Refeeding Syndrome

Catherine Sumner, DVM, DACVECC
www.angell.org/emergency
emergency@angell.org
781-902-8400
MSPCA-Angell West, Waltham

Refeeding syndrome is infrequently recognized in veterinary patients, but is a serious condition when it occurs.  Animals that have been historically malnourished or those that have had minimal caloric intake for a number of days are at risk.  When nutrition is reintroduced to these animals, either via oral, enteral or parenteral feeding, they can exhibit fluid and electrolyte shifts that are characterized as refeeding syndrome.

When a patient is malnourished, they experience decreased serum levels of glucose.  The body starts the process of gluconeogenesis, using triglycerides and protein to create glucose.  There is depletion of lean body mass, and total body stores of phosphate, potassium, and magnesium are decreased.  Importantly, serum concentrations of these electrolytes may be normal despite depleted total body stores.  At the time of refeeding, carbohydrates (ie. glucose) are reintroduced, and the body shifts to using carbohydrates for fuel again.  This results in increased insulin secretion, which in turn increases cellular uptake of phosphorus (needed for the cell to make ATP and 2,3-DPG, as well as proteins).  Other contributing factors to hypophosphatemia include decreased intake in the diet and absorption from the gastrointestinal tract, as well as loss via vomiting and diarrhea and changes in acid base balance.  Potassium and magnesium are also driven intracellularly as a result of feeding and increased insulin.

The hallmark sign of refeeding syndrome is hypophosphatemia.  However, other electrolyte abnormalities are also noted, including hypokalemia and hypomagnesemia.  Patients can also suffer from fluid retention (ascribed to decreased cardiac function), vitamin deficiencies (thiamine – vitamin B1 – deficiency reported in humans), and glucose intolerance.

Hypophosphatemia has many effects on the body.  Red blood cells are at risk of hemolysis and also have a decreased release of oxygen.  White blood cells do not function properly, with impaired chemotaxis, phagocytosis, and bactericidal activity.  Patients will suffer from a myopathy due to decreased ATP formation and availability.  Signs include muscle weakness, myocardial insufficiency, respiratory insufficiency, and rhabdomyolysis.  Effects on acid base balance are noted, due to changes in the renal tubules.  Hypophosphatemia also causes impaired glucose metabolism and impaired phospholipid synthesis.  Seizures and mental dysfunction are possible.

Clinical signs associated with hypokalemia include muscle weakness and arrhythmia.  Clinical signs associated with hypomagnesemia include arrhythmias, tremors, tetany, and weakness.  Additionally, hypomagnesemia can result in secondary hypokalemia and hypocalcemia.  Fluid overload and fluid retention can occur, even in the face of conservative IV fluid rates.  Clinical signs can include weight gain, dyspnea, tachypnea, pulmonary crackles, chemosis, and serous nasal discharge.

The time frame in which refeeding syndrome is noted is typically within 5 days of the reintroduction of nutrition.  Animals that are older or critically ill may be at an increased risk of development of refeeding syndrome. Also, in humans with critical illness, refeeding syndrome can develop quickly, with signs noted in patients that did not receive nutrition for only 48 hours.  Refeeding syndrome should be suspected in a patient where nutrition was recently reintroduced when there is a >20% drop in a patient’s phosphorus, potassium, or magnesium levels.  The incidence of refeeding syndrome in veterinary patients has not been determined.  In humans, the reported incidence of electrolyte changes in patients receiving TPN has been as high at 59%.  It appears that the incidence in our veterinary patients is much lower.  It is unclear why refeeding syndrome develops in some patients, but not others that are also at risk.

