CONTENTS

• Basics
• EPIDEMIOLOGY: At-risk patients
• Clinical presentation
• Laboratory abnormalities
• Clinical definition
• CLINICAL APPROACH
  • [1] Prevention & monitoring for at-risk patients
  • [2] Treatment of established refeeding syndrome
• Podcast
• Questions & discussion
• Pitfalls

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basics

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• Refeeding syndrome is a potentially fatal complication which generally occurs within 24-72 hours after starting nutrition (although it may occur later on). (31895231)
• The primary physiologic problems are deficiencies of thiamine, phosphate, magnesium, and potassium (especially phosphate).
• A major cause of refeeding syndrome seems to be an endogenous insulin surge, which is triggered by carbohydrate intake. As such, this might be most accurately termed “carbohydrate refeeding syndrome.” Refeeding syndrome is similar to the resuscitation of a patient with diabetic ketoacidosis, except that the source of insulin is endogenous.

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epidemiology

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general scenario for refeeding syndrome

• [#1] Underfeeding for ≧5 days. (36482748) Increased risk occurs with:
  • (i) Longer duration of underfeeding (e.g., >7-14 days).
  • (ii) Complete fasting.
  • (iii) Greater metabolic stress (e.g., postoperative or septic patient).
• [#2] Initiation of any modality of nutritional support, including:
  • Enteral nutrition.
  • Parenteral nutrition (initiation of TPN is usually high risk).
  • IV dextrose.

high-risk patient populations include:

• Psychosocial issues:
  • Anorexia.
  • Substance use (especially alcoholism).
  • Abuse, neglect, food insecurity.
• Gastrointestinal:
  • Dysphagia.
  • Hyperemesis gravidarum or protracted vomiting.
  • Malabsorption (e.g., inflammatory bowel disease, short gut syndrome, s/p bariatric surgery).
• Cancer-induced cachexia.
• Patients maintained NPO.

other risk factors

• Low baseline levels of K, Phos, and/or Mg. (29901461, 31895231)
• Ketones detectable in urine/serum (starvation ketoacidosis).
• Diuretic use (causes wasting of Mg, K, thiamine).
• Poor nutritional reserves:
  • Low body mass index (e.g., BMI < 16).
  • Recent weight loss.

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clinical presentation

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timing

• Symptoms usually appear within 2-5 days of refeeding. (33074463)

most common symptoms:

• Cardiovascular:
  • Arrhythmia, tachycardia.
  • Volume overload can occur.
• Neurological:
  • Wernicke encephalopathy (ocular abnormalities, ataxia, delirium).
  • Delirium, coma.
  • Seizure.
  • Weakness (including respiratory muscle weakness).
• Abdominal pain.

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laboratory abnormalities

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• Hypophosphatemia is the hallmark abnormality.
• Hypokalemia, hypomagnesemia.
• Hyperglycemia.
• Rhabdomyolysis can occur (causing an elevated creatinine kinase).

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clinical definition

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The following criteria seem reasonable: (29901461)

• [1] Cessation of nutrition (usually >5 days) followed by refeeding.
• [2] Hypophosphatemia that occurs within three days of refeeding. The optimal cutoff is unclear, possibly an absolute serum phosphate level below ~1.5 mg/dL (0.5 mM).
• [3] Absence of another obvious cause of hypophosphatemia that is felt to account for the hypophosphatemia (alternative causes of hypophosphatemia are listed here: 📖).

The American Society of Parenteral and Enteral Nutrition (ASPEN) has proposed the definition of refeeding syndrome shown below (32115791):

• A decrease in phosphate, potassium, and/or magnesium levels by >10-20% (mild refeeding syndrome) and/or organ dysfunction due to a decrease in any of these and/or due to thiamine deficiency.
• Occurring within five days of reinitiating or substantially increasing energy provision.

The ASPEN definition is somewhat unique in its incorporation of potassium and magnesium changes. A broader view of electrolyte shifts may be a welcome addition, given that prior definitions have focused excessively on phosphate. However, this new definition may be insufficiently specific for clinically relevant electrolyte changes and requires clinical validation.

