Definition

Refeeding syndrome (RFS) is a life-threatening condition characterized by deficiencies in electrolytes, minerals, and vitamins, along with fluid imbalance, salt retention, and organ dysfunction. It can occur in malnourished, catabolic patients when food, especially carbohydrates, is rapidly or inadequately reintroduced (orally, enterally, or parenterally) ¹. Zeki et al. demonstrated that severe hypophosphatemia was more common in patients receiving enteral nutrition than in those on parenteral nutrition (21% vs. 8%, p<0.05). The main cause was an increase in insulin secretion, most likely associated with the release of Glucagon-Like Peptide 1 (GLP-1) in the upper gastrointestinal tract ². Nutritional intake can also reveal latent thiamine deficiency, potentially leading to various complications: lactic acidosis, acute Wernicke’s encephalopathy ("Dry Beriberi": consciousness disturbances, disorientation, ocular motor dysfunction, and/or gait ataxia) and/or heart failure ("Wet Beriberi"). This metabolic reaction may result in a range of pathophysiological impairments affecting the cardiac, respiratory, hematologic, hepatic, and neuromuscular systems, potentially leading to severe complications or even death ³.

Diagnosis

Phosphate (PO₄) shift is the main diagnostic criterion for RFS, although shifts in potassium (K) and magnesium (Mg) can also indicate RFS. If PO₄ decreases by more than 30% from baseline or falls below 0.6 mmol/L within the first 72 hours after refeeding initiation, or if two additional electrolyte shifts fall below the normal range (Mg <0.75 mmol/L, K <3.5 mmol/L, or PO₄ <0.80 mmol/L), this is defined as imminent RFS. The presence of clinical symptoms, such as edema, tachycardia, or tachypnea, confirms a manifest RFS ⁴.

Prevalence

In a secondary analysis of the EFFORT study, a 14% prevalence of manifest RFS was observed in medical patients ⁵. Gonzalez et al. reported a prevalence of 25% among oncology patients, and Hernandez-Aranda et al. found a rate of 48% among malnourished patients ^6,7.

Risk Stratification and Predictors for RFS

Risk stratification for the development of RFS is usually based on the NICE criteria ⁸:

The initial energy intake recommendations are based on three risk categories (low risk, high risk, very high risk), with a gradual increase to full energy requirements over 5 to 10 days  ^1,4.

BW = body weight; d = day

Low Risk of Refeeding Syndrome

High Risk of Refeeding Syndrome

Very High Risk of Refeeding Syndrome

Prophylactic Administration of Electrolytes and Vitamins

The prophylactic administration of phosphate, potassium, magnesium, and thiamine is crucial for patients at very high risk of RFS to prevent complications arising from severe electrolyte imbalances or thiamine deficiency.

Vitamins, Minerals, and Trace Elements

• Thiamine Supplementation: 200-300 mg orally or intravenously at least 30 minutes before the start of refeeding.
• Days 1-3: Thiamine 200-300 mg orally or intravenously.
• Days 1-10: Multivitamin preparation twice daily, orally or intravenously (containing 200% of both water- and fat-soluble vitamins, and 100% of trace elements).

Sufficient and Early Electrolyte Replacement

• Potassium: 2-4 mmol/kg BW
• Phosphate: 0.3-0.6 mmol/kg BW
• Magnesium: 0.05-0.1 mmol/kg BW
• Calcium: 0.05-0.1 mmol/kg BW

Goals of Daily Adjusted Nutrition and Fluid Therapy

• Prevention of electrolyte imbalances, nutrient deficiencies, and salt and fluid overload
• Avoidance of complications, morbidity, and mortality
• Prevention of malnutrition and nutrient deficiencies
• Gradual increase and optimization of food intake

Oral Nutrition

A high-protein and high-energy diet aids in improving nutritional status. Early integration of nutritional counseling is essential for managing diet-related symptoms and optimizing food intake. Key elements of nutritional counseling include: (i) Explaining the rationale and objectives of dietary recommendations and (ii) Motivating patients to adhere to dietary recommendations.

If necessary, build up oral nutrition therapy if there is a high risk of refeeding syndrome:

Enteral Nutrition

Enteral nutrition helps maintain nutritional status in patients who are unable to consume adequate food orally. Two recommended enteral feeding options are available: nasogastric/nasojejunal tubes (for short-term use) and percutaneous tubes (PEG, PRG, PEG/J, Witzel fistula, button for long-term use). The choice of feeding tube should follow a risk-benefit analysis, considering the expected duration, individual circumstances, and patient preferences. Many patients prefer PEG tubes over nasal tubes. If appropriate, the tolerability of enteral feeding may first be tested with a nasogastric tube before PEG placement.

