REFEEDINGSYNDROME

Definisi
The term refeeding syndrome (RS) is used in order to describe the metabolic
alterations that occur when administering nutrition, whether by oral, enteral, or
parenteral means, to severely malnourished or food-deprived individuals. The
fundamental condition in RS is severe hypophosphataemia, which is accompanied by
fluid balance abnormalities, carbohydrate metabolism alterations, certain vitamin
deficiencies such as thiamine deficiency, as well as hypopotassaemia and
hypomagnesaemia. Clinically, this signifies the appearance of neurological,
respiratory, cardiovascular, haematological, and other abnormalities a few days after
resuming feeding, which increases patient morbidity and even mortality.
Epidemiologi
First reports of the syndrome appeared in the 1950s after observations of
malnourished prisoners of war who developed cardiac and neurological symptoms
soon after the recommencement of feeding. There is no internationally agreed
definition of RS. In 2001 Crook et al. referred to a syndrome of severe electrolyte and
fluid shifts associated with metabolic abnormalities in malnourished patients
undergoing refeeding, whether orally, enterally, or parenterally.
As there is no strict definition, it is not surprising that the incidence of RS is unclear.
Robust epidemiological studies are lacking in part due to the absence of accepted
diagnostic criteria or internationally agreed guidelines for detecting RS. Most
published data from prospective and retrospective case series do not reflect overall
incidence.
Faktor Risiko
Identification of high risk patients is crucial.
Any patient with negligible food intake for more than five days is at risk of
developing refeeding problems.

Patients with anorexia nervosa

Patients with chronic alcoholism

Oncology patients

Postoperative patients

Elderly patients (comorbidities, decreased physiological reserve)

Patients with uncontrolled diabetes mellitus (electrolyte depletion, diuresis)

Patients with chronic malnutrition:

o

Marasmus

Prolonged fasting or low energy diet

Morbid obesity with profound weight loss

High stress patient unfed for >7 days

Malabsorptive syndrome (such as inflammatory bowel disease, coeliac

disease, chronic pancreatitis, cystic fibrosis, short bowel syndrome).

Patogenesis

Patofisiologi

Prolonged fasting
In early starvation, blood glucose levels decline, resulting in a decrease in insulin and
an increase in glucagon levels. This stimulates glycogenolysis in the liver and
lipolysis of triacetylglycerol in fat reserves producing fatty acids (FAs) and glycerol
which are used by tissues for energy and converted to ketone bodies in the liver. As
glycogen reserves then become depleted, gluconeogenesis is stimulated in the liver,
utilising amino acids (derived from the breakdown of muscle), lactate and glycerol
resulting in the synthesis of glucose for use by the brain and red blood cells. The main
result of these changes is that the body switches the main energy course from
carbohydrate to protein and fat. The basal metabolic rate decreases by as much as 20

25%

During prolonged fasting, hormonal and metabolic changes are aimed at preventing
protein and muscle breakdown. The tissues decrease their use of ketone bodies, and
use fatty acids as their main energy source. This results in an increase in blood levels
of ketone bodies, stimulating the brain to switch from glucose to ketone bodies as its
main energy source. The liver decreases its rate of gluconeogenesis, due to the
reduced need for glucose by the brain, thus preserving muscle protein which is its
source of amino acids. During the period of prolonged starvation, several intracellular
minerals become severely depleted. However, serum concentrations of these minerals,
including phosphate, may remain normal. This is because these minerals are mainly in
the intracellular compartment, which contracts during starvation. In addition, there is
a reduction in renal excretion.
Refeeding
The reintroduction of nutrition to a starved or fasted individual results in a rapid
decline in both gluconeogeneis and anaerobic metabolisms. This is mediated by the
rapid increase in serum insulin that occurs on refeeding. Insulin stimulates
glycogen, fat, and protein synthesis. This process requires minerals such as phosphate
and magnesium and cofactors such as thiamine. Insulin stimulates the absorption of
potassium into the cells through the sodium-potassium ATPase symporter, which also
transports glucose into the cells. Magnesium and phosphate are also taken up into the
cells. Water follows by osmosis. Depleted intracellular stores and a large
concentration gradient ensure a rapid fall in the extracellular concentration of these
ions. Osmotic neutrality must be maintained resulting in the retention of sodium and
water. Reactivation of carbohydrate-dependent metabolic pathways increases demand
for thiamine, a cofactor required for cellular enzymatic reactions. The deficiencies of
phosphate, magnesium, potassium, and thiamine occur to varying degrees and have
different effects in different patients.