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prevention & monitoring for at-risk patients

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[1] electrolyte monitoring & repletion

• Follow lytes (including Ca/Mg/Phos) for 3 days:
  • Any hypophosphatemia should be aggressively treated (e.g., <2.5 mg/dL or <1.6 mM).
  • If phosphate falls below <1.5 mg/dL (<0.5 mM) this indicates refeeding syndrome (see treatment section below).
• Aggressive repletion of K and Mg (target K>4 mM and Mg >2 mg/dL).
• Consider early enteral phosphate in very high-risk patients:
  • Criteria for prophylactic phosphate supplementation:
    • [1] Very high risk of refeeding syndrome.
    • [2] GFR >>30 ml/min.
    • [3] Phosphate is low or low-normal (below ~3.5 mg/dL). (33074463)
    • [4] Absence of hypercalcemia (which could increase risk of Ca-Phos precipitation).
  • A reasonable dose might be 8 mM PO TID for three days. 📖

[2] micronutrients

• Thiamine 100 mg IV daily.
  • It's unclear whether IV thiamine is absolutely required here, or whether oral thiamine would be adequate. Some studies have demonstrated that the bioavailability of oral thiamine is substantial. (22305197) However, sufficient thiamine might not be absorbed rapidly enough for patients at the highest risk of refeeding syndrome. Thus, the choice of IV versus PO may depend on clinical factors (e.g. individual risk of refeeding syndrome and functionality of the gastrointestinal tract).
• Vitamin B12, 1000 mcg PO daily.
• Daily multivitamin.

[3] for the highest risk patients: gradual initiation of nutrition

• Ideal composition?
  • Carbohydrate intake should probably be limited, because this stimulates an endogenous insulin surge which contributes to electrolyte depletion.
  • Perhaps carbohydrates should initially be limited to <40% of the total energy intake. (25280426)
• Ideal rate?
  • Many sources recommend starting conservatively (e.g., 50% energy requirement), with gradual advancement.
  • For patients with the highest risk of refeeding syndrome, starting with 5 kcal/kg/day might even be considered (e.g., for a patient with BMI <14 kg/m2 and no nutritional intake for two weeks). (20886063)
• (More on how to calculate tube feeding rates here: 📖)

[4] permissive glycemic control

• Insulin appears to play a central role in the generation of refeeding syndrome.
• It seems logical to avoid aggressive insulin administration (e.g., allowing glucose to rise to ~250 mg/dL).

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treatment of established refeeding syndrome

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[1] electrolyte monitoring & repletion

• Close monitoring of electrolytes (including Ca/Mg/Phos).
• Replete K/Mg/Phos aggressively:
  • Mg repletion: 📖
  • K repletion: 📖
  • Phos repletion: 📖
• Avoid giving calcium if possible (it may exacerbate hypophosphatemia).

[2] micronutrients

• Thiamine:
  • 200 mg IV q12 hours for most patients.
  • 500 mg IV q8hr for anyone with mental status changes.
• B12 1,000 mcg PO BID.
• Multivitamin.

[3] nutritional support

• Reduce the caloric intake to 20 kCal/hr for at least two days. After electrolyte levels stabilize, increase caloric intake to 40 kCal/hr for a day, then increase to 60 kCal/hr for a day. Monitor electrolytes carefully. If this is tolerated, continue to gradually increase intake up to full nutritional support. (26597128)
• Escalation in protein calories provided may occur more rapidly than escalation in carbohydrate calories. Whenever possible, attempt to provide the full protein requirement (typically ~1.5 grams/kg/day in a critically ill patient).

[4] cautious use of insulin

• ⚠️ Exogenous insulin will exacerbate the electrolyte abnormalities involved in refeeding syndrome (e.g., hypophosphatemia, hypokalemia).
• [a] Uncontrolled hypokalemia or hypophosphatemia are contraindications to insulin. Hold insulin until electrolytes can be repleted appropriately.
• [b] Avoid aggressive insulin administration (e.g., allowing glucose to rise to ~250 mg/dL).

[5] volume overload

• Severe refeeding syndrome may lead to volume overload due to sodium retention.
• Diuretics should be avoided if possible, as they may exacerbate electrolyte shifts. (32884632) If diuresis is necessary, consider a combination of loop diuretic plus amiloride 💉 to minimize potassium and magnesium excretion.

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podcast

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• The potential risk of refeeding syndrome should be considered whenever starting any previously underfed patient on nutrition.
• It should be recognized that refeeding syndrome can occur among stressed ICU patients if nutrition is interrupted for only a short period of time (e.g., one week).
• Remember the underlying theme of electrolytic derangement – when you encounter any severe electrolyte abnormality, check all of them.

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