Refeeding Syndrome (RFS)

Refeeding Syndrome (RFS)

Brenna C Chen, MD

Table of Contents

Definition
Pathophysiology
Causes
Presentation and Complications
Identifying Patients at Risk
Diagnosis
Treatment

Definition

Definition: A Syndrome of Clinical Complications that Can Occur When Providing Nutrition to Previously Malnourished Patients Due to Resulting Fluid and Electrolyte Shifts

  • Note: There is No Universally Accepted Definition of Refeeding Syndrome
  • It Is Associated with Hypophosphatemia, Hypokalemia, Hypomagnesemia, Thiamine Deficiency, and Resultant Neurologic, Cardiac, and Respiratory Dysfunction
  • It is a Metabolic Response that Occurs When Calories are Reintroduced After a Period of Decreased or Absent Caloric Intake
  • Some Studies Report Hypophosphatemia is the Hallmark Finding of Refeeding Syndrome
  • First Described in World War 2 Among Prisoners of War, Concentration Camp Survivors, and Victims of Famine

Pathophysiology

Starvation Leads to Depletion of Energy Stores, Vitamins, and Intracellular Electrolytes

Patients Are in a Catabolic State

When Glucose is Reintroduced to the Body, Insulin is Secreted Which Further Depletes Serum Levels of Phosphate, Potassium, and Magnesium by Shifting Electrolytes Intracellularly

Phosphate Loss

  • Increased Insulin Levels Lead to an Intracellular Shift of Phosphorus
  • Phosphorus is Needed for Glycolysis and ATP Synthesis – Promoted by Increased Insulin Levels
  • Phosphorus is a Key Component of ATP – In States of Malnutrition, ATP Stores Are Depleted Which Leads to Respiratory Dysfunction
  • Phosphorus Plays an Important Role in Cardiac Conduction, Leading to Decreased Cardiac Contractility and Arrhythmias
  • Lack of Phosphate Also Leads to Decreased Production of 2,3-Diphosphoglycerate – Increases Hemoglobin’s Affinity for Oxygen, Which May Result in Tissue Hypoxia

Potassium Loss

  • Secretion of Insulin Stimulates Na+/K+ ATPase, Leading to Intracellular Influx of Potassium
  • Potassium is Important for Transmission of Nerve Impulses and Muscle Contraction
  • Hypokalemia May Cause Cardiac Arrhythmias, Respiratory Muscle Weakness, and Neuromuscular Dysfunction

Magnesium Loss

  • Hypomagnesemia Can Worsen Hypokalemia by Impairing Reuptake of Potassium in Nephrons, Impacting the Magnesium Dependent Na+/K+ ATPase
  • Overall, Mechanism in Refeeding Syndrome is Not Well Known

Thiamine Loss

  • Thiamine Demand Increases During a Feeding State Since it is a Cofactor for Glucose Dependent Metabolic Pathways

Causes

Primary Cause: Reintroduction of Calories After Period of Caloric Deficit

Can Be Triggered by Reintroduction of Calories Through Either Oral, Enteral or Parenteral Nutrition

Risk Factors

  • Anorexia Nervosa
  • Alcohol or Substance Use Disorders
  • Other Mental Health Disorders that May Cause Self Neglect or Food Avoidance
  • Malabsorption (Such as Those with Celiac Disease, Bariatric Surgery, or Short Gut Syndrome)
  • Starvation Which May Be Secondary to Famine, Migration, or Protest
  • Critically Ill Patients
  • Malignancy
  • Child or Elderly Abuse

Patients on Hemodialysis (HD) are Less Likely to Develop Refeeding Syndrome, Despite Prevalent Malnutrition, Due to Impaired Phosphorus/Potassium Clearance – Risk May Be Greater in Patients with CVVH or Peritoneal Dialysis Due to Increased Clearance

Presentation and Complications

Hypophosphatemia is Generally Considered to be the Hallmark of Refeeding Syndrome

In Severe Cases, RFS Can Lead to Multiorgan Failure and Death

Hypophosphatemia

  • Neurologic Effects: Paresthesias, Weakness, Delirium, Disorientation, Encephalopathy, Areflexic Paralysis, Seizures, Coma, and Tetany
  • Cardiac Effects: Hypotension, Shock, Decreased Stroke Volume, and Increased Wedge Pressure
  • Respiratory Effects: Diaphragm Weakness, Dyspnea, and Respiratory Failure
  • Hematologic Effects: Hemolysis, Thrombocytopenia, and Leukocyte Dysfunction
  • Musculoskeletal Effects: Rhabdomyolysis

