Introduction

Refeeding syndrome refers to a potentially fatal constellation of metabolic derangements that occur following refeeding a patient after an extended period of anorexia or severe malnutrition. These metabolic derangements include severe hypophosphataemia, hypomagnesaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hyperglycaemia, and vitamin deficiencies. Clinical manifestations of these abnormalities include peripheral oedema, haemolytic anaemia, cardiac failure, neurological dysfunction, and respiratory failure. These patients often have an intracellular depletion of electrolytes that may not be identified on evaluation of serum electrolytes.

Upon refeeding, there is increased utilization of phosphorus and magnesium to drive metabolic pathways as substrate and co-factors for adenosine triphosphate (ATP) synthesis. This increased intracellular need, in conjunction with cotransport of potassium into the cell with insulin-driven glucose uptake, results in the depletion of these electrolytes. Many of these metabolic changes are believed to result from sudden release of insulin (stimulated by carbohydrate intake) in the presence of total body nutrient depletion. Hypophosphataemia is the most common and consistent abnormality seen in refeeding syndrome and also results in many of the complications seen. Moreover, depletion of magnesium and potassium further contribute to development of complications. The successful management and refeeding of a patient with a history of prolonged starvation, therefore, involves careful use of fluid therapy, nutritional replacement, and support of cardiac and respiratory function.

Pathophysiology

This syndrome is believed to result when enteral or parenteral nutrition, are fed to starved or severely malnourished patients leading to changes and redistribution of fluid and electrolytes that cannot be accommodated by the weakened cardiovascular system. The ensuing depletion in phosphate results in neuromuscular, cardiovascular and respiratory compromise (e.g., diaphragmatic muscle fatigue, respiratory failure). Arrhythmias could be induced by hypokalaemia in combination with hypocalcaemia and hypomagnesaemia. Upregulation of carbohydrate metabolism may explain increased demand for magnesium and thiamine, which then leads to neurological and neuromuscular complications. Typically, refeeding syndrome occurs within the first 2 to 5 days after initiation of feeding, but signs can be detected within hours of refeeding or delayed up to 10 days.

Systemic responses to prolonged starvation reported in people with severe weight loss secondary to anorexia nervosa include severe bradycardia, hypothermia, and hypoventilation. These changes reflect a decrease in resting metabolic rate that occurs within a few days of cessation of nutrition. Decreased metabolism results from decreased insulin activity, reduction of glucose utilization, and loss of metabolically active lean body mass. Skeletal muscle wasting and reduction in respiratory muscle function leads to poor shivering ability and further compromises ventilatory function and body temperature regulation. Eventually, decreased myocardial mass and ventricular contractility occur, leading to decreased cardiac output. The reported incidence of cardiovascular related complications in anorexia nervosa is high (up to 95%), and these include bradycardia, postural hypotension, fluid overload, and cardiac arrhythmias, and result in a high incidence of cardiovascular-related mortality. During starvation, depletion of electrolytes such as potassium and magnesium, occur because of decreased dietary intake. Catabolism of fat and muscle also contributes to further electrolyte losses. Adjustments in renal electrolyte excretion maintain serum concentrations and clinical signs of electrolyte depletion may not be seen initially. During refeeding, intake of carbohydrate stimulates insulin release, resulting in conversion from a catabolic to an anabolic state, which increases cellular demand for phosphorus, potassium, and water. Newly synthesized cells require potassium for maintenance of electrical gradients and translocate serum potassium and phosphorus intracellularly. Stimulated processes such as glycolysis and protein synthesis also require cellular uptake of phosphate and magnesium. The increase in cellular activity resulting from insulin release, therefore, rapidly increases cellular requirement for magnesium, depleting serum magnesium concentration. As starvation leads to whole-body depletion of these electrolytes, cellular translocation can cause severe serum depletion and life-threatening complications. Inorganic phosphate is required for generation of high-energy substrates such as adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG). Protein phosphorylation is also required for many intracellular enzymatic processes. Hypophosphataemia decreases ATP synthesis causing an energy deficit that is responsible for many of the clinical signs associated with refeeding syndrome. Refeeding-associated hypophosphataemia has been reported previously in cats when it resulted in haemolytic anaemia. Thiamine deficiency is an important component of refeeding syndrome in people and has also been reported in cats. Signs of thiamine deficiency include ataxia, vestibular dysfunction, and visual disturbances. Thiamine is a cofactor in many enzymatic reactions involved in carbohydrate metabolism and clinical deficiencies may develop as refeeding of carbohydrates dramatically increase cellular thiamine utilization.

