What are the appropriate interventions to prevent potential complications from refeeding syndrome?

CONTENTS

• Rapid Reference 🚀
• Basics
• Epidemiology
• Signs & symptoms
• Laboratory abnormalities
• Prevention in at-risk patients
• Clinical definition
• Treatment of established refeeding syndrome
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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Inhaltsverzeichnis Show

• rapid reference
• epidemiology
• signs and symptoms are nonspecific
• laboratory abnormalities
• prevention in at-risk patients
• clinical definition
• treatment of established refeeding syndrome
• questions & discussion
• Can you identify appropriate interventions to prevent refeeding syndrome?
• What are the appropriate interventions to prevent potential complications of diarrhea?
• What is refeeding syndrome NICE guidelines?
• Which patient is most likely at risk of refeeding syndrome?

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Refeeding prevention/monitoring package ✅

• This is for at-risk patients, including:
  • Substance or EtOH use.
  • Underweight or recent weight loss.
  • Anorexia nervosa.
  • Dysphagia or hyperemesis.
  • Extended period NPO (>5 days).
  • Low baseline levels of K/Phos/Mg.
• Preventative therapies:
  • Thiamine 100-200 mg q12-24.
  • B12, 1000 mcg PO daily.
  • Multivitamin.
  • Gradual initiation of nutrition for the highest risk patients.
• Monitoring:
  • Follow lytes including Mg & Phosphate for three days.
  • If phosphate falls <1.5 mg/dL (0.5 mM) this indicates refeeding syndrome –> see treatment below.

Treatment of established refeeding syndrome ✅

• Vitamins
  • Thiamine (e.g., 500 mg IV q8hr, if mental status changes).
  • B12 1,000 mcg PO BID.
  • Multivitamin.
• Electrolyte repletion
  • Follow Mg/K/Phos & replete aggressively.
    • Mg repletion: 📖
    • K repletion: 📖
    • Phos repletion: 📖
  • Avoid giving calcium if possible.
  • Avoid/limit giving insulin.
• Nutritional support
  • Cut back rate of nutrition (e.g., 25-50% of usual caloric target, depending on severity).  Advance diet gradually as tolerated.
  • Still try to provide adequate protein.

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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.”

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epidemiology

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general causes of refeeding syndrome

• Refeeding syndrome results from underfeeding for a period of time, followed by re-initiation of nutritional support (including enteral nutrition, parenteral nutrition, or even IV dextrose).
• The duration of underfeeding is typically >7-10 days.
  • Less time spent being underfed may still result in refeeding syndrome if the patient were under metabolic stress while not being fed (e.g., a postoperative patient).

high-risk patient populations

• Psychosocial issues
  • Anorexia
  • Depression
  • Alcoholism, other severe substance use
  • Abuse, neglect, inadequate access to food
• Gastrointestinal
  • Dysphagia
  • Hyperemesis gravidarum or protracted vomiting
  • Malabsorption (e.g., inflammatory bowel disease, short gut syndrome, s/p bariatric surgery)
• Iatrogenic
  • Patients maintained NPO (e.g. post-operative patients)

other risk factors

• Older age.
• Malignancy.
• Catabolic state (e.g., due to infection or surgery).
• Baseline low levels of K, Phos, or Mg. (29901461, 31895231)
• Poor nutritional reserves
  • Low body mass index (e.g., BMI < 16)
  • Recent weight loss

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signs and symptoms are nonspecific

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• Cardiovascular
  • Arrhythmia, tachycardia
• 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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prevention in at-risk patients

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upon starting nutrition

• Check electrolytes (including magnesium and phosphate), with aggressive repletion as needed.
• Start thiamine prophylactically (e.g., thiamine 100-200 mg IV q12-q24hr).
  • 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).
• Start vitamin B12 (cyanocobalamin) 1,000 micrograms PO daily.
• Start multivitamin.

nutritional therapy to prevent refeeding syndrome

• 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?
  • This is unknown.  Many sources recommend starting conservatively (e.g., 50% energy requirement), with gradual advancement.  However, there is no high-quality evidence that this reduces the risk of refeeding syndrome.
  • 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: 📖

permissive glycemic control?

• Insulin appears to play a central role in the generation of refeeding syndrome.
• It seems logical to avoid administering insulin if possible (e.g., allowing glucose to rise to ~200-300 mg/dL).

