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Nutritional support needs to be cautious and be alert to tumor refeeding syndrome!

 Last Update: 2023-02-02
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What is refeeding syndrome?

Refeeding syndrome (RFS) refers to a syndrome in which the body re-ingests nutrients after long-term starvation or malnutrition, and a series of electrolyte abnormalities (hypophosphatemia, hypokalemia, hypomagnesemia), glucose metabolism abnormalities, vitamin deficiencies, and related symptoms¹^,²
.

The prevalence of RFS in malnourished elderly patients, tumor patients, anorexia nervosa, long-term hospitalization, and chronic infectious diseases is significantly increased
.
Among them, the prevalence of RFS in tumor patients is as high as 25%, and the incidence of RFS in severe patients > 34%³.

How is RFS diagnosed?

There is currently no uniform diagnostic criterion for RFS, and a decrease in serum phosphorus after re-administration of nutritional support is a characteristic manifestation of RFS, and RFS³
is diagnosed when serum phosphorus level < 0.
5 mmol/L.

Clinical manifestations and pathogenesis of refeeding syndrome

During starvation, decreased insulin secretion is accompanied by insulin resistance, increased glucagon secretion, intracellular glycogenolysis, fat and protein breakdown to provide energy and participate in gluconeogenesis
.
This catabolic process leads to the depletion of micronutrients such as phosphorus, potassium, magnesium, and vitamins, but serum concentrations of phosphorus, potassium, and magnesium may be normal¹^,⁴
.

After restarting nutritional therapy, especially after supplementing with large amounts of carbohydrates, blood sugar rises, so that insulin secretion is restored, and glycolysis-oxidative phosphorylation is the main energy supply route again
.
Insulin acts on various tissues of the body, causing potassium, phosphorus and magnesium to transfer into cells, forming hypophosphatemia, hypokalemia and hypomagnesemia; Enhanced glucose metabolism and protein synthesis also deplete vitamin B1 (Vit B1), which leads to a decrease
in Vit B1.
This metabolic feature of RFS usually occurs within 3~4 days after nutritional therapy¹^,⁴
.

1.
Hypophosphatemia

Hypophosphatemia is the main pathophysiological feature of RFS, and the blood phosphorus concentration of 0.
8~0.
5mmol/L is mild hypophosphatemia, 0.
5~0.
3mmol/L is moderate hypophosphatemia, and below 0.
3mmol/L is severe hypophosphatemia
.
For RFS, hypophosphatemia is defined as a concentration of inorganic phosphorus in the blood below 0.
5 mmol/L
.

Hypophosphatemia is involved in the development of RFS by:

(1) Phosphorus is a component of nucleotides, nucleoproteins and phospholipids, and magnesium enters the cell during nutritional therapy, promotes cell proliferation and the synthesis of the above substances, and causes the consumption of phosphorus in cells;

(2) Due to the recovery of glycolysis and oxidative phosphorylation, cell adenine nucleoside triphosphate (ATP), creatinine phosphokinase and other substances and fermentation intermediate 6-phosphate glucose (G-6-P) are produced in large quantities, resulting in phosphorus consumption;

(3) uneven phosphorus distribution among organizations;

(4) The transmembrane transport of phosphorus in red blood cells depends on the gradient formed by the concentration of blood phosphorus, and hypophosphatemia depletes phosphorus and 2,3-DPG in red blood cells, and hemoglobin oxygen and curve are biased to the left, affecting the oxygen supply of myocardium, nerves and other tissues;

(5) Causes metabolic acidosis, depletes intracellular ATP, 2,3-bisphosphoglyceric acid (2,3-DPG), and promotes phosphorus to move
outside the cell.

2.
Hypokalemia

Hypokalemia is the leading cause
of death from RFS.
During starvation, the ability of cells to pump potassium through Na+-K+-ATP decreases, and the concentration of potassium ions in cells decreases.
During nutritional therapy, insulin and ATP enhance the transfer of Na+-K+-ATP pumps, which increases intracellular potassium concentration and decreases extracellular potassium concentration, leading to hyperpolarization of cells and inhibition of nerve fiber electrical conduction, resulting in abnormalities in various systems throughout the body:

Symptoms of paralysis, paralysis, respiratory depression, and muscle weakness of the nervous system and muscles;
symptoms of intestinal paralysis and constipation in the digestive tract;
Potassium release by cells is inhibited, resulting in vasodilation and insufficient blood supply when muscle cells contract, resulting in rhabdomyolysis;
Short-term hyperpolarization of cardiomyocytes is manifested as prolonged ECG QT interval, decreased heart rate and blood pressure, and long-term hyperpolarization induces arrhythmia, manifested as sinus tachycardia, atrial premature beats or ventricular premature beats, and even cardiac arrest leading to the death of patients;
Hypokalemia is often associated with metabolic alkalosis, which further aggravates respiratory depression
.

