Refeeding syndrome

Refeeding syndrome is an adverse clinical and biochemical response to feeding in severely malnourished patients.

Refeeding syndrome (RFS) is generally defined as potentially fatal shifts in fluids and electrolytes that can occur in severely malnourished patients undergoing feeding.

Throughout human history, it has been described following famines or in prisoners of war who start eating again after long periods of starvation. The overzealous reintroduction of diet leads to profound electrolyte and fluid derangements that can cause cardiac arrhythmias or cardiac and respiratory failure.

It is difficult to estimate the true incidence of RFS due to varied definitions and at times lack of recognition.

RFS is common among patients receiving parenteral nutrition. Across various observational studies, a significant proportion of patients are at risk of refeeding syndrome with malnutrition being one of the strongest risk factors. In some ITU cohorts, up to one-third of patients may have evidence of refeeding syndrome following initiation of feeding.

Any patient regardless of weight, who has had little or no nutritional intake for > 5 days is at risk of RFS. Other risk factors for RFS are discussed further below.

RFS is due to the reintroduction of feeding in a patient who has had a period of starvation.

In the absence of sufficient oral intake, the body undergoes a number of adaptive responses to maintain physiological function. Following refeeding, severe alterations in electrolytes and fluid shifts can occur leading to dangerous complications and potentially death.

Biochemical response to starvation

Reduced oral intake leads to a fall in glucose levels with a subsequent fall in insulin. This is followed by a rise in counter-regulatory hormones such as glucagon in an attempt to maintain glucose levels. During this period there is an increased use of glycogen stores in the liver (glycogenolysis).

Over 6 hours to 3 days, glycogen stores are depleted. This leads to a move to fat and protein as alternative energy sources. This change is associated with a fall in basal metabolic rate (BMR) by up to 25%. Metabolic and hormonal changes are aimed at preventing protein and muscle breakdown. Fatty acids become the main source of energy. The brain switches to using ketone bodies and the liver reduces its rate of gluconeogenesis to preserve protein.

Concurrently, key intracellular minerals become severely depleted, partly owing to the downregulation of sodium-potassium ATPase pumps that require energy. This alters electrolyte handling leading to intracellular loss. Despite this intracellular depletion, serum levels are kept relatively constant due to the movement into the extracellular space and can even be elevated in the presence of kidney disease.

This stage is characterised by:

• Loss of glycogen stores
• Low insulin levels
• Ketogenesis
• Relatively normal serum electrolyte levels
• Severe intracellular depletion
• Fatty liver (reduced very-low-density lipoprotein transport)

Biochemical response to refeeding

During refeeding, the introduction of glucose leads to a rise in insulin levels from the pancreatic beta cells and a fall in concentration of counter-regulatory hormones. Insulin is an anabolic hormone that drives the synthesis of glycogen, protein and fat. These anabolic processes require key minerals including phosphate, magnesium, and vitamins (e.g. thiamine a co-factor in carbohydrate metabolism).

Insulin also stimulates activation of sodium/potassium ATPases to drive intracellular movement of potassium, which allows the transport of glucose, magnesium and phosphate. Collectively, this results in a dramatic fall in phosphate, potassium, magnesium and thiamine within patients who already have depleted stores. Insulin also stimulates sodium retention in the distal nephrons which promotes water reabsorption. The influx of water can result in fluid overload and cardiac failure.

These problems are greater with oral/enteral feeding due to the ‘incretin effect’. This refers to a greater release of insulin with feeding via the gastrointestinal tract due to the release of gut peptides that accentuate the insulin response (e.g. glucagon-like peptide 1).

This stage is characterised by:

• Hypophosphataemia
• Hypokalaemia
• Hypomagnesaemia
• Low thiamine
• +/- Fluid overload
• +/- Cardiac arrhythmias

Any patient, regardless of weight, who has had little or no nutritional intake for > 5 days is at risk of RFS.

Classic patient groups at high risk of RFS include those with eating disorders (e.g. anorexia nervosa), chronic alcoholism, morbid obesity with massive weight loss, chronic malnutrition from underfeeding and patients unfed for > 5 days (highest risk > 10 days).

The NICE CG32: Nutrition Support for Adults (2017 update), details risk factors for the development of RFS.

Consider RFS if one or more of the following:

• BMI < 16 kg/m²
• Unintentional weight loss >15% within last 3-6 months
• Little or no nutritional intake for > 10 days
• Low potassium, magnesium or phosphate prior to feeding

Consider RFS if two or more of the following:

• BMI < 18.5 kg/m²
• Unintentional weight loss >10% within last 3-6 months
• Little or no nutritional intake for > 5 days
• History of alcohol excess or drugs including insulin, chemotherapy, antacids or diuretics

RFS is characterised by hypophosphataemia, hypomagnesaemia and hypokalaemia.