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clinical definition

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Unfortunately, there is no uniform definition of refeeding syndrome.  Until a consensus definition is obtained, the following criteria seems reasonable:  (29901461)

• (1) Cessation of nutrition followed by refeeding.
• (2) Hypophosphatemia which 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).  This 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 relevent electrolyte changes and requires clinical validation.

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treatment of established refeeding syndrome

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There is no high-quality evidence on this.  Available literature suggests the following interventions may be reasonable:  

micronutrients

• Thiamine 200-500 mg IV q8hr-q12hr (use higher dose in the context of any mental status changes, which could reflect the possibility of Wernicke encephalopathy).
• Start vitamin B12 (cyanocobalamin) 1,000 micrograms orally twice daily.
• Start multivitamin.

aggressive electrolyte repletion

• Cycle electrolytes (including phosphate, magnesium, and potassium).
• Aggressive repletion of electrolytes, with the exception of calcium (IV calcium may exacerbate hypophosphatemia).
  • Mg repletion: 📖
  • K repletion: 📖
  • Phos repletion: 📖

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).

glycemic control

• Insulin resistance is seen in refeeding syndrome – with high levels of insulin and hyperglycemia.
• Exogenous insulin could theoretically exacerbate the electrolyte abnormalities involved in refeeding syndrome (e.g., hypophosphatemia, hypokalemia).
• Permissive hyperglycemia could be safer than the administration of high doses of insulin.

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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.

Guide to emoji hyperlinks 

Going further

• Maryland CC project, by David Wacker:  Refeeding syndrome

References

• 20886063.  Khan LU, Ahmed J, Khan S, Macfie J. Refeeding syndrome: a literature review. Gastroenterol Res Pract. 2011;2011:410971. doi:10.1155/2011/410971.  [PubMed]
• 22305197.  Smithline HA, Donnino M, Greenblatt DJ. Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects. BMC Clin Pharmacol. 2012;12:4. Published 2012 Feb 4. doi:10.1186/1472-6904-12-4.  [PubMed]
• 25280426.  Crook MA. Refeeding syndrome: problems with definition and management. Nutrition. 2014;30(11-12):1448‐1455. doi:10.1016/j.nut.2014.03.026.  [PubMed]
• 26597128.  Doig GS, Simpson F, Heighes PT, et al. Restricted versus continued standard caloric intake during the management of refeeding syndrome in critically ill adults: a randomised, parallel-group, multicentre, single-blind controlled trial. Lancet Respir Med. 2015;3(12):943‐952. doi:10.1016/S2213-2600(15)00418-X.  [PubMed]
• 28087222.  Friedli N, Stanga Z, Sobotka L, et al. Revisiting the refeeding syndrome: Results of a systematic review. Nutrition. 2017;35:151‐160. doi:10.1016/j.nut.2016.05.016.  [PubMed]
• 29901461.  Boot R, Koekkoek KWAC, van Zanten ARH. Refeeding syndrome: relevance for the critically ill patient. Curr Opin Crit Care. 2018;24(4):235‐240. doi:10.1097/MCC.0000000000000514.  [PubMed]
• 31758276.  McKnight CL, Newberry C, Sarav M, Martindale R, Hurt R, Daley B. Refeeding Syndrome in the Critically Ill: a Literature Review and Clinician's Guide. Curr Gastroenterol Rep. 2019;21(11):58. Published 2019 Nov 22. doi:10.1007/s11894-019-0724-3.  [PubMed]
• 31847205.  Reber E, Friedli N, Vasiloglou MF, Schuetz P, Stanga Z. Management of Refeeding Syndrome in Medical Inpatients. J Clin Med. 2019;8(12):2202. Published 2019 Dec 13. doi:10.3390/jcm8122202.  [PubMed]
• 31895231  Friedli N, Odermatt J, Reber E, Schuetz P, Stanga Z. Refeeding syndrome: update and clinical advice for prevention, diagnosis and treatment. Curr Opin Gastroenterol. 2020 Mar;36(2):136-140. doi: 10.1097/MOG.0000000000000605  [PubMed]
• 32115791.  da Silva JSV, Seres DS, Sabino K, et al. ASPEN Consensus Recommendations for Refeeding Syndrome [published correction appears in Nutr Clin Pract. 2020 Jun;35(3):584-585]. Nutr Clin Pract. 2020;35(2):178‐195. doi:10.1002/ncp.10474.  [PubMed]