Nutritional Management Strategies

The risk of developing refeeding syndrome may be related to the degree of prior malnutrition, although it has been reported to occur in critically ill patients after a brief period of starvation (48 hours). Proposed guidelines for identification of patients at high risk for developing refeeding syndrome in people include decreased body mass index (BMI), unintentional weight loss >10% in previous 3 to 6 months, complete lack of food intake, decreased serum concentrations of potassium, phosphorus, or magnesium before initiation of feeding.

General guidelines for the prevention of refeeding syndrome state that nutritional support should not be initiated prior to correction of fluid and electrolyte imbalances. Once stabilization is achieved, nutrition should be administered gradually and only increased incrementally. Recommendations for prevention of refeeding complications in people suggest that initial refeeding should not exceed 20 kcal/kg/day. Refeeding syndrome has been reported to occur in cats fed only approximately 6 kcal/kg/day; it is, therefore, possible that refeeding complications in cats may be triggered at a lower level of caloric intake than is typically seen with people. A loading dose of thiamine, followed by daily injections until day 3 of therapy is also recommended before initiation of feeding.

Although there is insufficient information available from dogs and cats at risk for developing refeeding syndrome, protocols for reducing the risk for this disorder are available in people. In a protocol proposed by Hofer et al. (2014), which have been adopted by the European Society of Clinical Nutrition and Metabolism (ESPEN), there should be careful patient assessment of patients at risk for developing refeeding syndrome, restoration of fluid balance without overloading the cardiovascular system, initiation empirical supplementation of phosphate, potassium and magnesium (unless serum concentrations of these electrolytes are increased), initiation of thiamine and other B vitamins and trace mineral with the exception of iron. The caloric intake is gradually increased from 10 kcal/kg to 30 kcal/kg over the course of 10 days with daily monitoring of potassium, phosphate, magnesium, and glucose.

Extrapolating from recommendations in people and recommended supplementation regimens in animals, a sensible approach would be to empirically supplement high risk patients with phosphate at 0.01–0.03 mmol/kg/h, potassium at 0.05 mmol/kg/h, and magnesium at 0.01 to 0.02 mmol/kg/h for first 24 hours of therapy, provided the patient does not have any of these electrolytes above the reference interval for the first 3 days. Thiamine should be administered prior to feeding at 25 mg total dose (cats) or 100 mg total dose (dogs) either subcutaneously or intramuscularly daily until signs resolve. When nutritional support is instituted, no greater than 20% of RER should be provided in first day and nutritional support should be increased gradually over 4–10 days.

Monitoring

Patients considered at risk for developing refeeding syndrome should be monitored daily as successful treatment may be dependent in identifying this condition in the early stages. Body weight, urine output, serum electrolytes, electrocardiography, serum glucose, cardiovascular and respiratory function should also be monitored closely. The specific electrolytes that should be monitored closely include potassium, phosphate, magnesium, and calcium.

Summary

Refeeding syndrome is an uncommon but potentially fatal complication associated with the initiation of nutritional support in severely malnourished animals, particularly cats. Typical metabolic derangements include severe hypophosphataemia, hypomagnesaemia, hypokalaemia, hyponatraemia, hypocalcaemia, hyperglycaemia, and vitamin deficiencies. Clinical manifestations of these abnormalities include peripheral oedema, haemolytic anaemia, cardiac failure, neurological dysfunction, and respiratory failure. The successful management and refeeding of a patient with a history of prolonged starvation, involves careful use of fluid therapy, nutritional replacement, and support of cardiac and respiratory function. Before initiation of feeding, patients should be supplemented with thiamine as well as phosphorus, potassium, and magnesium. Energy targets should be very conservative (e.g., 20 to 30% of RER on first day) and only gradually increased over the next several days. With careful management of cases at risk for developing refeeding syndrome, nutritional support can play a key role in the recovery of these patients.

References

References are available upon request.