Background

Refeeding syndrome (RS) is a fatal condition characterized by acute metabolic changes following the resumption of nutritional support, particularly in malnourished patients, resulting in severe complications, including death. It was first described in studies of prisoners in the 1950s, which reported the clinical aspects of starvation and malnutrition. Refeeding hypophosphatemia in critically ill patients was initially identified in a 1996 retrospective study aiming to illustrate the decrease in phosphorus levels upon the initiation of nutritional support [1].

In 2006, the U.S. National Institute for Health and Care Excellence (NICE) defined patients at high-risk of RS and delineated nutritional protocols aimed at its prevention [2]. The latest guideline on RS was introduced by the American Society of Parenteral and Enteral Nutrition (ASPEN) and provides a consensus definition, updated consensus recommendations for screening and identifying patients at risk for RS, and guidance for avoiding and treating RS [3].

Many subsequent studies on RS in critically ill patients have been conducted using the traditional definition of hypophosphatemia and criteria for identifying high-risk groups. However, the incidence of RS has varied widely among these studies, and a consensus on its management in critical care has yet to be established [4-6].

Objectives

The aim of this study is to provide a narrative review of the most recent studies on RS in critically ill patients and to summarize recent advancements in the treatment of such patients.

In a prospective study conducted by Marik and Bedigian [1] in 1996 with patients in the intensive care unit (ICU), refeeding hypophosphatemia was initially defined as a decrease in serum phosphorus level from >0.16 mmol/L to <0.65 mmol/L within 72 hours of initiating nutrition. Diagnostic criteria for RS suggested by King’s College Hospital in 2012 included a decrease in electrolytes such as phosphorus, potassium, and magnesium, as well as the presence of circulatory problems or organ dysfunction; however, these criteria have rarely been used due to their low sensitivity [7,8]. In the latest consensus recommendations for RS introduced by ASPEN in 2020, RS was stratified into mild, moderate, and severe categories using specific proportional decrements in serum phosphorus, potassium, and/or magnesium, as outlined in Table 1. Severe RS was characterized by organ dysfunction alongside electrolyte imbalance or thiamine deficiency and should be observable within 5 days after initiating or gradually increasing caloric support. This updated definition offers a more comprehensive and detailed approach to identifying and managing RS [3].

Table 1

Diagnostic criteria for RS (ASPEN consensus recommendations)

• Decrease in serum phosphorus, potassium, and/or magnesium levels by 10%–20% (mild RS), 20%–30% (moderate RS), or >30% and/or the presence of organ dysfunction resulting from a decrease in any of these and/or due to thiamin deficiency (severe RS)

• The above event(s) occurred within 5 days of re-initiating or substantially increasing energy provision

RS = refeeding syndrome; ASPEN = American Society of Parenteral and Enteral Nutrition.

Most previous research with ICU patients employed the traditional definition of refeeding hypophosphatemia, with reported incidence rates ranging from 17%–52%. Heterogeneity in these findings can be attributed to differences in patient populations and periods of caloric support [9-13]. Recently, a few studies have adopted the definition suggested by ASPEN, aiming to address this discrepancy in incidence. However, the reported incidence rates in these studies remain inconsistent. For instance, a 2022 retrospective study involving 1,261 patients in a pediatric ICU reported an overall incidence of 7.4%, with an incidence among at-risk patients of 46.7% [14]. Conversely, a 2021 study with 86 critically ill adult patients in a surgical ICU reported a much higher overall incidence rate of 89% when evaluated according to the provision of “dextrose infusion” and of 75% when evaluated according to the provision of “balanced nutritional support” [15].

These findings are consistent with those of a systematic review of RS incidence in 2021, which also raised doubts about the applicability of the ASPEN criteria. In this review, the authors applied the ASPEN criteria to 21 studies on RS incidence and concluded that there was no substantial change from the originally reported incidence [16].

In critically ill patients, metabolic reactions associated with severe insults, such as infection or hemorrhage, include hyperglycemia, insulin resistance, increased hepatic glucose production, and muscle protein breakdown. As damage severity increases, so does the severity and damage caused by metabolic derangement [17]. Furthermore, critically ill surgical patients, such as those who have undergone procedures like bowel resection or are experiencing bowel ischemia with unstable hemodynamics, are prone to malnourishment [18].