Manifestasi Klinis

Hypophosphatemia

The predominant manifestation of refeeding syndrome is hypophosphatemia

rapidly progressive. The phosphate is essential for cell function. It has a structural role
as a component making up phospholipids, nucleoproteins and nucleic acids; it plays a
key

part

in

metabolic

pathways,

such

as

glycolysis

and

oxidative

phosphorilation, and it is implicated in the control of enzymatic processes through

protein phosphorilation.
Phosphate acts as a cofactor of glyceraldehyde-3-phosphate dehydrogenase.
Therefore, in the event of hypophosphataemia, it decreases production of 2,3
diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP). 2,3-DPG makes up
80% of the organic phosphate composition of erythrocytes and it is involved in
regulating the oxygen-haemoglobin dissociation curve, and therefore, the liberation of
oxygen to tissues. Hypophosphataemia in RS typically appears in the 3 first days after
beginning nutritional therapy. Symptoms appear when phosphorus levels are <1.5
mg/dL, or at higher levels if the decrease is rapid, and they are very apparent when
levels are <1 mg/dL.

Severe hypophosphataemia induces significant alterations on the neurological,

cardiac, respiratory, and haematological levels, and can lead to death. The mortality
rate in patients with severe hypophosphataemia is 30%.

Hypopotassaemia

Potassium has various physiological functions and contributes to the maintenance

of membrane potential and the regulation of glycogen and protein synthesis.
Hypopotassaemia alters the transmembrane action potential, resulting in its
hyperpolarisation and altered muscle contractility. We speak of mild to moderate
hypopotassaemia when serum potassium levels are between 2.5 and 3.5 mEq/L. The
patient may present gastrointestinal symptoms, such as nausea, vomiting, and
constipation as well as weakness. If it is untreated, it can progress to severe
hypopotassaemia (serum potassium <2.5 mEq/L) with the appearance of
neuromuscular dysfunction and disorders affecting myocardial contractility and signal
conduction. Severe hypopotassaemia provokes electrocardiographic changes. The
patient may present cardiac arrhythmias, from atrial tachycardia, bradycardia,
atrioventricular block and ventricular extrasystoles to tachycardia, ventricular
fibrillation, and even sudden death.

Hypomagneasemia

It acts as a cofactor of numerous enzymes and participates in regulating different

biochemical reaction, such as oxidative phosphorylation. Hypomagnesaemia is
frequent in critically ill patients, and it is associated with increased morbidity and
mortality. Normal serum levels are between 1.8 and 2.5 mg/dL (0.65-1 mmol/L).
Patients with mild to moderate hypomagnesaemia (serum magnesium level between 1
and 1.5 mg/dL) are generally asymptomatic, which is not the case for those with
severe hypomagnesaemia (serum levels <1 mg/dL). It has diverse clinical
manifestations: neuromuscular dysfunction, electrocardiographic changes, cardiac
arrhythmias, and even death.

Thiamine deficiency

Thiamine or vitamin B is a hydrosoluble vitamin which is necessary for

carbohydrate metabolism because it acts as a cofactor for pyruvate dehydrogenase and
transketolases.

Malnourished patients have vitamin several changes, including hypotiaminemia.

In advanced stages may induce brain disorders such as Wernicke-Korsakoff
syndrome, also observed in obese undergoing bariatric operations.
Thiamine deficiency causes an increase in blood levels of pyruvate, which is
transformed into lactate. This excessive lactate formation gives rise to lactic acidosis.
Thiamine deficiency can lead to the appearance of heart failure.
Pencegahan
All guidelines recommend that vitamin supplementation should be started
immediately, before and for the first 10 days of refeeding. Circulatory volume should
also be restored. Oral, enteral, or intravenous supplements of the potassium,
phosphate, calcium, and magnesium should be given unless blood levels are high
before refeeding.
Electrolyte levels should be measured once daily for one week, and at least
three times in the following week. Urinary electrolytes could also be checked to help
assess body losses and to guide replacement.

Terapi
If a patient is diagnosed with RS, nutrition therapy must be discontinued immediately.
Treatment will include taking the necessary supplementary steps (treating
cardiovascular and respiratory manifestations, etc) and correcting electrolytic
anomalies. In the event of neurological changes, a dose of 100 mg IV thiamine must
also be administered. Nutrition may be reintroduced when the patient is asymptomatic
and stable. A slow pace is recommended when resuming feeding (approximately 50%
of the pace that had been followed previously), with gradual increases over 4 to 5
days, supplementing electrolytes and vitamins appropriately and carefully monitoring
the patient.