The refeeding syndrome is a potentially lethal complication of refeeding in patients who are severely malnourished from whatever cause. Too rapid refeeding, particularly with carbohydrate may precipitate a number of metabolic and pathophysiological complications, which may adversely affect the cardiac, respiratory, haematological, hepatic and neuromuscular systems leading to clinical complications and even death. We aimed to review the development of the refeeding syndrome in a variety of situations and, from this and the literature, devise guidelines to prevent and treat the condition. We report seven cases illustrating different aspects of the refeeding syndrome and the measures used to treat it. The specific complications encountered, their physiological mechanisms, identification of patients at risk, and prevention and treatment are discussed. Each case developed one or more of the features of the refeeding syndrome including deficiencies and low plasma levels of potassium, phosphate, magnesium and thiamine combined with salt and water retention. These responded to specific interventions. In most cases, these abnormalities could have been anticipated and prevented. The main features of the refeeding syndrome are described with a protocol to anticipate, prevent and treat the condition in adults.
The refeeding syndrome was first reported among those released from concentration camps following the Second World War (Burger et al., 1948; Schnitker et al., 1951). Oral feeding of these grossly malnourished individuals often resulted in fatal diarrhoea, heart failure and neurological complications, including coma and convulsions. Milder symptoms were later reported by Keys et al. (1950) during the refeeding of healthy volunteers with a mean weight loss of 23% after starvation.
Severely malnourished patients (Table 1) appear to be at particular risk of developing the refeeding syndrome, whose features (Figure 1) (Travis et al., 1971; Craddock et al., 1974; O'Connor et al., 1977; Patrick, 1977; Heymsfield et al., 1978; Weinsier and Krumdieck, 1981; Powers, 1982; Isner et al., 1985; Cumming et al., 1987; Gustavsson and Eriksson, 1989; Faintuch, 1990; Beumont and Large, 1991; Brooks and Melnik, 1995; Birmingham et al., 1996; Marik and Bedigian, 1996; Paula et al., 1998; Crook et al., 2001; Hadley and Walsh, 2003; Marinella, 2003; Whyte et al., 2003; Hearing, 2004; Crook and Panteli, 2005; Kraft et al., 2005) include:
salt and water retention leading to oedema and heart failure, which may be exacerbated by cardiac atrophy,
hypokalaemia due to rapid cellular uptake of potassium as glucose and amino acids are taken up during cellular synthesis of glycogen and protein,
hypophosphataemia due to increased phosphorylation of glucose,
rapid depletion of thiamine, a cofactor in glycolysis, leading to Wernicke's encephalopathy and/or cardiomyopathy, and
hypomagnesaemia due to cellular uptake of this mineral.
In severe nutritional depletion, atrophy of the gut mucosa and impairment of pancreatic function may predispose to severe diarrhoea following oral or enteral refeeding, precipitating further electrolyte and mineral imbalance.
It is difficult to give a precise definition for the refeeding syndrome, since many otherwise well nourished patients, refed after only a few days starvation, will show a modest change in biochemical values, for example a fall in serum potassium and phosphate concentrations, without displaying any symptoms. There is a spectrum or gradation in the features of this condition from such asymptomatic cases to those with severe malnutrition who are at risk of overt and even life-threatening symptoms. The cutoff point at which the ‘refeeding syndrome’ can be said to be present is, therefore, somewhat arbitrary. We have taken the view that the full-blown syndrome should be defined by the presence of symptoms, but that biochemical changes of sufficient degree to pose a potential risk should be acted upon without delay in order to prevent the clinical features developing. Perhaps, we should adopt the terms ‘symptomatic refeeding syndrome’ and ‘potential or biochemical refeeding syndrome’.
We report seven cases illustrating various aspects of this syndrome and, on the basis of these cases and a review of the literature, propose a refeeding regimen in adults to avoid this complication.
