Refeeding Syndrome

By Nathalie Suciu, VMD
angell.org/emergency
emergency@angell.org
617-522-7282

April 2025

Introduction

Patients who are malnourished, starved, or present with specific conditions are at risk for metabolic disturbances when nutrition is rapidly reintroduced. These patient populations include those who have experienced prolonged starvation or malnourishment, hepatic lipidosis, diabetic ketoacidosis, or hyperadrenocorticism. This phenomenon is known as refeeding syndrome. It leads to shifts in electrolytes and fluids that can be life-threatening. The hallmark feature of refeeding syndrome is hypophosphatemia, but it can also cause other electrolyte imbalances, metabolic alterations, or cardiopulmonary complications.^1,5

Pathophysiology of Starvation

The metabolic response to starvation is characterized by both acute and delayed phases. The acute response occurs within the first 72 hours of starvation,³ involving a decrease in basal metabolic rate, depletion of muscle and hepatic glycogen stores, and reduced insulin levels.⁴ As insulin levels drop, counterregulatory hormones increase, promoting hepatic glycogenolysis, gluconeogenesis, lipolysis, and skeletal muscle catabolism. In the initial stages, gluconeogenesis and protein catabolism serve as the primary sources of energy. However, during the delayed response, there is a shift from using glucose and protein as the primary energy source to fat catabolism.³ This shift helps prevent further breakdown of muscle and protein. Ketoneogenesis increases, allowing the body’s metabolic needs to be predominantly met by ketone bodies and free fatty acids.^5,8

The response to starvation also includes electrolyte imbalances and a depletion of functional reserves in all organ systems. Electrolyte shifts occur during prolonged starvation, as phosphorus, potassium, and magnesium move from the intracellular to the extracellular space, resulting in their depletion.¹ Natriuresis contributes to fluid loss and further depletion of these electrolytes. Gastrointestinal and cardiopulmonary functions are also affected during prolonged starvation. The GI tract undergoes various physiological changes, including reduced motility, absorption, and intestinal villus atrophy.⁴ Cardiac mass may also be reduced, impairing cardiac function, leading to reduced cardiac output and decreased ventricular compliance. Potential complications include cardiac arrhythmias, hypotension, bradycardia, and congestive heart failure.²

Pathophysiology of Refeeding

During refeeding after chronic malnourishment, hormonal and metabolic changes occur as the body shifts from using fat as its primary energy source back to utilizing protein and carbohydrates. When nutrition is reintroduced, insulin is released, inhibiting fatty acid mobilization, glycogenolysis, and gluconeogenesis. Insulin instead promotes glycolysis and stimulates lipogenesis, glycogenesis, and protein synthesis.⁸ These cellular processes require minerals such as phosphate and magnesium, as well as cofactors like thiamine, and there is consequently an increased demand for these substrates. Circulating insulin also stimulates rapid intracellular uptake of phosphorus, magnesium, and potassium, further depleting serum levels of these electrolytes.⁴ Additionally, insulin’s antinatriuretic effect can lead to fluid overload¹ and potential heart failure in patients with reduced cardiac reserve.

The clinical manifestations of refeeding syndrome are primarily related to deficits in these key electrolytes:

Hypophosphatemia

Hypophosphatemia is the most common and significant electrolyte disturbance associated with refeeding syndrome. Serum phosphorus levels typically decrease within the first 24-72 hours of refeeding, although serum concentrations are not always representative of the extent of deficiency.⁴ Hypophosphatemia can result from decreased absorption, transcellular shifts, or decreased dietary intake. Severe cases of hypophosphatemia can cause hemolytic anemia, immune suppression, skeletal muscle weakness, reduced tissue oxygenation, and central nervous system dysfunction.⁷ Intravenous supplementation is necessary for patients with total serum phosphorus concentrations below 1.5 mg/dL or those at high risk of depletion.⁵

Hypokalemia

Hypokalemia is another electrolyte disturbance associated with refeeding syndrome, resulting from insulin secretion and intracellular potassium uptake.⁸ Potassium is vital for maintaining electrochemical membrane potential, and depletion can lead to muscle weakness, cardiac arrhythmias, ileus, and paresis.⁷ Moderate to severe hypokalemia (serum potassium <3 mEq/L or <3 mmol/L) warrants intravenous supplementation, especially in patients at high risk of depletion.