Under such conditions accelerating the depletion of energy and intracellular electrolytes, insulin resistance occurs with rapid glycogenolysis and gluconeogenesis following intracellular shifts of phosphorus, potassium, and magnesium. Following the re-initiation of energy support, even as only glucose, there is an increase in insulin secretion that stimulates cellular uptake of glucose, potassium, phosphorus, and magnesium. This shift from a catabolic to an anabolic state leads to increased cellular activity and metabolism, requiring these electrolytes for energy production and cellular function. The sudden influx of carbohydrates and subsequent insulin release can lead to rapid intracellular uptake of these electrolytes, causing a sharp decrease in serum levels or that of thiamine [19]. This can result in various complications such as cardiac arrhythmias, respiratory failure, seizures, and even death. Critically ill patients often experience various stressors and metabolic alterations, such as increased energy expenditure, altered nutrient metabolism, and fluid shifts, which can exacerbate the risk of RS when nutrition is re-introduced [20-24].

Thiamin deficiency may be involved in RS. The demand for thiamin greatly increases during the transition from starvation to feeding, as it is a cofactor for glucose-dependent metabolic pathways [25].

The traditional risk criteria suggested by NICE in 2006 were body mass index (BMI); amount of weight loss; length of malnourishment; levels of serum electrolytes like phosphorus, potassium, and magnesium; and history of alcohol or drug abuse (Table 2) [2]. Although most previous studies on anorexia nervosa or other malnourished inpatient groups applied NICE criteria in their analysis, recent studies on ICU patients have demonstrated low efficacy of the NICE guideline for risk identification. Buitendag et al. [8] posited that NICE criteria should be used only as a reference, not as guidelines, as they showed a sensitivity of 33% and a specificity of 70% in a prospective study on 200 surgical ICU patients. A randomized controlled trial conducted with ICU patients at refeeding risk based on NICE criteria in 2021 concluded there were no differences in outcomes including decrease of serum electrolytes, corrected QT abnormalities, infections, and length of hospital stay between moderate- and high-risk groups [26].

Table 2

NICE criteria for determining people at high risk of refeeding problems

The patient has one or more of the following:

• BMI<16 kg/m2

• Unintentional weight loss>15% within the last 3–6 months

• Little or no nutritional intake for >10 days

• Low levels of potassium, phosphate, or magnesium prior to feeding

Or, the patient has two or more of the following:

• BMI<18.5 kg/m2

• Unintentional weight loss>10% within the last 3–6 months

• Little or no nutritional intake for >5 days

• A history of alcohol abuse or drug use, including insulin, chemotherapy, antacids, or diuretics

NICE = National Institute for Health and Care Excellence; BMI = body mass index.

In 2020, ASPEN designed the newest criteria for evaluation of RS risk. The update included more specific stratifications of caloric intake, amount of subcutaneous fat, and amount of muscle mass compared to those in the consensus statement for identifying adult malnutrition suggested by the group in 2012 [27]. Patients were classified as either moderate or significant risk (Table 3) [3]. Despite the attempt to evaluate more accurately the malnourished state, a few studies showed the 2020 ASPEN criteria were not suitable for identification of refeeding risks in critically ill patients. In a retrospective study of neurocritically ill patients, Liu et al. [28] compared the performances of 4 tools for assessment of refeeding risks, the Short Nutritional Assessment Questionnaire, the Global Leadership Initiative on Malnutrition (GLIM), the modified criteria of Britain’s National Institute for Health and Care Excellence (mNICE), and the ASPEN scales. All 4 tools showed low areas under the receiver operating characteristic curve (AUCs)<0.6. The modified ASPEN scale, which combined age and the Glasgow Coma Scale with the ASPEN criteria, showed an AUC of 0.664, still displaying low predictability, though it was a significant improvement from the original scale. Ha and Hong [15] demonstrated that even initial administration of dextrose solution and propofol could cause severe RS in critically ill patients. In addition, significant risk of RS was a predictive factor for 6-month mortality. Thus, it is essential to monitor the occurrence of RS even during initial resuscitation in patients with unstable metabolic state. Xiong et al. [9] reported the Malnutrition Universal Screening Tool and Sequential Organ Failure Assessment scores to be independent risk factors for RS in their retrospective study of neurocritically ill patients. Theirs is the only observational study that has investigated relevant factors other than those included in previous criteria. A tool for identifying RS risk only applicable to ICU patients should be created based on additional controlled studies.

Table 3

ASPEN consensus criteria for identifying adult patients at risk for RS

	Moderate risk (2 risk criteria need to be met)	Significant risk (1 risk criterion needs to be met)
Body mass index (kg/m2)	16.0–18.5	<16.0
Weight loss	5% in 1 month	7.5% in 3 months or >10% in 6 months
Caloric intake	None or negligible oral intake for 5–6 days OR <75% of estimated energy requirement for >7 days during an acute illness or injury OR <75% of estimated energy requirement for >1 month	None or negligible oral intake for >7 days OR <50% of estimated energy requirement for >5 days during an acute illness or injury OR <50% of estimated energy requirement for >1 month
Abnormal prefeeding potassium, phosphorus, or magnesium serum concentrations	Minimally low levels or normal current levels and recent low levels necessitating minimal or single-dose supplementation	Moderately/significantly low levels or minimally low or normal levels and recent low levels necessitating significant or multi-dose supplementation
Loss of subcutaneous fat	Evidence of moderate loss	Evidence of severe loss
Loss of muscle mass	Evidence of mild or moderate loss	Evidence of severe loss
Higher-risk comorbidities	Moderate disease	Severe disease

ASPEN = American Society of Parenteral and Enteral Nutrition; RS = refeeding syndrome.

