barré syndrome may occur.36 These abnormalities are infrequent
with phosphate levels >1 mg/dl and, although its aetiology is not
clear, they seem to be related to cellular hypoxia secondary to the
decrease of 2,3-DPG and ATP.3
Muscle-skeletal involvement is the most common manifes-
tation of hypophosphataemia (30%). It is characterized by
weakness, myalgias, rhabdomyolysis (more common in alco-
holics), diaphragmatic weakness or symptomatology of proximal
myopathy.3,32,35
Hypokalaemia
K is the main intracellular monovalent cation (98% intracellu-
lar). It is essential for the maintenance of membrane potential and
the regulation of glycogen and protein synthesis.37 In addition, it
participates in water, osmotic and acid-base balance.
Clinical manifestations range from mild gastrointestinal
symptoms and muscle weakness in case of mild-moderate
hypokalaemia, to more severe clinical symptoms with serum
levels <2.5 mEq/l: areflexic paralysis, paraesthesias, rhabdomy-
olysis, muscle necrosis, respiratory distress or confusion. Elec-
trocardiographic changes (ST segment depression, flattened
or inverted T-waves, U waves) are also observed; increased
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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-

Thiamine or vitamin B1 is a water-soluble vitamin, with a short
half-life (9.5–18.5 days), resulting in a rapid depletion of its deposits
in case of malnutrition. It acts as a cofactor of pyruvate dehy-
drogenase and transketolases, its presence being necessary for
carbohydrate metabolism.41
tifying patients at risk is crucial to improve their management.
There are some key steps to avoid its development, however, some
cases of RS have been reported despite its correct application. It is
also important to request an assessment by the nutrition depart-
ment at an early stage. The points considered most important
are1–6,14,16,19,26,29,33,34 (Table 4):
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Table 4
Preventive measures in refeeding syndrome. 2006 NICE Guidelines.
1. Patient at risk
2. Determination of potassium, calcium, phosphorus and magnesium
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
supplement 1/day
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
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)
6 Monitor potassium, phosphorus, calcium and magnesium in the first 2
weeks and treat when necessary
NS: nutritional support.
Source: management guidelines, adapted from the NICE Guidelines and the British
Association of Parenteral and Enteral Nutrition.15
a
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.
1. Identify patients with RS risk through a complete medical and
nutritional assessment before initiating NS. The criteria pro-
posed by the 2006 NICE Guidelines must be taken into account
(Table 2).
2. Request a complete blood count and biochemistry before and
during refeeding. It should be taken into account that serum
levels of phosphorus, potassium and magnesium do not always
reflect TBR reliably. Daily monitoring of phosphorus, potassium,
magnesium and sodium should be carried out during the first
week and then at least 3 times a week.
3. Ensure haemodynamic stability and correct electrolyte anoma-
lies before initiating NS. The 2006 NICE Guidelines indicate that
their correction can be made during refeeding, thus avoiding a
delay in the start of NS (prolonging malnutrition even further).
Give some recommendations on the amounts of electrolytes to
be administered (Table 4). However, it is important to individu-
alize the dose in each particular case to avoid under or overdose.
4. Perform an adequate distribution of the macronutrients. An ini-
tial contribution of 150–200 g/day of glucose, 1.2–1.5 g/kg/day
of proteins (their needs being highly variable depending on
the degree of stress) and a maximum of 1.5 g/kg/day of fats
(adjusting their intake according to the level of triglycerides) is
considered an appropriate guideline.
5. Start caloric repletion with caution (start low, advance slow) in
patients with RS risk, especially in the first week of NS. There is
no consensus about the number of kilocalories with which one
should start. Generally, in adults it is recommended to start with
20 kcal/kg/day or 1000 kcal/day and gradually increase per week
until the patient is metabolically stable. The 2006 NICE Guide-
lines recommend a more cautious start (Table 4). In patients
with AN, they consider a weight gain of 0.5–1 kg/week as a safe
therapeutic goal.44
6. Empirical electrolyte supplementation before and during NS,
with a minimum contribution of 10–15 mmol of phosphorus per
non-protein 1,000 kcal, taking into account that in case of severe
malnutrition, critical illnesses, trauma or burns the requirements
will be higher.45
7. Individualize the administration of water and sodium, monitor
the inputs and outputs, in order to avoid volume overload. Any
increase >1 kg of weekly weight should be attributed to water
retention.
8. The general recommendation regarding vitamin supplemen-
tation is the administration of thiamine empirically before
starting NS (at least 30 min before), and during the first 10 days
in patients with RS risk. The doses recommended by the NICE
Guidelines are 200–300 mg/day orally or intravenously.25,45 In
5
some cases, as in malnutrition secondary to chronic alcoholism,
in addition to thiamine, a multivitamin supplementation must
be administered to avoid other associated deficiencies.