Hypomagnesemia

Magnesium is the second most abundant intracellular cation and is essential for ATP production, enzyme function, and cellular processes. Hypomagnesemia can result from decreased intake, increased losses, or redistribution. Clinical signs include cardiac arrhythmias, muscle weakness, and metabolic abnormalities, often in conjunction with hypokalemia and hypocalcemia. Supplementation is necessary for serum magnesium concentrations less than 1.5 mg/dL, refractory hypokalemia, or when clinical signs are present.⁷

Treatment

Before starting nutritional support, any dehydration or cardiovascular instability should be corrected.² Baseline electrolytes should be evaluated and corrected, recognizing that serum concentrations may appear normal even when total body stores are depleted. Therefore, it is essential to monitor phosphorus, magnesium, and potassium levels at least once daily.⁵

Identifying patients at risk for refeeding syndrome and gradually reintroducing nutrition is critical for its prevention. A nutritional plan should be developed based on the patient’s resting energy requirements (RER) using the following formulas:

• kcal/day = 70 (BW in kg)^0.75
• kcal/day = 30 (BW in kg) + 70

The actual body weight should be used to calculate the RER, and the use of the illness factor should be avoided to minimize the risk of over-estimating energy needs and the incidence of refeeding syndrome.⁴ The goal of refeeding is to reach the RER over the first week gradually. Nutritional support should begin at 25-30% of the RER⁵ and be gradually increased to 100% over the next 7-10 days, as demonstrated to be safer in recent studies in individuals with refeeding syndrome.⁴ Furthermore, offering diets high in protein and fat and low in carbohydrates is beneficial. Such a diet aims to lower the postprandial insulin release and reduce the likelihood of developing refeeding syndrome. Additionally, patients should be fed smaller and more frequent meals during the initial week of recovery.⁴ Recent studies in humans have shown that constant rate infusions (CRIs) of enteral nutrition in the early stages of refeeding may minimize the risk of refeeding syndrome³, and it is therefore preferred over bolus feedings.

Electrolytes should ideally be supplemented intravenously and administered as constant-rate infusions. Potassium chloride, potassium phosphate, magnesium chloride, or magnesium sulfate can be used for supplementation. Electrolyte levels should be monitored closely every 4-6 hours during refeeding, and adjustments to CRIs should be based on these results or trends.

Table 1: Electrolyte Supplementation Guide 

*Calculate for phosphorus and then add KCl as needed for additional K+ requirement
** Do not exceed 0.5 mEq/kg/hour (Kmax)

A packed cell volume (PCV) and total solids (TS) should be monitored daily. If hemolysis is detected or if PCV is declining, phosphorus levels should be checked for hypophosphatemia.⁵ Vital parameters and weight should also be closely monitored during electrolyte supplementation and rehydration. If refeeding syndrome is detected, nutritional support should be reduced or temporarily stopped. Nutrition can be reintroduced gradually once electrolyte levels improve and return to the normal range.²

Prognosis

Refeeding syndrome is a potentially fatal condition that can occur when malnourished animals are reintroduced to nutrition too rapidly. The prognosis depends on several factors, including the severity of the malnutrition, the speed at which the syndrome is recognized, and the care with which the patient is reintroduced to food. In general, the key to a better prognosis is careful and gradual refeeding, close monitoring, and early intervention to manage any electrolyte imbalances.

With appropriate patient selection and medical intervention, the prognosis for refeeding syndrome is generally favorable. However, without treatment, fatal outcomes are possible.

References

1. Boateng, AA, Sriam K, Meguid MM, Crook M. Refeeding syndrome: treatment considerations based on collective analysis of literature case reports. Nutrition (Burbank, Los Angeles County, Calif). 2010;26(2):156-167.
2. Chan, EA, O’Toole T, Chan DL. Management of prolonged food deprivation, hypothermia, and refeeding syndrome in a cat. Journal of Veterinary and Emergency Critical Care. 16(2)(S1) 2006, pp S34-S41.
3. DeAvilla, M. Hypoglycemia associated with refeeding syndrome in a cat. Journal of Veterinary and Emergency Critical Care. 2016; 00(0):1-6.
4. Khoo, A, Taylor SM, Owens TJ. Successful management and recovery following severe, prolonged starvation in a dog. Journal of Veterinary and Emergency Critical Care. 2019;29:542-548.
5. Lippo N, Byers CG. Hypophosphatemia and refeeding syndrome. Standards of Care: Emergency and Critical Care Medicine. 2008;10(4):6-10.
6. Macintire DK. Metabolic derangements in critical patients. Proceedings ACVIM 2003.
7. Martin GM, Allen-Durrance AE. Magnesium and phosphate disorders. Small Animal Critical Care Medicine (Third Edition). 2023;342-349.
8. Mehanna HM, Moledina J, Travis J. Refeeding syndrome: what it is, and how to prevent and treat it. British Medical Journal. 2008;336(7659):1495-1498.