REFEEDING SYNDROME
DEFINITION
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.
EPIDEMIOLOGY
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.
Refeeding syndrome:a literary review, 2011
RISK GROUPS
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:
- 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).
PATHOGENESIS
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.
CLINICAL MANIFESTATIONS
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%.
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.
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 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.
PREVENTION
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.
TREATMENT
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.
REFERENCES
Refeeding syndrome: what it is, and how to prevent and treat it,2008
Refeeding syndrome – awareness, prevention and management,2009
Refeeding syndrome: clinical and nutritional relevance,2012