Outcomes related to RS in critically ill patients remain unclear. A few studies have reported worsened outcomes in RS patients, but many other research studies have identified no difference in outcomes between patient groups with and without RS. Xiong et al. [9] insisted that longer ICU stay, higher 1- and 6-month mortality rates, and poorer functional outcomes at 6 months were found in RS patients in their retrospective study on neurocritically ill patients. A retrospective study on medical ICU patients in Turkey showed a higher mortality rate and longer length of ICU stay in refeeding hypophosphatemia patients [13]. However, in their prospective cohort study involving mixed medical and surgical ICU patients, Md Ralib and Mat Nor [29] observed no difference in major outcomes of duration of mechanical ventilation, length of ICU stay, and mortality. In a retrospective review by Fuentes et al. [30] of patients receiving enteral nutrition in the surgical ICU, refeeding hypophosphatemia was common but was not related to timing or amount of enteral nutrition administered. Additionally, while hypophosphatemia also was common among critically ill patients, it was not a predictor of worse clinical outcomes irrespective of its underlying cause.

Some studies have documented poorer outcomes in patients at refeeding risk based on previously suggested criteria. Despite the unclear definition of RS, Yoshida et al. [31] demonstrated high 30-day mortality in high- and very high-risk groups. Elsewhere, Ha and Hong [15] conducted a study to investigate factors associated with 6-month mortality rates, and revealed that patient groups at significant risk of RS according to ASPEN criteria exhibited higher 6-month mortality rates compared to the group diagnosed with RS.

It is crucial to identify patients at risk of RS, and this requires a comprehensive understanding of the event.

Most guidelines recommend initiating support for at-risk patients by supplying 20%–25% of estimated goals and then gradually increasing the caloric intake over 3–5 days. Close monitoring of electrolyte changes and supplementation for any depletion of phosphorus, potassium, magnesium, or thiamine are strongly recommended, particularly in patients with severe malnutrition, critical illness, severe trauma, or burns [32].

Though the ASPEN recommendations simply combined the results of previous studies and were not based on a related randomized controlled trial, they emphasize the administration of conservative calories for at-risk patients and for correction of underlying electrolyte abnormalities (Table 4) [3]. The initial feeding protocol recommends starting with 100–150 g of dextrose or 10–20 kcal/kg for the first 24 hours, with subsequent increase of 33% of the goal every 1–2 day(s). For patients at moderate to high risk with low electrolyte levels, it is advisable to postpone initiating or increasing calorie intake until electrolytes are adequately supplemented. Likewise, in patients presenting with severely low levels of phosphorus, potassium, or magnesium, it is prudent to delay the initiation or escalation of calorie intake until these electrolyte imbalances are corrected. In high-risk patients, it is recommended to test the subject every 12 hours for the first 3 days, with more frequent monitoring carried out based on the clinical situation. In addition, thiamine administration is advised at a dosage of 2 mg/kg up to a maximum of 100–200 mg/day prior to the initiation of feeding or intravenous fluids containing dextrose in high-risk patients. Prompt repletion of electrolyte deficiencies should be conducted according to established standards of care. Additionally, thiamine supplementation should be maintained for ≥5–7 days in patients with severe starvation, chronic alcoholism, or other conditions posing a high risk for deficiency and/or those presenting with signs of thiamine deficiency.