 Hypokalemia

  • Neurologic Effects: Paralysis, and Weakness
  • Cardiac Effects: Cardiac Arrhythmias, and Contraction Changes
  • Respiratory Effects: Respiratory Failure
  • Gastrointestinal Effects: Nausea, Vomiting, and Constipation
  • Musculoskeletal Effects: Rhabdomyolysis, and Muscle Necrosis

 Hypomagnesemia

  • Neurologic Effects: Weakness, Tremor, Muscle Twitch, Tetany, Altered Mental Status, Convulsion, Seizure, and Coma
  • Cardiac Effects: Arrhythmia
  • Gastrointestinal Effects: Anorexia, Nausea, Vomiting, and Constipation

 Thiamine Deficiency

  • Neurologic Effects:
    • Wernicke’s Encephalopathy (Reversible) – Ataxia, Altered Mental Status, Nystagmus, Diplopia, and Ptosis
    • Korsakoff Syndrome (Irreversible) – Confabulation, Amnesia, Cognitive and Behavioral Changes
    • Dry Beriberi – Muscle Weakness, Paralysis, Paresthesias, Numbness, Areflexia, Ataxia, Nystagmus, Altered Mental Status, and Foot Drop (Late Stage)
  • Cardiac Effects:
    • Wet Beriberi – Dyspnea, Tachypnea, Pulmonary Edema, Tachycardia, Chest Pain, Cardiomegaly, Fatigue, and Peripheral Edema
  • Oculomotor Abnormalities:
    • Most Commonly Horizontal Ophthalmoplegia

Fluid Balance

  • Historically, Refeeding Syndrome Was Thought to Cause Extracellular Fluid Expansion and Congestive Heart Failure
  • Evidence Supporting Intravascular Volume Overload as a Direct Consequence of Refeeding Syndrome is Limited
  • Many Early Reports of “Heart Failure” May Have Represented Sudden Cardiac Death or Arrhythmias Related to Electrolyte Abnormalities Rather Than True Congestive Heart Failure
  • Patients With Underlying Cardiac or Renal Disease May Still Develop Fluid Overload During Nutritional Rehabilitation, Particularly with Aggressive Fluid Administration

Identifying Patients at Risk

Screening Tools

  • ASPEN (American Society for Parenteral and Enteral Nutrition) – Generally Considered to Have the Best Validity
  • NICE (National Institute for Health and Care Excellence)
  • mNICE (Modified National Institute for Health and Care Excellence)
  • GLIM (Global Leadership Initiative on Malnutrition)
  • MUST (Malnutritional Universal Screening Tool)
  • NRS-2002 (Nutritional Risk Screening 2002)
  • SNAQ (Short Nutritional Assessment Questionnaire)

ASPEN Consensus Criteria for Identifying Adult Patients at Risk for Refeeding Syndrome

  • Moderate Risk: 2 Criteria Needed
    • BMI: 16-18.5 kg/m2
    • Weight Loss: 5% in 1 Month
    • Caloric Intake:
      • Negligible Oral Intake for 5-6 Days
      • < 75% of Estimated Energy Requirements for > 7 Days During Acute Illness/Injury
      • < 75% of Estimated Energy Requirements for > 1 Month
    • Loss of Subcutaneous Fat: Moderate
    • Loss of Muscle Mass: Mild to Moderate
    • Pre-Feeding Electrolytes: Minimally Low Levels or Recent Low Levels Needing Minimal or Single-Dose Supplementation
    • High-Risk Comorbidities: Moderate Disease
  • Significant Risk: 1 Criteria Needed
    • BMI: < 16 kg/m2
    • Weight Loss: 7.5% in 3 Months or > 10% in 6 Months
    • Caloric Intake:
      • Negligible Oral Intake for > 7 Days
      • < 50% of Energy Needs for > 7 Days During Acute Illness/Injury
      • < 50% Of Estimated Energy Needs > 1 Month
    • Loss of Subcutaneous Fat: Severe
    • Loss of Muscle Mass: Severe
    • Pre-Feeding Electrolytes: Moderately/Significantly Low Levels or Recent Low Levels Needing Significant or Multiple-Dose Supplementation
    • High-Risk Comorbidities: Severe Disease

ASPEN Consensus Criteria for Identifying Pediatric Patients at Risk for Refeeding Syndrome