Without meticulous attention to clinical status and electrolyte derangements, patients are at risk of dangerous cardiac arrhythmias and cardiac failure.

Hypophosphataemia

Hypophosphataemia is a hallmark feature of RFS. Phosphate is needed for multiple intracellular processes, without it ATP is reduced leading to slow metabolic pathways. It also leads to reduced levels of 2,3-diphosphoglycerate (2,3-DPG). This molecule is found in erythrocytes (red blood cells) and enhances the ability of erythrocytes to release oxygen near tissues.

Hypophosphataemia may be asymptomatic, but when moderate-severe features of low phosphate include:

• Lethargy
• Weakness
• Bone pain
• Altered mental status
• Neurological sequelae (e.g. paraesthesia, seizures)
• Ileus (smooth muscle)
• Rhabdomyolysis (skeletal muscle)
• Arrhythmias

For more information see our notes on Hypophosphataemia.

Hypomagnesaemia

Magnesium is an important intracellular ion. It acts as a cofactor in enzyme systems and is needed for the structural integrity of genomic material (e.g. DNA) as well as having important effects on the membrane potential. Hypomagnesaemia can cause neuromuscular excitability.

Features of low magnesium include:

• Neuromuscular: tremor, tetany, seizures, weakness, confusion
• Cardiovascular: palpitations, chest pain, arrhythmias

Features of hypocalcaemia may occur because hypomagnesaemia impairs the action of parathyroid hormone (PTH) leading to resistance and in severe cases reduced secretion. Features of hypocalcaemia include paraesthesia (tingling) and tetany (muscle spasm).

For more information see our notes on Hypomagnesaemia.

Hypokalaemia

Potassium is a major intracellular ion, its serum concentration is affected by insulin, which drives potassium intracellularly.

Features of low potassium include:

• Fatigue
• Generalised weakness
• Muscle cramps & pain
• Palpitations
• Constipation
• Arrhythmias
• Muscle paralysis & rhabdomyolysis (if severe)

For more information see our notes on Hypokalaemia.

Thiamine deficiency

Thiamine is vitamin B1, which is an essential co-factor in carbohydrate metabolism. Body stores last approximately 7 days. Deficiency can exacerbate electrolyte derangements seen in RFS.

Clinical syndromes associated with thiamine deficiency include:

• Wernicke’s encephalopathy: characterised by a triad of confusion, ataxia and nystagmus.
• Korsakoff’s syndrome: the end-stage result of untreated Wernicke’s. An irreversible amnesic syndrome characterised by short-term memory loss, long-term memory is preserved.
• Wet beriberi disease: refers to thiamine deficiency with cardiovascular involvement. Causes high-output cardiac failure.
• Dry beriberi disease: refers to thiamine deficiency with peripheral nerve involvement. Causes weakness and paralysis.

Sodium and fluid

Reactivation of sodium/potassium pumps causes retention of sodium and water. In addition, carbohydrate reintroduction causes a rapid decrease in renal excretion of sodium and water.

In patients with poor baseline cardiac function due to severe malnutrition, the sudden sodium and fluid load can lead to oedema, left ventricular failure and cardiac arrhythmias.

Features of cardiac dysfunction include:

• Relative tachycardia (if low BMI, should expect to find bradycardia)
• Tachypnoea +/- dyspnoea
• Oedema
• Bilateral crackles on auscultation
• Hypotension

Other clinical abnormalities

• Hypoglycaemia: due to depleted glycogen, decreased gluconeogenesis and increased peripheral utilisation. It may also be a sign of underlying sepsis.
• Hyperglycaemia: may occur due to blunted basal insulin secretion. Excess glucose can therefore lead to raised glucose, metabolic acidosis and ketosis.
• Infection: patients with severe malnutrition often do not mount the same systemic inflammatory response. Suspect in patients with hypoglycaemia, hypothermia and low BMI.
• Liver dysfunction: fatty liver is common in starvation due to altered lipid metabolism and transport. May see mild transaminitis (rise in ALT/AST) before and during refeeding. Insulin promotes lipogenesis and deposition of fat in the liver.

Diagnosis of RFS is based on biochemical and clinical deterioration following refeeding.

The hallmark of RFS is the development of hypophosphataemia following refeeding in a patient who is deemed at high risk or malnourished. The severity of RFS is variable and usually more severe the more malnourished the patient is.

Any patient deemed at risk of refeeding syndrome needs baseline investigations and at least daily monitoring of electrolytes, blood sugar and oral intake.