Case 1: hunger striker
Protesting against a deportation order, a 27-year-old asylum seeker, with no previous medical history, went on hunger strike over a period of 4 months, refusing all nourishment apart from tea and coffee with sugar. At this time, he was admitted to hospital and, over the subsequent 2 weeks, lost a further 10 kg in weight (to 49 kg, body mass index (BMI) 14.7 kg/m2). He became progressively weaker, more inactive and apathetic. At this point, he was treated by enteral and parenteral nutrition with a total intake of 6.7 MJ/day (1600 kcal/day). He was also given a daily infusion of 500 ml 0.9% saline with 20 mmol KCl and vitamins and trace elements according to the dietary reference intakes (DRI) (Food and Nutrition Board, 2005) (Supradyn one tablet/day: 100% of DRI). After 3 days, his condition had deteriorated. He had gained 5 kg in weight, due to salt and water retention, and developed hypokalaemia (2.8 mmol/l, normal range: 3.5–4.7 mmol/l), hypomagnesaemia (0.49 mmol/l, normal range: 0.7–1.0 mmol/l) and hypophosphataemia (0.05 mmol/l, normal range: 0.74–1.55 mmol/l). He showed neurological symptoms and signs with vertigo and vertical nystagmus. Artificial nutritional support was discontinued; a single dose of thiamine 200 mg was given intravenously (i.v.) and potassium phosphate 40 mmol was infused daily for 3 days. He also received a single i.v. dose of magnesium sulphate 20 mmol. After 3 days his electrolyte and mineral concentrations had risen into the normal range (K+ 4.2 mmol/l, Mg2+ 0.77 mmol/l and PO42− 1.16 mmol/l). Three days later, oral nutrition (6.7 MJ/day (1600 kcal/day)) was started and micronutrients were given i.v. according to the DRI (one ampoule each of Soluvit, Vitalipid and Addamel). After 37 days, his vertigo resolved. His mood and physical strength gradually improved and he was discharged after 57 days in hospital with a weight of 64.4 kg (gain of 15.4 kg) and a BMI of 19.2 kg/m2. Unfortunately, the vertical nystagmus continued, preventing him from reading or watching television.
This case illustrates the vulnerability of patients with extreme weight loss and a very low BMI to the refeeding syndrome. The rapid falls in potassium, magnesium and phosphate within 24–48 h without adequate supplements were typical, although his main neurological sequelae were due mainly to Wernicke's encephalopathy from acute thiamine deficiency. Thiamine is not stored in appreciable amounts, so that any acceleration of carbohydrate metabolism—for which it is a cofactor—may precipitate acute deficiency. In such cases, this should always be anticipated by giving prophylactic thiamine at a dose of 200–300 mg i.v. daily, with the first dose being given 30 min before refeeding. The incidence of some form of the refeeding syndrome in severely malnourished patients started on artificial feeding is approximately 50%, with half of these developing the syndrome within 3 days of starting treatment (Hernandez-Aranda et al., 1997).
Case 2: anorexia nervosa
A 40-year-old woman with long standing anorexia had suffered several complications of the condition in the past, including electrolyte disorders, arrhythmias, amenorrhoea, osteoporosis, depression and progressive social isolation. Before admission, she had lost further weight to 40 kg (BMI 13.5 kg/m2). While admission was being contemplated, she resumed eating several large meals a day, precipitating the refeeding syndrome. On admission, she had ankle oedema and hypotension (95/70 mm Hg). Serum concentrations of phosphate, magnesium and potassium were low and the electrocardiogram (ECG) showed sinus bradycardia (51 b.p.m.) and a prolonged QT interval (490 ms). Within 4 h of admission and continuation of oral nutrition and, despite oral supplements of vitamins and electrolytes, she developed muscle weakness and drowsiness. The ECG showed short runs of ventricular tachycardia. i.v. supplementation of electrolytes and minerals was started and the serum electrolyte concentrations returned to normal within 2 days, with resolution of the muscle weakness and the ventricular tachycardia. However, the QT interval remained prolonged at 460 ms.
Severe anorexia nervosa with a very low BMI is a common cause of the refeeding syndrome in hospital practice. In this case, refeeding was begun by the patient herself and was continued after hospital admission.
In severe and prolonged malnutrition, there may be cardiac atrophy as well as electrolyte abnormalities, including sinus bradycardia and a prolonged QT interval (Heymsfield et al., 1978; Powers, 1982). These changes make the heart more vulnerable to hypophosphataemia and hypokalaemia with ventricular arrhythmias and sudden death (Isner et al., 1985; Beumont and Large, 1991), especially, if the QT interval exceeds 470 ms (Cooke et al., 1994). It should also be remembered that the concomitant abuse of diuretics, laxatives and alcohol by anorectic patients may exacerbate electrolyte and vitamin deficiencies. It is, therefore, important to be alert to the danger of the refeeding syndrome in patients with these problems.