When refeeding syndrome is suspected, the rate of feeding should be reduced immediately by 50-75%.  A change to a diet with a lower carbohydrate amount can be considered.  Hypophosphatemia, hypokalemia, and hypomagnesemia are addressed via supplementation of a combination of the following: potassium phosphate (supplies 4.4 mEq K⁺ per mL and 3 mmol PO₄^2- per mL), magnesium sulfate (supplies 500 mg Mg per mL) or magnesium chloride (supplies 200 mg Mg per mL), and potassium chloride (supplies 2 mEq K⁺ per mL).  Of course, it is always important to check labels to confirm the correct concentration is being used for calculations.  Dose ranges for potassium phosphate supplementation range from 0.03 mmol PO₄^2- kg/hour to 0.12 mmol PO₄^2- /kg/hour.  Dose ranges for magnesium salts range from 1.4 mg/kg/hour to 4.9 mg/kg/hour.  The total rate of potassium supplementation should not exceed 0.5 mEq/kg/hour (Kmax), so if a patient is receiving crystalloid fluids containing potassium, this needs to be taken in to account as well as potassium phosphate and potassium chloride infusions.  Sometimes, hypokalemia is refractory until hypomagnesemia is addressed.  Hypocalcemia can also occur as a result of hypomagnesemia, but typically resolves as hypomagnesemia is treated.  Electrolyte supplementation is best administered via a continuous rate infusion, not as a bolus.  Potassium and magnesium can be administered orally, as an alternative.  If phosphorus supplementation occurs too rapidly, it can result in renal failure and hypocalcemia.

It is of utmost importance to monitor electrolyte levels during supplementation.  Ideally, electrolytes and glucose should be monitored every 4-6 hours until they have stabilized.  Adjustments to the electrolyte supplementation CRIs are made based on these results.  It is potentially more useful to monitor the trend of electrolyte values rather than just looking at the absolute values.  It is also important to monitor heart rate, heart rhythm and blood pressure during supplementation of electrolytes.  If electrolyte values are not increasing, it may be necessary to stop nutrition completely until they are improved and then reintroduce food.  The PCV should be monitored, as hypophosphatemia can result in hemolytic anemia.  An increase in bilirubin may be noted concurrently with a drop in PCV in these cases.  A red blood cell transfusion should be administered if indicated.

As the patient’s electrolytes improve, the amount of nutrition can be slowly increased.  Recommendations are that from the time of reintroduction of nutrition to when Resting Energy Requirement is reached should take 4-7 days in patients with refeeding syndrome.  Additionally, supplementing vitamin B in affected patients can be considered, or beginning vitamin B supplementation prior to the reintroduction of food in at risk patients may be warranted.

Ideally, if one is cognizant of the potential for refeeding syndrome, you can avoid development of this syndrome in your patient.  There is no data that shows that any specific diets are more likely to lead to refeeding syndrome than another.  Rather, risk of development of refeeding syndrome is tied to how many calories are given to the patient and how fast they are administered.  Theoretically, providing more calories via fat and protein instead of only carbohydrates may decrease the incidence and severity of refeeding syndrome, as there will be less insulin release.  However, the ideal balance between carbohydrate and other energy sources is not known. Nutritional supplementation should be delayed until dehydration has been corrected and cardiovascular stability has been achieved.  Historical recommendations have been to start at 25-50% of the resting energy requirement and slowly increase from there over 2-3 days.  This works out to 5-10 kcal/kg/day.  However, there are reports of refeeding syndrome development in cats started at conservative rates (5.9 kcal/kg/day and 6 kcal/kg/day).  Electrolytes should be checked daily as the amount of nutrition is increased to monitor for development of refeeding syndrome.  Recent human studies suggest that a slow introduction of nutrition actually can prolong the time over which refeeding syndrome can occur.  It appears that using a CRI of enteral nutrition may minimize the risk of refeeding syndrome in humans, versus bolus enteral feeding or parenteral feeding.

In general, patients that are at risk for refeeding syndrome are usually critically ill such that hospitalization at a 24 hour referral hospital is warranted.  Enteral and parenteral feeding options will be available, as well as point of care lab testing for monitoring and other treatments as necessary.

For more information about Angell’s Emergency/Critical Care service, please visit www.angell.org/emergency or call MSPCA-Angell West in Waltham at 781-902-8400.

References:

Armitage-Chan EA, O’Toole T, Chan DL.  Management of prolonged food deprivation, hypothermia, and refeeding syndrome in a cat.  JVECC 2006; 16(2)(S1):S34-S41.

DeAvilla MD, Leech EB. Hypoglcemia associated with refeeding syndrome in a cat. JVECC 2016; 00(0):1-6.

Thomovsky E, Backus R, Reniker A, et al. Parenteral Nutrition: Formulation, Monitoring, and Complications.  Comp Vet Med 2007;29(2):88-103.