Refeeding Syndrome

Etiology

Refeeding syndrome's causes are multifactorial and linked to nutritional replenishment following starvation. Accordingly, patients with poor nutrition who are rapidly or suddenly fed are at increased risk for refeeding syndrome. Causes include eating disorders, chronic alcoholism, malabsorptive conditions like inflammatory bowel disease, chronic malnutrition, poorly controlled diabetes, oncological conditions, and post-operative state.[2]

Epidemiology

Refeeding syndrome has been described in high-risk populations, including patients with eating disorders, depression, renal failure, malabsorptive conditions, previous bariatric surgery, and alcohol abuse. One of the main guidelines used for the evaluation and treatment of refeeding syndrome is the National Institute for Health Care and Excellence (NICE) guideline, which defines risk factors for refeeding syndrome as a “low body mass index (BMI), unintentional weight loss, starvation, history of alcohol abuse, and low initial electrolyte concentrations.”[2] 

The incidence of refeeding syndrome has been hard to establish due to a lack of uniform definitions and study methodology. Hypophosphatemia has been used as a surrogate marker for refeeding syndrome.[1] In 1 prospective cohort study of a heterogeneous group of ICU patients who were starved for at least 48 hours, hypophosphatemia was reported in 34% of patients an average of 1.9 days after feeding was restarted.[4] Reported incidences of refeeding syndrome range from 0.43% to 18% in hospitalized patients.[5] 

Numerous cases of refeeding syndrome patients are also observed in the critical care setting when patients have been nutritionally sustained with total parenteral nutrition (TPN); Use of TPN has been linked to hyperglycemia and a corresponding increase in insulin levels, which further exacerbate electrolyte abnormalities in refeeding syndrome.[6]

Pathophysiology

In considering the human body's metabolic demand and nutritional states, such as absorptive (fed), postabsorptive (fasting), and starvation, starvation increases gluconeogenesis and proteolysis. In contrast, metabolic substrates, including vitamins and intracellular electrolytes, are depleted.[7][8] Sudden initiation of nutritional replenishment following extended periods of starvation results in rising glucose levels in the bloodstream. With rising glucose levels, the body produces a countermeasure that increases insulin levels, which then drive phosphorus and potassium intracellularly, causing a decrease in the amount of available extracellular potassium or hypokalemia. This occurs in part due to the need for phosphorylation of glucose in glycolysis but also through direct stimulation of the sodium-potassium ATP pump.[9] This increase in insulin and the effects on electrolyte migration (intracellular vs. extracellular) are compounded by nutritional electrolyte deficiencies. Hypokalemia may lead to cardiac arrhythmias or weakness, fatigue, paralysis, hypoventilation and respiratory distress, and metabolic alkalosis.[10]

Phosphorus is a critical component of human energy storage and is required to produce adenosine triphosphate (ATP). As the body continues to experience starvation, existing phosphorous stores are depleted to sustain metabolic activity, leading to hypophosphatemia, widely observed in patients with refeeding syndrome. In refeeding syndrome, long-term starvation may have already depleted the body of phosphorous stores. This is often worsened by increasing amounts of insulin, similar to the physiology of potassium. Physiologically, phosphorous also plays a vital role in maintaining cardiac conduction.[11] Low levels of phosphorous are linked to decreased cardiac contractility and arrhythmias, which could be fatal. A depletion of phosphorous can also decrease the production of 2,3 diphosphoglycerate (2,3 DPG), which causes a leftward shift in the oxygen-hemoglobin dissociation curve, increasing hemoglobin’s affinity for oxygen and decreasing oxygen release to the tissues, ultimately starving metabolically active tissues of oxygen and worsening prognosis through secondary organ failure.[12] Lastly, phosphorous is implicated in preserving respiratory muscle function, and in severe cases, hypophosphatemia can lead to acute respiratory failure. 

Hypomagnesemia is also observed in refeeding syndrome; however, its mechanism of involvement in refeeding syndrome is less understood.[13] Hypomagnesemia may be implicated in refeeding syndrome due to its effect on other electrolyte levels. Notably, decreased magnesium levels can exacerbate hypokalemia and increase renal potassium wasting.[14] Several enzymes utilized in ATP production are also dependent on magnesium as well. Changes in magnesium levels can also manifest in neuromuscular symptoms, including ataxia, vertigo, convulsions, paresthesia, and depression in refeeding syndrome patients.[15]