  • Mild Risk: 3 Criteria Needed
    • Weight-for-Length (1-24 mo) or BMI-for-Age (2-20yr) Z-Score: -1 to -1.9 Change from Baseline
    • Weight Loss: < 75% of Normal Expected Weight Gain
    • Energy Intake: 3-5 Consecutive Days of Protein or Energy Intake < 75% of Estimated Need
    • Loss of Subcutaneous Fat:
      • Mild Loss, or
      • Mid-Upper Arm Circumference Z-Score of -1 to -1.9
    • Pre-Feeding Electrolytes:
      • Mildly Abnormal, or
      • < 25% Below Lower Limit of Normal
    • High-Risk Comorbidities: Mild Disease
  • Moderate Risk: 2 Criteria Needed
    • Weight-for-Length (1-24 mo) or BMI-for-Age (2-20yr) Z-Score: -2 to -2.9 Change from Baseline
    • Weight Loss: < 50% of Normal Expected Weight Gain
    • Energy Intake: 5-7 Consecutive Days of Protein or Energy Intake < 75% of Estimated Need
    • Loss of Subcutaneous Fat:
      • Moderate Loss, or
      • Mid-Upper Arm Circumference Z-Score of -2 to -2.9
    • Loss of Muscle Mass:
      • Mild-Moderate Loss, or
      • Mid-Upper Arm Circumference Z-Score of -2 to -2.9
    • Pre-Feeding Electrolytes:
      • Moderately/Significantly Abnormal, or
      • 25-50% Below Lower Limit of Normal
    • High-Risk Comorbidities: Moderate Disease
  • Significant Risk: 1 Criteria Needed
    • Weight-for-Length (1-24 mo) or BMI-for-Age (2-20yr) Z-Score: -3 or Greater Change from Baseline
    • Weight Loss: < 25% of Normal Expected Weight Gain
    • Energy Intake: >7 Consecutive Days of Protein or Energy Intake < 75% of Estimated Need
    • Loss of Subcutaneous Fat:
      • Severe Loss, or
      • Mid-Upper Arm Circumference Z-Score of -3 or Greater
    • Loss of Muscle Mass:
      • Severe Loss, or
      • Mid-Upper Arm Circumference Z-Score of -3 or Greater
    • Pre-Feeding Electrolytes:
      • Moderately/Significantly Abnormal, or
      • 25-50% Below Lower Limit of Normal
    • High-Risk Comorbidities: Severe Disease

Diagnosis

Generally a Clinical Diagnosis, Based Upon History of Malnutrition and New Onset Metabolic and Electrolyte Derangements Shortly After Restarting Nutritional Support

However, There Is No Universally Accepted Diagnostic Criteria for Refeeding Syndrome

ASPEN 2020 Definition: A Decrease in Serum Phosphorus, Potassium, and/or Magnesium Levels by ≥ 10% Within 5 Days of Refeeding

Severity 

  • Mild: 10-20% Decrease
  • Moderate: 20-30% Decrease
  • Severe: > 30% Decrease and/or Organ Dysfunction Resulting from Electrolyte Abnormalities or Thiamine Deficiency

 Supporting Labs

  • Hypophosphatemia
  • Hypokalemia
  • Hypomagnesemia
  • Thiamine Deficiency
  • Likely to Be Refeeding Syndrome If:
    • Serum Phosphate Drops > 30% Below the Lower Limit of Normal or Under 0.6 mmol/l
    • If Two Out of the Three (Phosphorus, Magnesium, Potassium) Are Under the Lower Limit of Normal Within 72 Hours

Additional Supporting Findings

  • May Be Used to Diagnose Sequelae of Refeeding Syndrome Which Can Support the Diagnosis
  • Chest X-Ray/CT: Pulmonary Edema or Cardiomegaly
  • EKG: Cardiac Arrhythmias

Treatment

General Management: Decrease Feeding Rate and Replace Electrolytes

Feeding Rate

  • Start at a Slower Feeding Rate (10-20 Kcal/kg/day)
  • Advance by 33% of Goal Every 1-2 Days
  • Ideally Reach Goal Feeds in 3-7 Days – But Advanced Slowly Based on Clinical Status and Electrolyte Stability
  • If Pre-Feeding Electrolytes are Low, Consider Holding Initiation/Increase of Calories Until Electrolytes are Supplemented/Corrected – Particularly if Severely Low
  • Decrease Calories by 50% if Electrolytes Drop Precipitously or Become Difficult to Correct

Monitoring Electrolytes

  • Check Electrolytes Prior to Initiating Nutrition in Patients with Any Risk of RFS
  • Repeat Labs Every 12 Hours for the First 3 Days for High-Risk Patients
  • Repeat Labs More Frequently if Needed

Supplementation

  • Prophylactic Thiamine (100-300 mg) Daily Prior to Restarting Feeding If Patient is at High Risk
  • Add a Multivitamin Once Daily for ≥ 10 Days if Receiving Oral/Enteral Nutrition
  • Add a Multivitamin Injectable (MVI) Once Daily if Receiving Parenteral Nutrition for as Long as Parenteral Nutrition is Continued
  • Replace Electrolytes as Needed, Consider Daily Prophylactic Electrolytes Such as 10-15 mmol of Phosphate for Every 1,000 Calories