3.
Hypomagnesemia

Plasma magnesium ions are attracted by negative charge and accumulate on the outer surface of the cell membrane, reducing the opening of sodium channels, resulting in hyperpolarization of cells, so hypomagnesemia in the nutritional therapy stage can reduce the polarization degree of nerve cells, enhance nerve cell conduction, and thus appear convulsions, epilepsy and other symptoms
of increased nerve excitability.

4Vit B1 lacks

The body is under starvation conditions, anabolism declines, and the liver and other organs need less
Vit B1.
During nutritional therapy, although a large number of amino acids are supplemented, due to the lack of Vit B1, protein synthesis is blocked, blood branched-chain amino acids increase, and its ketogenic and oxidative pathways are also enhanced, resulting in lactate and ketoate accumulation and metabolic acidosis, aggravating respiratory failure, dilating arterioles and veins, and aggravating congestive heart failure
.

In addition, Vit B1 is a cholinease inhibitor, nutritional therapy stage, the body's demand for Vit B1 increases, coupled with less VitB1 reserves (30mg), can lead to nervous system VitB1 deficiency, acetylcholine decomposition increased, nerve conduction blockage, manifested as ascending symmetric sensory, motor, reflex disorders and memory disorders, such as paralysis, myalgia, Wernicke's encephalopathy
.

5.
Circulatory congestion

During starvation, long-term hypovolemia and intracellular ATP depletion lead to cardiac atrophy, bradycardia, and decreased
beating volume.
During nutritional therapy, hyperglycemia, hyperinsulinemia, hypophosphatemia, and excessive fluid replacement lead to sodium and water retention, circulatory congestion, and aggravation of preload, but due to total phosphorus depletion, cardiomyocyte ATP synthesis is relatively insufficient, cardiac function is decompensated, and symptoms
of systemic and pulmonary failure occur.

How to deal with RFS?

1Accurately identify patients at high risk of RFS

To deal with RFS, it is necessary to accurately identify patients at high risk of RFS [2], and there are usually two types of patients at high risk of RFS in the clinic:

>>>>

There are one or more of the following manifestations

BMI＜16kg/㎡
Unintentional weight loss greater than 15% in the past 3~6 months
There is little or no nutrient intake for more than 10 days
Low potassium occurs before feeding
Hypophosphatemic or hypomagnesaemia

>>>>

There are two or more of the following manifestations

BMI＜18.
5kg/㎡
Unintentional weight loss greater than 10% in the past 3~6 months
Almost or completely no nutrient intake for more than 5 days
History of alcohol abuse or drug abuse (eg, insulin, chemotherapy, diuretics).

2 RFS processing

For patients with RFS, refer to the 2021 CSCO guidelines for nutrition therapy for malignancies: for patients with a significant reduction in food intake for 5 days or more, it is recommended to slowly increase nutrient intake (oral, enteral or parenteral) in the first few days, take preventive measures to prevent the development of refeeding syndrome, and monitor vital signs and water and electrolyte balance during nutrition therapy⁵
.

It is recommended that when high-risk patients receive nutritional therapy, the daily energy supply in the first 2 days should not exceed half of the energy requirement, starting from 10~15kcal/(kg·d), and gradually increasing in the subsequent 4~7 days until the energy demand
is met.
Closely monitor circulating volume, fluid balance, electrolyte levels, heart rate and rhythm, and clinical presentation
.
In addition, in the process of nutritional therapy, Vit B1 200~300mg/d and trace elements
need to be supplemented.
In patients with electrolyte metabolism disorders, electrolyte balance should be closely adjusted⁵
.

Nutritional support treatment strategies

for malignant tumors According to the 2021 CSCO guidelines for nutritional therapy for malignant tumors⁵, the following nutritional support strategies
can be used for patients with RFS.
1 Energy

The energy requirements of tumor patients can be estimated by estimation: 20~25kcal/(kg·d) for bedridden patients and 25~30kcal/(kg·d)
for active patients.

The energy supply ratio of the three major nutrients in the non-insulin resistance state is similar to that of healthy people, which is 50%~65% carbohydrate, 20%~30% fat, and 10%~15% protein; Patients with insulin resistance should reduce the proportion of carbohydrates in total energy supply and increase the proportion
of fat energy.
The energy of nutritional therapy should meet more than
70% of the patient's needs.

2 Water and electrolytes

Recommended water intake throughout the day (including diet and water contained in food): 30~40ml/(kg·d).

The lost water must be supplemented, and the urine output is maintained at 1000~2000ml/d
.
For patients with heart, lung, kidney and other organ dysfunction, attention should be paid to prevent excessive
intake.
Electrolytes should be maintained within the normal range
.