Due to cardiac fatalities being directly tied to electrolyte abnormalities, it is important to understand that both hypomagnesemia and hypokalemia may equally contribute to torsades de pointes, a potentially fatal polymorphic ventricular tachycardia associated with QT prolongation.[16] Management of torsades de pointes includes correcting underlying modifiable risk factors, such as electrolyte imbalances. While some patients spontaneously resolve, hypotensive or hemodynamically unstable patients with a pulse may require synchronized cardioversion. Magnesium is also helpful in stabilizing the cardiac membrane, and giving 2 g IV is recommended as an initial dose.[16]

Thiamine deficiency is another characteristic of refeeding syndrome. Thiamine is an important cofactor in the metabolism of glucose and the conversion of lactate to pyruvate. When the body is replenished following starvation, thiamine requirements increase, and lactate levels can accumulate.[17][18] Neurological manifestations of thiamine deficiency include Wernicke's (memory impairment, ophthalmoplegia, ataxia) and Korsakoff encephalopathy (anterograde/retrograde amnesia, confabulation). The classic triad seen in some patients who develop Wernicke-Korsakoff includes ophthalmoplegia, gait disturbances such as a wide-spaced gait, and mental status changes, which may progress to hallucinations and confabulation. Thiamine deficiency is also implicated in cardiac tissue dysfunction due to insufficient ATP production. Thiamine deficiency may also be exacerbated by alcohol use, which should be considered in refeeding syndrome patients.[19]

Summary of Pathophysiology and Associated Clinical Changes

History and Physical

The clinical symptoms associated with refeeding syndrome are highly varied. Symptoms reflect electrolyte changes compromise biochemical changes as cell membrane potentials and cellular functions. Consequently, patients present with multisystem complaints ranging from nausea to hypotension. Clinically, it has been observed that a patient's first described feeling of nausea can be interpreted as a precursor to hypotension.

Reported cardiovascular changes include arrhythmias, hypotension, cardiomyopathy, shock, bradycardia, tachycardia, and cardiac arrest. Renal changes such as acute tubular necrosis, renal failure, and metabolic acidosis have been reported due to sodium and phosphate alterations. Respiratory manifestations in refeeding syndrome include respiratory failure, pulmonary edema, and hypoventilation. Several musculoskeletal manifestations have also been reported, including rhabdomyolysis, myalgias, fatigue, muscle twitching, and diaphragm weakness. Gastrointestinal symptoms have been linked to hypokalemia and hypomagnesemia in refeeding syndrome and include diarrhea and constipation, nausea and vomiting, and paralytic ileus.[13][20][21]  Of note, many refeeding syndrome patients have comorbidities such as electrolyte and vitamin deficiencies that may be exacerbated in the setting of alcohol use disorder.[22]

Evaluation

Given the wide range of symptoms and a lack of clear diagnostic criteria, the American Society for Parenteral and Enteral Nutrition (ASPEN) established an interprofessional task force to develop a consensus on recommendations and the clinical definition of refeeding syndrome. ASPEN proposed unifying diagnostic criteria to stratify patients based on 3 levels of severity (mild, moderate, severe):

• Mild - a decrease in any 1, 2, or 3 of serum phosphorus, potassium, or magnesium levels by 10% to 20%
• Moderate - a decrease in any 1, 2, or 3 of serum phosphorus, potassium, or magnesium levels by 20% to 30%
• Severe - a decrease in any 1, 2, or 3 of serum phosphorus, potassium, or magnesium levels by >30% or organ dysfunction resulting from a decrease in any of these or due to thiamine deficiency (severe), occurring within 5 days of a reintroduction of calories [1]

Though ASPEN guidelines provide a reasonable working definition, it should be noted this definition has limitations in assessing nutritional status as the guideline only relies on laboratory changes rather than capturing a patient’s clinical presentation. Additionally, laboratory values such as albumin and prealbumin are often used in the assessment of nutrition, with prealbumin being a better assessment of short-term nutritional changes compared to albumin; the half-life of prealbumin is 2 to 3 days, while the half-life of albumin is around 20 days. These markers are unreliable as they are acute-phase reactants.[23] Clinical examination remains crucial in such patients. 

Refeeding syndrome is a severe and potentially lethal condition that should be readily recognized to ensure vulnerable patients are appropriately diagnosed and managed to avoid reaching a critically ill state with electrolyte abnormalities that are seemingly refractory to correction - leading to a high risk of mortality. The heterogeneity of refeeding syndrome definitions and lack of robust scientific data harm high-risk patients requiring additional nutritional support. Accordingly, there is a need for further understanding of refeeding syndrome for improved diagnosis and prevention.