Parenteral Nutrition

Parenteral nutrition is utilized when oral and/or enteral nutrition can no longer adequately meet energy and protein requirements. It can help maintain or improve nutritional status in cases of severe intestinal failure. Typical indications include severe mucositis, intractable vomiting, ileus, severe malabsorption, persistent diarrhea, symptomatic gastrointestinal graft-versus-host disease, radiation enteritis, chronic obstruction, short bowel syndrome, peritoneal carcinomatosis, or chylothorax/chylous ascites.

Practical Notes on Managing Refeeding Syndrome (RFS) ^1,4, if indicated:

General Recommendations:

• Raise awareness among medical staff about RFS risk in vulnerable patients.
• Identify patients at risk of RFS.
• Ensure thorough clinical assessment and develop interdisciplinary treatment plans.
• Promote vigilant monitoring of vital signs, fluid balance, serum electrolytes, renal function, and blood glucose in at-risk patients before and during refeeding. Urine electrolytes may assist in evaluating losses.

Before Initial Refeeding (Pre-Feeding):

• Measure serum electrolytes (especially Na, K, PO₄, Mg), creatinine, urea, and glucose.
• Correct any existing fluid deficits based on hydration status.
• Adjust serum electrolytes if levels are low.
• Supplement with thiamine (200–300 mg orally or intravenously).
• Replace additional fluid losses due to vomiting, diarrhea, stoma output, or urinary losses in renal patients. Electrolyte and protein content of these losses can guide replacement amounts. Carefully monitor rehydration and cardiac function.
• Begin refeeding according to the recommended energy and fluid amounts specified in Section 1.1.2.
• Protein intake: 1–1.5 g/kg/day.
• For severe malnutrition (body weight loss >20%): Administer glucose intravenously as follows:
  • Days 1–6: max 1.5–2 g/kg/day
  • From Day 7 onwards: max 4 g/kg/day
• Diarrhea during oral or enteral feeding is common and often due to gastrointestinal mucosal atrophy.
• Calcium and Vitamin D supplementation are indicated if osteoporosis is suspected or diagnosed.

Average Daily Fluid and Electrolyte Requirements:

• Fluids: 20–40 mL/kg/day of water
• Sodium (Na): 0.5–1.5 mmol/kg/day
• Potassium (K): 0.3–1.0 mmol/kg/day
• Phosphate (PO₄): 0.7–1.0 mmol/kg/day
• Magnesium (Mg): 0.1–0.3 mmol/kg/day
• Calcium (Ca): 0.3–0.5 mmol/kg/day

Monitoring

Monitoring Patients at Risk for Refeeding Syndrome (RFS): ^{[1, 4]} Studies indicate that RFS commonly occurs within the first 72 hours after the initiation of refeeding. During this period, metabolic changes shift from catabolic to anabolic states, accompanied by electrolyte and fluid shifts. Therefore, the following monitoring protocol is suggested:

Special Considerations

• Most common clinical symptoms: Tachycardia, tachypnea, edema
• Other nonspecific symptoms:
• Cardiac: Hyper-/hypotension, congestive heart failure, cardiomyopathy, sudden death
• Pulmonary: Respiratory failure or ventilator dependency, pulmonary edema
• Neurological: Weakness, paresthesia, altered mental state, seizures, ataxia, tremor, dizziness, tetany, rhabdomyolysis, myalgia
• Hematological: Platelet dysfunction, hemolytic anemia, leukocyte dysfunction
• Gastrointestinal: Constipation, abdominal pain, diarrhea, anorexia, paralytic ileus
• Renal: Impaired urine concentration ability
• Metabolic: Alkalosis, glucose intolerance, hypernatremia, ketoacidosis, metabolic acidosis

Oral or Enteral Medications/Supplements

Parenteral Medications/Supplements

Important Notes

• Daily phosphorus requirement for healthy individuals (100%) with normal weight (70 kg): 700 mg (= 22 mmol), maximum intravenous phosphorus infusion rate: 15 mmol/h.
• Potassium phosphate, ampoules (10 mL = 10 mmol) require 250 mL carrier solution; 20 mL (= 20 mmol) require 500 mL carrier solution.

Note: In cases of fluid restriction, an infusion pump (perfusor) should be used to reduce the amount of carrier solution.

• Sodium phosphate, ampoules (10 mL = 2.5 mmol) require 50 mL carrier solution; 20 mL (= 5 mmol) require 100 mL carrier solution.
• Zinc chloride ampoules (7.6 μmol/mL, vial 10 mL; 0.5 mg zinc per mL = 0.0076 mmol/mL = 7.6 μmol/mL).

Note: Zinc chloride solutions produced in hospital pharmacies must always be diluted due to their acidic pH (3.7–4.3), which can cause tissue irritation and phlebitis. Bolus injections may lead to increased mineral loss. Literature on this topic is limited. A 10 mL vial containing zinc (0.5 mg/mL) should be diluted to at least 250 mL. Suitable carrier solutions include 5% glucose, 0.9% NaCl, or mixed infusions. The infusion duration should be at least 8 hours.

• Conversion Factors and Units