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Refeeding syndrome

This underinvestigated syndrome often goes unnoticed until it’s too late, say Joyce Cheung and Richard Johnston

Refeeding syndrome was first reported among survivors of Japanese concentration camps in the second world war who became acutely unwell soon after their release.¹ These cases followed extreme and prolonged starvation. Refeeding syndrome develops in malnourished patients who receive nutritional support after a period of inadequate intake. Malnutrition is alarmingly common among hospital inpatients. A recent meta-analysis of 18 European and North American studies, which assessed more than 10 000 inpatients, found that 31% are malnourished.² Failure to identify patients at risk of developing refeeding syndrome, while they are being refed, results in inadequate monitoring and support of such patients. This can lead to morbidity and mortality.

What is refeeding syndrome?

Although no consensus definition exists, refeeding syndrome can be defined as the consequences of severe fluid and electrolyte shifts in malnourished patients when they are refed.³ It can develop after oral, enteral (through a tube), or parenteral (intravenous) nutritional support. The biochemical derangements usually occur in the first 3-4 days of initiating nutritional support.⁴

Refeeding syndrome can affect every system in the body. The biochemical hallmark is hypophosphataemia (low concentration of phosphate in the blood). Phosphate is vital for cellular respiration. The first step, glycolysis, involves the phosphorylation of glucose (the addition of a phosphate). Cellular respiration also needs adequate phosphate stores to form the energy storing molecule adenosine triphosphate (ATP), which contains three phosphate groups. Phosphate also plays a part in maintaining intracellular enzyme functions, including the synthesis of 2,3-diphosphoglycerate, which regulates oxygen dissociation from haemoglobin. So severe phosphate depletion disrupts almost every cellular physiological process. Other biochemical abnormalities often seen in refeeding syndrome include hypomagnesaemia and hypokalaemia, which result in symptoms by altering cellular transmembrane potentials (see box 1 for clinical features).

Why does it occur?

Glycogen, the body’s store of carbohydrates, is the main source of energy used in the first 24-72 hours of starvation. After depletion of glycogen the body switches from using carbohydrates as an energy source to using protein. Finally, fatty acids are metabolised to produce ketone bodies. Consequently, after prolonged starvation, muscle and fat stores are used, and in advanced malnutrition substantial depletion of muscle occurs.

Malnourished patients also become deficient in electrolytes and vitamins. Intracellular stores of phosphate, magnesium, and potassium become depleted as a result of low oral intake and low concentrations of insulin in plasma. However, despite low intracellular stores, serum concentrations of these electrolytes may remain within normal ranges.⁵ In refeeding, the reintroduction of carbohydrates leads to a sudden reversal from fat to carbohydrate metabolism, and raised insulin secretion. Glucose is again the main source of fuel. Insulin stimulates magnesium and potassium to return to cells and promotes glycogenesis and fat and protein synthesis. These anabolic processes require the phosphorylation of intermediates and create high intracellular demand for phosphate, which is reuptaken into cells. Consequently the intracellular stores of these electrolytes become replenished, though at the expense of plasma concentrations, which can diminish rapidly.

Clinical consequences

The clinical features occur primarily because of deficiencies in phosphate, magnesium, and potassium (box 1). The low concentrations of electrolytes in plasma affect transmembrane potentials, which are critical to the normal functioning of nerve, cardiac, and skeletal muscle cells. Altered potentials result in neurological symptoms, cardiac arrhythmias, impaired gastrointestinal motility, skeletal muscle myopathy, and, hence, rhabdomyolysis. Depletion of ATP exacerbates this cellular dysfunction, resulting in cardiac failure and impaired skeletal and respiratory muscle function.^{6 7} Peripheral oedema commonly develops because of excessive fluid administration, and fluid and sodium retention as a consequence of impaired renal function.⁸

Malnourished patients can also become deficient in thiamine, an important cofactor for carbohydrate metabolism. Wernicke’s encephalopathy and lactic acidosis develop if patients who are deficient in thiamine are refed carbohydrates without prior adequate thiamine replacement.