Baseline investigations

• Body mass index
• Observations
• ECG
• Full blood count
• Urea & electrolytes
• Bone profile
• Magnesium
• Liver function tests

Before initiation of feeding, electrolyte derangements should be corrected (see management) and patients started on thiamine or Pabrinex (intravenous vitamin B substances with ascorbic acid). An ECG is important to identify any arrhythmias and the baseline QTc interval.

‘Refeeding’ bloods

• Urea & electrolytes (gives a potassium)
• Bone profile (gives a phosphate)
• Magnesium
• Blood glucose monitoring

Management involves the slow introduction of nutrition, electrolytes and vitamin replacement.

All patients at high risk of refeeding syndrome should be identified and local refeeding guidelines followed. This usually involves close working with a dietitian or nutrition team who have excellent experience in managing RFS, particularly with prescribing enteral or parenteral feeds.

General principles

In all patients, follow these general principles for the prevention and management of refeeding syndrome.

• Identification: identify high-risk patients based on established risk factors
• Baseline investigations: check and replace electrolytes
• Vitamin replacement: prescribe thiamine and vitamin B replacement
• Feeding: NICE recommends no more than 50% of energy requirements if > 5 days with minimal intake. Alternatively, aim for 10-20 kcal/kg/day in high-risk patients and increase over 5-7 days as possible with electrolyte correction. Certain conditions (e.g. anorexia nervosa) have clear guidelines for feed administration (MARSIPAN guidelines).
• Monitoring: check and replace electrolytes, rehydrate, consider high-level care if required (e.g. HDU/ITU)

Nutrition

The NICE CG32: Nutrition Support for Adults provides information on the recommended daily intake amongst adults:

• Total energy: 25-35 kcal/kg/day
• Protein: 0.5-1.5 g/kg/day
• Fluid: 30-35 ml/kg/day
• Electrolytes: minerals and micronutrients as appropriate

This guideline advises no more than 50% of energy requirements over the first two days if patients have gone for > 5 days with little or no intake. This recommendation may be too restrictive in some patients. An alternative regimen may be 10-20 kcal/kg/day of nutrition, which can be increased over 5-7 days as able with electrolyte and fluid replacement.

Over the 5-7 days, the aim should be to build up to 100% of energy requirements. If severe electrolyte derangements or fluid shifts occur, the current nutritional intake may need to be reduced and/or given over a longer period.

Electrolyte replacement

Daily monitoring of ‘refeeding’ bloods is critical to identify and respond to changes in electrolytes. In severe derangement or very high-risk patients, more frequent monitoring may be required. Local guidelines should always be followed. Oral treatment can be combined with intravenous if necessary.

Phosphate

Normal serum phosphate concentration is 0.8-1.5 mmol/L.

• Oral: Phosphate-Sandoz
• Intravenous: Phosphate polyfusor or Glycophos

Magnesium

Normal serum magnesium concentration is 0.7-1.1 mmol/L.

• Oral: Magnesium glycerophosphate
• Intravenous: Magnesium sulphate

Always follow local guidelines for intravenous administration and monitoring of magnesium.

Potassium

Normal serum potassium concentration is 3.5-5.5 mmol/L.

• Oral (3.0-3.4 mmol/L): SANDO-K (1-3 tablets up to three times per day)
• Intravenous (<3.0 mmol/L): Intravenous potassium chloride in 0.9% sodium chloride.

The maximum rate of potassium replacement on a normal ward via peripheral access without cardiac monitoring is 10 mmol/hr. The maximum concentration that can be given is 40 mmol within 1000 mls. Faster rates or higher concentrations may be considered in ITU via a central line with cardiac monitoring.

Vitamin replacement

Thiamine supplementation should be started before the initiation of feeding. Treatment is usually given for 10 days and then reviewed. Options include:

• Oral thiamine and vitamin B co-strong
• Intravenous vitamin B preparation: IV preparation known as Pabrinex (also contains ascorbic acid)

Patients can also receive a balanced multivitamin/trace element supplement daily (e.g. Forceval Soluble). If there is suspicion of Wernicke’s encephalopathy, patients need to be treated with high dose Pabrinex (e.g. two pairs three times daily for 3-5 days, then review).

Fluid balance

Daily monitoring of fluid balance and assessing for signs of fluid overload and cardiac failure is essential. If this develops, patients may require diuretics, but this can worsen electrolyte derangement. Senior help should be sought.

Cardiac monitoring

Patients at high risk of cardiac arrhythmias should be considered for cardiac monitoring. This includes patients with very low BMIs who are at risk of dangerous bradyarrhythmias.

RFS can be a life-threatening condition presenting with cardiac or respiratory failure and/or cardiac arrhythmias.

Cardiac

• Arrhythmias
• Wet beriberi
• Cardiac failure

Non-cardiac

• Respiratory failure
• Dry beriberi
• Wernicke’s encephalopathy
• Korsakoff’s syndrome