9. Daily monitoring of heart rate (HR) and respiratory rate, blood
early sign of development of RS and in patients with AN even a
HR of 70–80 bpm should alert us to its possible development.46
Treatment
Once RS has been diagnosed, a series of general measures must
be carried out together with an aggressive correction of the elec-
trolyte disorder.1–6,13,18,27,44,47,48
Regarding general measures, the first is to diminish, or even dis-
continue, the supply of nutrients immediately.32,34 In addition, the
necessary support measures should be established to manage its
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
at a low rate (50% of the initial NS) and perform a slow progression.
Adequate supplementation of electrolytes and vitamins should also
be carried out together with a strict monitoring of the patient.
When treating hypophosphataemia phosphate levels, the pres-
ence of symptoms and the available route of administration must
be taken into account.29,30,35,49
In the case of mild–moderate hypophosphataemia, absence
of symptoms and functioning digestive tract, the usual is oral
treatment, taking into account the common development of
diarrhoea with oral preparations. In severe hypophosphataemia,
symptomatic or non-functioning digestive tract, its intravenous
administration is recommended.29,30,50,51
In moderate hypophosphataemia, sodium or potassium phos-
phate is recommended orally (depending on electrolyte status and
renal function) in divided doses (2–3 daily doses), not exceed-
ing 2 g/day, monitoring phosphataemia every 24 h. Supplements
should be discontinued with values > 2.5 mg/dl.
In severe hypophosphataemia, intravenous administration is
recommended. The recommended doses are 0.08–0.16 mmol/kg
to be administered in 6 h, and in severe cases the infusion can
be increased to 0.25–0.5 mmol/kg in 8–12 h. For the intravenous
route, sodium phosphate is preferable to potassium phosphate.
Do not exceed 0.81 mmol/kg in 6 h, phosphataemia should be
checked every 6 h, making a transition to the oral route with levels
>1.5 mg/dl.46,50,52,53
In the treatment of hypokalaemia, replacement can be oral
or intravenous, depending on the clinical features, severity of
hypokalaemia and available route of administration. In case of
severe deficiency, symptomatic patients or non-functioning diges-
tive tract, the intravenous route is preferable. The side effects of oral
and intravenous potassium should be taken into account: diarrhoea
and abdominal discomfort (oral) and phlebitis (intravenous).37,38,53
The recommended initial doses are 1.2–1.5 mEq/kg, with doses
up to 2.5 mEq/kg in severe hypokalaemia. The administration
should be slow, with a maximum allowed of 40 mEq/h and, in case
of administering >10 mEq/h, a central line administration is rec-
ommended, with electrocardiographic monitoring due to the risk
of arrhythmia. Its concentration should not exceed 80 mEq/l by
peripheral route and 120 by central line.53
Treatment of hypomagnesaemia can be done with oral sup-
plements (preferably prolonged-release preparations, such as
chloride or magnesium lactate). Their low absorption and com-
mon gastrointestinal side effects is a disadvantage, therefore in
severe, symptomatic hypomagnesaemia, or intolerance to oral
magnesium, parenteral administration should be chosen, with
magnesium sulfate being the drug of choice.39
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A possible regimen is to administer 8–32 mEq of magnesium,
with a maximum dose of 1 mEq/kg/day, and in severe cases
between 32–64 mEq, with a maximum of 1.5 mEq/kg. The infusion
should be slow, with a maximum rate of 1 g/h of magnesium sulfate
and a maximum dose of 12 g (1 g of magnesium sulfate contains
8 mEq of magnesium).54 Magnesaemia should be monitored and
signs of toxicity should be sought. In cases of toxicity, the antidote
is calcium chloride or intravenous calcium gluconate.39
In the replacement of phosphorus, potassium and/or magne-
sium, doses are indicative, they should always be individualized in
each case, since there is a lack of correlation between serum lev-
els and TBR. In patients with impaired renal function (creatinine
clearance < 50 ml/min, plasma creatinine > 2 mg/dl or oligoanuria
that are not in renal replacement therapy) the initial administration
should be <50% of the recommended empirical doses.45
Conclusions
RS is a potentially fatal situation, caused by a rapid initiation
of refeeding after a period of malnutrition. The most important
symptom is the presence of hypophosphataemia, which is associ-
ated with other abnormalities in electrolyte balance and different
clinical and metabolic complications.
The identification of patients at risk is key in the prevention of
RS as well as to consider the potential complications associated
with the reintroduction of feeding in malnourished patients. The
main risk groups are patients with chronic malnutrition and fasting
longer than 10 days.
NS should be reinitiated with a low energy intake, with thiamine
supplementation from the beginning and for at least 10 days. If
diagnosed, NS should be reduced or even discontinued immedi-
ately, and any electrolyte disorder should be corrected, together
with the specific treatment of the associated complications
of RS.
Conflict of interest
The authors declare no conflict of interest.
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