Table 4

Comparison of feeding protocols for prevention of RS

	NICE (2006) [2]	ASPEN (2020) [3]
Initiation of calories & feeding advancement	Starting nutrition support at a maximum of 10 kcal/kg/day, increasing levels slowly to meet or exceed full needs by 4–7 days, using only 5 kcal/kg/day in extreme cases (e.g., BMI<14 kg/m2 or negligible intake for more than 15 days)	Initiate 100–150 g of dextrose or 10–20 kcal/kg for the first 24 hours; advance by 33% of goal every 1–2 day(s) In patients with moderate to high risk with low electrolyte levels, holding the initiation of or increase in calories until electrolytes are supple­mented should be considered Initiation of or increase in calories should be delayed in patients with severely low phosphorus, potassium, or magnesium levels until corrected
Electrolytes & thiamine	Provided immediately before and during the first 10 days of feeding: oral thiamin 200–300 mg daily, vitamin B co strong 1–2 tablet(s), three times a day (or full dose given daily as intravenous vitamin B preparation, if necessary), and a balanced multivitamin/trace element supplement once daily Provide oral, enteral, or intravenous supplements of potassium (likely requirement 2–4 mmol/kg/day), phosphate (likely requirement 0.3–0.6 mmol/kg/day), and magnesium (likely requirement 0.2 mmol/kg/day intravenously, 0.4 mmol/kg/day orally) unless prefeeding plasma levels are high. Prefeeding correction of low plasma levels is unnecessary	Monitor every 12 hours for the first 3 days in high-risk patients (more frequent based on the clinical picture) Give thiamine 2 mg/kg to a maximum of 100–200 mg/day before feeding commences or before initiating intravenous fluids containing dextrose in high-risk patients Replete low electrolytes based on established standards of care Continue thiamine supplementation for ≥5–7 days in patients with severe starvation, chronic alcoholism, or at high risk for other deficiency and/or signs of thiamine deficiency
Other recommendations		Calories from intravenous dextrose solutions and medications being infused in dextrose should be considered in patients at moderate to severe risk for RS If electrolytes become difficult to correct or drop precipitously during the initiation of nutrition, decrease calories/grams of dextrose by 50% and advance the dextrose/calories by approximately 33% of the goal every 1–2 day(s) based on clinical presentation

RS = refeeding syndrome; NICE = National Institute for Health and Care Excellence; ASPEN = American Society of Parenteral and Enteral Nutrition; BMI = body mass index.

Until the early 2010s, most research on the requirement of nutritional support for improving major outcomes in ICU patients applied traditional recommendations in their randomized controlled trials to avoid selection bias originating from concerns about refeeding risks [33-35]. A few studies reporting no efficacy of initial caloric restriction in ICU patients were introduced. Doig et al. [36] randomized 339 ICU patients with hypophosphatemia following initiation of nutrition in a caloric-restriction group and continued standard nutritional support group. They reported no difference between those two groups in the mean number of survival days after ICU discharge over a 60-day follow-up despite an improved overall survival time in the caloric-restriction group. In a 2021 systemic review carried out by ASPEN regarding energy initiation rates and the incidence of RS, researchers compared two types of studies based on feeding rates: assertive (>20 kcal/kg/day) and conservative (<20 kcal/kg/day). Among the 24 studies analyzed, 15 were classified as assertive and nine were classified as conservative. No significant difference was observed in RS incidence, which reached up to 20% in both groups [37]. Additionally, the duration to achieve the goal feeding rate did not seem to impact the incidence of RS-related adverse outcomes. However, the study had a significant limitation in that most participants were recruited from a general population rather than based on specific RS risk criteria or malnutrition cutoffs. Liu et al. [38] reported prolonged hospital stays in malnourished patients with RS, while initial higher caloric intake decreased the length of hospital stay in those with a history of undernourishment.

Reintam Blaser et al. [39] conducted a systematic review of hypophosphatemia in critically ill patients in 2020 and concluded that there was no clear standard in electrolyte level or time for supplementation of phosphorus and did not establish an optimal frequency of phosphate measurement. Although some of the studies included were not directly associated with RS, this result indicated the challenge in predicting metabolic changes and subsequent electrolyte changes in ICU patients. There is still no alternative to frequent evaluation and close monitoring of patients at risk for RS.

There remains no consensus on nutritional support in critically ill patients to prevent RS. Moreover, in such patients, electrolyte imbalances can arise due to conditions such as sepsis, hypovolemia, or organ dysfunction. Therefore, randomized controlled trials targeting critically ill patients are needed to prevent and treat RS in this population.

The RS occurring in critically ill patients is a highly fatal and complex condition characterized by significant metabolic shifts and often exacerbated by underlying malnutrition. Although numerous studies have been conducted recently, it remains challenging to carry out research that accurately depicts the incidence, risk factors, and clinical outcomes of RS in critically ill patients given the condition’s complex clinical context distinct from general malnutrition. However, clinicians must continue their efforts to promptly identify patients at high risk for RS and strive to prevent and treat this potentially fatal condition, particularly when initiating nutritional therapy in critically ill patients.

Conceptualization: SWH, SKH. Formal analysis: SWH. Project administration: SKH. Resources: SWH. Supervision: SKH. Writing – original draft: SWH. Writing – review & editing: all authors.

Suk-Kyung Hong is the Editor-in-Chief of the journal, but was not involved in the review process of this manuscript. Otherwise, there is no conflict of interest to disclose.

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