3 carbohydrates

The optimal ratio of carbohydrates and fats in the diet of cancer patients has not been established
.
Referring to the standard of healthy people, the carbohydrate energy supply ratio is 50%~65%.

However, tumor cells have the Warburg effect, regardless of whether oxygen supply is sufficient, tumor cells tend to obtain energy through glycolysis, and the high sugar environment promotes tumor cell metastasis
.
Therefore, for patients with insulin resistance and weight loss, it is recommended to increase the proportion of fat energy supply, reduce the proportion of carbohydrate energy supply, and consider the glycemic index (GI) and glycemic load (GL)
of food when choosing a diet.

4 proteins

It is recommended that the protein intake of tumor patients should exceed 1g/(kg·d), and it is recommended to reach 1.
5~2g/(kg·d).

For tumor patients the optimal nitrogen supply is currently inconclusive, protein intake increase can promote tumor patients muscle protein anabolism, conducive to maintaining nitrogen balance, therefore, tumor patients protein requirements are higher than normal people, 2017 ESPEN tumor patient nutrition guidelines suggest that tumor patients protein intake should be in the minimum supply of 1g/(kg·d) to target supply of 1.
2~2g/(kg·d), elderly patients with chronic diseases recommended protein supply of 1.
2~1.
5g/ （kg·d）
。

In patients with acute or chronic renal failure, protein supplementation should not exceed 1.
0 or 1.
2 g/kg / day
, respectively.

Protein supplementation should meet 100% of the required amount
.
The best sources of food protein are eggs, low-fat dairy products, fish, poultry, lean red meat, etc.
, and try to eat less processed meat
.

5 fats

Referring to the standard of healthy people, the proportion of fat energy supply is 20% ~ 30%, in insulin-resistant tumor patients, muscle cells have impaired glucose uptake and oxidation, and the utilization of fat is normal or increased, while tumor cells mainly meet energy requirements through glucose, and the utilization rate of fatty acids and ketone bodies is very low, therefore, it is recommended to increase the proportion
of fat energy supply.

In 2017, China's health industry standard recommended that fat energy supply for patients with malignant tumors accounted for 35%~50%
of the total energy.
In view of the effect of fat on the heart and cholesterol levels, it is advisable to choose monounsaturated fatty acids and polyunsaturated fatty acids, reduce the intake of saturated fatty acids and trans fatty acids, and appropriately increase foods
rich in N-3 and N-9 fatty acids.

6 Micronutrients

Vitamins and trace elements are the basis for the effective use of energy substrates and amino acids by the body, and are important micronutrients
.
Vitamins are divided into two categories
: fat-soluble (vitamins A, D, E, K) and water-soluble (vitamins B and C).
Trace elements of practical clinical significance include zinc, copper, iron, selenium, chromium, manganese, etc.
, which need to be supplemented
.

summary

The occurrence of RFS is associated with pathophysiological changes, insulin secretion, electrolyte intracellular transfer, and anabolic enhancement, resulting in obvious metabolic abnormalities such as low phosphorus, low potassium, hypomagnesemia and water-electrolyte abnormalities
.

Early assessment and identification of high-risk patients prone to refeeding syndrome in clinical practice; Communicate with the clinic, formulate individualized nutrition treatment plan according to the condition, and dynamically adjust the treatment in time to evaluate the results, which is more conducive to achieving the perfect nutrition treatment effect; The supply of energy and nitrogen in the initial stage of refeeding should be low, and the supply should be gradually and slowly increased within 10~14 days until the expected target amount or the amount
tolerated by the patient is reached.

References
[1] SUN Guanqing, SHI Hanping.
Pathophysiology of refeeding syndrome[J].
Chinese Journal of General Surgery (Electronic Edition), 2008(01):8-9.
[2] QI Yumei.
Refeeding syndrome in tumor nutrition therapy (see CD-ROM) for details[J].
Electronic Journal of Cancer Metabolism and Nutrition, 2016,3(02):107.
GUO Jiwu, QI Yujing, GAO Caiyan, et al.
Diagnosis and treatment of refeeding syndrome[J].
Chinese Journal of Digestive Surgery, 2020,19(10):1108-1110.
[4] SHI Hanping, SUN Guanqing.
Emphasis on the diagnosis and treatment of refeeding syndrome[J].
New Medicine, 2009,40(10):631-633.
[5] Guidelines Working Committee of Chinese Society of Clinical Oncology.
Chinese Society of Clinical Oncology (CSCO) Guidelines for Nutritional Therapy for Patients with Malignant Tumors 2021[J].

Reviewer: Babel

Typesetting: Babel

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