What is the pathophysiology, clinical signs, risks, and treatment of refeeding syndrome?

Refeeding Syndrome Overview

Pathophysiology

Refeeding syndrome occurs when aggressive nutritional reintroduction in malnourished patients triggers a metabolic shift from catabolism to anabolism, causing life-threatening electrolyte redistribution and fluid imbalances. 1

The underlying mechanism involves:

• Insulin surge from carbohydrate refeeding drives glucose, phosphate, potassium, and magnesium intracellularly, causing severe extracellular depletion despite total body deficits already present 2, 3
• Phosphate depletion is the hallmark abnormality, as it becomes critically depleted during cellular ATP synthesis and protein/glycogen production 1, 2
• Thiamine deficiency becomes unmasked when carbohydrate metabolism suddenly increases thiamine requirements beyond depleted stores 1
• Sodium and water retention occurs as anabolic metabolism resumes, leading to volume overload 4

This represents the body's inability to handle the sudden metabolic demands of refeeding after prolonged adaptation to starvation 3.

Clinical Signs and Manifestations

Symptoms typically develop within the first 4 days of nutritional reintroduction, with cardiovascular complications being the most lethal. 1

Cardiovascular

• Cardiac arrhythmias from electrolyte imbalances (hypophosphatemia, hypokalemia, hypomagnesemia) 1
• Congestive heart failure from fluid overload 1
• Hypotension and sudden cardiac death (occurs in up to 20% of severe cases) 4

Neurological

• Delirium, confusion, and encephalopathy 1
• Seizures 1
• Wernicke's encephalopathy from thiamine deficiency (can progress to Korsakoff syndrome) 1
• Lethargy progressing to coma 1

Respiratory

• Respiratory failure requiring increased ventilatory support 1
• Difficulty weaning from mechanical ventilation 1

Neuromuscular

• Muscle weakness and rhabdomyolysis 4, 1
• Anemia 4

Other

• Peripheral edema 4
• Hepatic dysfunction with excessive fat and glycogen storage 1
• Organ failure (multi-system) 4, 2

Laboratory Abnormalities

• Hypophosphatemia (most frequent and clinically significant) 1
• Hypokalemia 1
• Hypomagnesemia 1
• Hypocalcemia 1
• Hyperlactatemia (suggests thiamine deficiency) 1
• Disturbed glucose homeostasis 1

Risk Factors

Any malnourished patient should be considered at risk, but specific criteria identify those at highest danger. 4, 5

High-Risk Criteria (NICE-based)

• BMI <16 kg/m² 1, 5
• Unintentional weight loss >15% in 3-6 months 1, 5
• Little or no nutritional intake for >10 days 1, 5
• Low baseline electrolytes (potassium, phosphate, or magnesium) before feeding 4, 1

Additional Risk Factors

• History of chronic alcoholism 4, 1
• Anorexia nervosa 1
• Chronic drug use (insulin, antacids, diuretics) 1
• Acute illness in depleted patients 1
• Older hospitalized patients (very high overlap between malnutrition and refeeding syndrome risk) 4
• Cancer patients with severe malnutrition 5
• Chronic vomiting or diarrhea 1

Critical caveat: Older patients warrant particular attention as risk factors are extremely common in this population, and even standard malnutrition screening tools identify refeeding syndrome risk 4.

Treatment and Prevention

Prevention is paramount—start nutrition at low caloric levels with aggressive electrolyte/vitamin supplementation before and during refeeding. 1, 5

Pre-Feeding Protocol (MANDATORY)

Never initiate feeding without thiamine supplementation, as this can precipitate Wernicke's encephalopathy, cardiac failure, and death. 1

• Thiamine 200-300 mg daily (start BEFORE any feeding) 1, 5
• Full B-complex vitamins intravenously 1
• Check baseline electrolytes (phosphate, potassium, magnesium, calcium) 1, 5
• Correct severe electrolyte deficiencies before feeding (but recognize this doesn't correct massive intracellular deficits) 1

Nutritional Reintroduction Strategy

Very high-risk patients:

• Start at 5-10 kcal/kg/day 1, 5
• Increase slowly over 4-7 days until full requirements reached 1

Standard high-risk patients:

• Start at 10-20 kcal/kg/day 1
• Progress gradually over first 3 days 4

Macronutrient distribution:

• 40-60% carbohydrate, 30-40% fat, 15-20% protein 1
• Protein at least 1 g/kg/day (actual body weight if BMI <30, adjusted if BMI ≥30) 1

Electrolyte Replacement During Refeeding

Aggressive supplementation is required even with mild deficiency: 4

• Potassium: 2-4 mmol/kg/day 1
• Phosphate: 0.3-0.6 mmol/kg/day 1
• Magnesium: 0.2 mmol/kg/day IV or 0.4 mmol/kg/day orally 1
• Calcium: as needed 1

Monitoring Protocol

The first 72 hours are critical—this is when most complications occur. 4

• Daily electrolyte monitoring for first 3 days, then regularly until stable 1, 5
• Monitor for clinical signs: edema, arrhythmias, confusion, respiratory failure 1
• Strict glucose monitoring to avoid hyperglycemia 1
• Thiamine supplementation for minimum 3 days 1

Route of Nutrition

• Enteral feeding is preferred if intestinal function preserved (maintains gut barrier, fewer infections, lower cost) 1
• Refeeding syndrome can occur with ANY route (oral, enteral, or parenteral) 1, 6
• Position patients at 30° or more during and 30 minutes after feeding to minimize aspiration 1

Special Considerations

Severe acute pancreatitis with refeeding risk:

• Limit to 15-20 kcal/kg/day non-protein calories 1
• Avoid overfeeding (detrimental to cardiopulmonary and hepatic function) 1

If feeding must be discontinued:

• Taper gradually to prevent rebound hypoglycemia 1

Older patients:

• Avoid sedation and physical restraints (causes muscle loss and cognitive deterioration) 4, 1
• Encourage physical activity during refeeding to maintain muscle mass 4

Critical Pitfalls to Avoid

• Never start feeding without prophylactic thiamine 1
• Do not rely on correcting baseline electrolytes alone—this provides false security without addressing massive intracellular deficits 1
• Do not advance calories too quickly even if patient tolerates initial feeding 1
• Do not assume hypophosphatemia alone equals refeeding syndrome—many other causes exist 3
• Do not use glucose-containing infusions liberally in at-risk patients 4