Prevention

The key to prevention is to identify patients at high risk of refeeding syndrome before starting nutritional support. This usually includes any patients who are below 80% of their ideal body weight and patients who have had little nutritional intake for more than five days (box 2).⁵

In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) recommends routine screening for malnutrition or risk of malnutrition in all hospital inpatients at admission.⁹ The most widely adopted screening process is the malnutrition universal screening tool (MUST), which has been validated as an easy routine screening tool for all adults.¹⁰ The MUST is based on a risk scoring system, which assesses three specific criteria—body mass index, amount of recent unintentional weight loss, and likelihood of inadequate nutritional intake in the short term (figure¹).¹¹ Patients with a high score are malnourished and should be referred to a dietician or nutritional support team. The characteristics of patients who are at a very high risk of developing refeeding syndrome are given in box 3. Baseline concentrations of the electrolytes phosphate, potassium, magnesium, and sodium should be checked before starting feeding in all malnourished patients.

Malnutrition universal screening tool. Adapted with permission¹¹

NICE advocates the simultaneous initiation of nutritional support and correction of electrolyte disorders.⁹ In practice, some clinicians withhold nutritional support while correcting severe electrolyte deficiencies. Evidence is limited in this area. It is essential to continue electrolyte monitoring and replacement throughout the refeeding period, and this should initially be done daily.⁹

The overall approach to refeeding malnourished patients can be described as “start low, go slow, and mind how you go,” especially in high risk patients. Such patients may not have the vitamin and electrolyte stores required to adequately metabolise a high carbohydrate and energy load. Patients who have eaten little or nothing for more than five days should receive an initial replacement rate of less than 50% of their energy requirements, whereas patients at high risk of refeeding syndrome (meeting the criteria in box 3) should receive an initial feeding rate of 42 kJ/kg/24 hr (10 kcal/kg/24 hr).⁹ The rate of nutritional replacement can be increased slowly in the following few days, according to the patient’s electrolyte and clinical status. It is important to start multivitamin supplementation, and specifically, thiamine, and vitamin B complex replacement, before initiating refeeding. Vitamin replacement should continue for at least 10 days.

Treatment

To date, there are no validated management protocols for the treatment of refeeding syndrome because of a lack of randomised controlled trials. However, if the syndrome is detected in routine biochemical tests, it is essential to liaise with the dieticians about the rate of feeding. It is also imperative to replace thiamine and correct electrolyte deficiencies, especially hypophosphataemia, hypomagnesaemia, and hypokalaemia, although the ideal replacement regimens are unknown.⁴ Close biochemical and clinical monitoring should continue on a daily basis. Patients who develop clinical complications should be actively monitored and their management reviewed by the inpatient multidisciplinary nutrition team.

Refeeding syndrome is a clinical condition that is often underdiagnosed and as a consequence undertreated.⁴ Not all healthcare professionals are aware of it. The first step towards preventing it is to increase awareness among hospital clinicians and nursing staff so that patients can be assessed for their risk and hence managed appropriately.

Case report: discussion

In this case, the patient was diagnosed as having established refeeding syndrome and end organ complications. Such patients should be transferred to a critical care unit and receive continuous cardiac monitoring, intravenous thiamine replacement, intravenous electrolyte correction, and either a complete cessation of their feeding or a marked reduction in its rate. Senior clinicians should also consider further investigations and treatment of complications, seizures in this case.

How could this have been prevented?

To prevent the development of refeeding syndrome, such a patient should have had a full biochemical profile performed at admission, including specific requests for phosphate, potassium, glucose, and magnesium. Had she been screened, her MUST score would have been calculated as 4. Her initial management should have been discussed with the dietician because she was at a high risk of developing refeeding syndrome. Thiamine and B complex vitamins should have been replaced before the start of her nutritional support, which should have been calculated to initially supply energy at 10 kcal/kg/24 hr. Daily clinical and biochemical assessments would have enabled her feeding to be increased safely and gradually to achieve her target rate in less than a week.

Competing interests: None declared

Patient consent not needed (patient anonymised, dead, or hypothetical).

Provenance and peer review: Not commissioned; externally peer reviewed.

Joyce Cheung foundation year 1 doctor
joyche3@googlemail.com
Richard Johnston gastroenterology research registrar, Wolfson Digestive Diseases Centre University Hospital, Nottingham
Student BMJ 2009;17:001-036-ISSN 0966-6494 | January 2009

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