Treatment / Management

Traditionally, clinicians evaluate refeeding syndrome individually when enteral feeding is initiated after prolonged periods of being metabolically starved. Recent recommendations on screening and surveillance of these patients focus on conserving calories and carefully repleting electrolytes. Additionally, in critically ill burn patients who are also at risk for refeeding syndrome, enteral feedings should be utilized rather than parenteral if the patient can tolerate it. Supplementation with glutamine and L-arginine has also been helpful for the reduction of systemic bacteremia, immune maintenance, and gut flora preservation in such patients.[24][25][26][27](A1)

Different management recommendations have been established; however, they remain controversial due to a lack of objective data and quantification standards. ASPEN guidelines include checking magnesium, phosphorus, and potassium levels before nutritional replenishment. High-risk patients should have electrolyte levels monitored every 12 hours for the first 3 days, and electrolytes should be replete based on the standard of care. ASPEN guidelines for nutritional replenishment begin with 100 to 150 g of dextrose or 10 to 20 kcal/kg in the first 24 hours and then increase by 33% of their overall replenishment goal every 1 to 2 days. 

NICE (National Institute for Health and Clinical Excellence) also recommended replacing electrolytes parallel to the commencement of feeding.[2] However, ASPEN recognizes that clinicians should consider holding nutritional replenishment until electrolytes are corrected in high-risk patients with severe electrolyte deficiencies. Replenishment should be delayed in patients with severely low potassium, phosphorous, or magnesium levels.

ASPEN’s proposed guidelines recommend 100 mg of thiamine supplementation before dextrose-based solutions. Routine thiamine checks are thought to have limited value. No recommendations for fluid, sodium, or protein restriction are proposed, often instituted in critically ill patients. Monitoring guidelines include checking vitals every 4 hours for the first 24 hours following nutritional replenishment and checking daily weights, inputs, and outputs.

The National Institute for Health and Clinical Excellence has also forwarded guidelines to identify high-risk patients for refeeding syndrome. Their guidelines recommend all critically ill patients should undergo a formal nutritional assessment, screening for previous alcohol use, and check for recent weight fluctuations. These guidelines recommend clinical evaluation in addition to the evaluation of baseline phosphate, sodium, magnesium, and potassium levels. Their replenishment recommendations are more specific to each electrolyte. They include “potassium (2 to 4 mmol/kg/day), phosphate (0.3 to 0.6 mmol/kg/day), and magnesium (0.2 mmol/kg/day intravenously or 0.4 mmol/kg/day orally).”[2] Electrolytes should be assessed daily during the first week of replenishment and 3 times the following week. However, like with the ASPEN guidelines, there is little quality evidence-based research for the NICE guidelines.

Thiamine at a dose of 100 mg should be given at least 30 minutes before starting nutritional replenishment and continued twice daily for 7 to 10 days to prevent neurological complications during nutritional rehabilitation. Replenishment strategies should identify high-risk patients and allow for close monitoring of electrolyte derangements. This approach helps to minimize the clinical sequelae associated with refeeding syndrome and sudden replenishment.

Differential Diagnosis

The differential diagnosis for refeeding syndrome is unique in the sense that it is a diagnosis of exclusion requiring other more acute conditions to be ruled out. Fluid overload is 1, which causes a decrease in many of the electrolytes in plasma. This could lead to grossly depleted amounts of Na, K, Mg, or P. The after-effects of refeeding syndrome must also be evaluated. Independent cardiac arrhythmias, which are high risk from electrolyte imbalances, must also be ruled out such as long QT syndrome.

Prognosis

Prognosis is variable based on the severity of biochemical and electrolyte changes. Of note, many refeeding syndrome patients have comorbidities such as electrolyte and vitamin deficiencies that may be exacerbated in the setting of alcohol use disorder and worsen prognosis.[22] In patients with mild electrolyte derangements, clinical symptoms may often not manifest, increasing the heightened vigilance of patients if they are at risk for developing refeeding syndrome, as it can occur rapidly and unpredictably.

Complications

Electrolyte imbalance from refeeding syndrome can result in several complications. As outlined in Table 1 for the main electrolyte imbalances, Potassium imbalances can lead to cardiac arrhythmias, QT prolongation weakness, fatigue, paralysis, and respiratory distress. Phosphorus can lead to cardiac arrhythmias, decreased 2,3 DPG production, and decreased respiratory muscle function. Magnesium can lead to ataxia, vertigo, paresthesia, convulsions, depression, and QT prolongation. Thiamine deficiency can lead to cardiac dysfunction and Wernicke and Korsakoff syndrome.