Case 3: post-bariatric surgery for obesity
A 30-year-old woman underwent gastric bypass surgery for severe obesity (BMI 60.9 kg/m2). She lost 35 kg (BMI 48.4 kg/m2) in the first 4 months after the operation. For 2 weeks before admission, she had felt unwell with vomiting after food and had been unable to ingest anything more than sips of liquid. On admission, she appeared to be salt and water depleted with a blood pressure of 110/70 mm Hg and a pulse rate of 110 b.p.m. Serum concentrations of phosphate and potassium were normal, but concentrations of folate (10.2 nmol/l, normal: >12.2 nmol/l) and iron (5 μmol/l, normal range: 6–30 μmol/l) were low. In the first 24 h of hospitalization, 2.5 l of i.v. 0.9% saline and a standard nasogastric feed (4.2 MJ/day (Isosource: 1000 kcal/day, K+ 35 mmol, PO42− 24 mmol)) were prescribed. Folate and iron supplements were given orally (Folvite 1 mg/day and Ferrum Hausmann 200 mg Fe (II)/day). Within 10 h, she developed tachypnoea, orthopnoea and dependent oedema. Her pulse rate rose to 128 b.p.m. and blood pressure fell to 85/55 mm Hg. Chest X-ray shows pulmonary oedema and cardiomegaly. Biochemical screen showed hypokalaemia (2.2 mmol/l), hypophosphataemia (0.68 mmol/l) and lactic acidosis. Thiamine deficiency was not considered. There was only limited improvement with diuretics, oxygen and K+ and PO42− supplementation. On the following day, she was seen by the nutrition support team and prescribed thiamine i.v. (300 mg/day) and an enteral feed (6.3 MJ/day (1500 kcal/day)). Within 4 h of thiamine administration her heart failure began to improve and acidosis to resolve. Supplements were continued for 7 days and after 2 weeks she had recovered and was discharged.
Despite continuing obesity, this patient had lost a large amount of weight over a short period and, additionally, had developed vomiting with gastrointestinal dysfunction, thereby increasing her vulnerability to micronutrient deficiencies and the refeeding syndrome. In contrast to Case 1 (dry beriberi), this patient showed classical features of heart failure secondary to thiamine deficiency (wet beriberi), proven also by her rapid response to thiamine supplementation. The possibility of beriberi as a cause of heart failure and adequate thiamine supplementation (Rolfe, 1994; Betrosian et al., 2004) should be considered in all high-risk patients, including those with malabsorption, malnutrition, malignancy or chronic alcohol abuse.
Case 4: malnutrition in an extreme vegetarian
A 52-year-old man with a schizoaffective disorder underwent a pancreaticoduodenectomy for a carcinoid tumour of the duodenum. Following surgery, he became an extreme vegetarian, eating only apples. Over the next 3 years, he lost half his body weight, ending up weighing only 30 kg (BMI 13.8 kg/m2). On admission, his serum levels of potassium (3.3 mmol/l), iron (3 μmol/l), vitamin B12 (96 pmol/l, normal range: 150–670 pmol/l) and albumin (23 g/l) were all low. He was started on 1250 ml/day (180 g carbohydrate, 10 g nitrogen, K+ 47 mmol, Mg2+ 5.3 mmol and PO42− 20 mmol) of parenteral nutrition. In addition, he was given an i.v. infusion of 250 ml/day of 0.9% saline along with oral vitamin supplements (Supradyn two tablets/day: 200% of DRI) and iron (Ferrum Hausmann 200 mg Fe (II)/day). After 48 h, he had dependent oedema, ascites, dyspnoea and sinus tachycardia (128 b.p.m.). There were falls in serum K+ (2.2 mmol/l), PO42− (0.53 mmol/l) and Mg2+ (0.61 mmol/l), which were corrected with i.v. supplements (PO42− 20 mmol/day, K+ 40 mmol/day, Mg2+ 10 mmol/day, iron 100 mg/day and a single dose of thiamine 100 mg). Vitamins and trace elements were administered i.v. according to their DRIs (one ampoule each of Soluvit, Vitalipid and Addamel).
It subsequently transpired that the patient had been secretly taking 4 l of distilled water and 15 apples daily, which he had delivered to him in hospital. This may have contributed to the severity of the biochemical and clinical changes. After a period of intense psychotherapy, he resumed a balanced diet and was discharged after 5 weeks, having gained 4.6 kg.
This patient not only suffered from malnutrition due to the extreme eccentricity of his diet, but also due to malabsorption from his previous surgery. The combination of salt and water retention and biochemical changes should be anticipated in vulnerable patients. Salt and water intake should be limited and appropriate supplements given. Macronutrient intake should be started at 30% of requirements and built up slowly over 5–7 days, calculated on the basis of the patient's actual, not ideal, body weight.
Case 5: chronic alcoholism
A 62-year-old man presented to the orthopaedic clinic with a proximal femoral fracture. He had been drinking 750 ml of wine daily (56 U alcohol/week) for the last 8 years and was found to have early signs of dementia, malnutrition (BMI 17.9 kg/m2) and osteoporosis. On admission to the orthopaedic ward for femoral surgery, a multivitamin tablet (Supradyn: 100% DRI) was prescribed and, postoperatively, he was given high-energy drinks (Ensure Plus: 2 × 200 ml/day, 2.5 MJ/day (600 kcal/day)). On the second postoperative (p.o.) day, he developed ophthalmoplegia, diplopia and hypotension. Investigations confirmed thiamine deficiency (erythrocyte thiamine pyrophosphate concentration 19 nmol/l, normal range: 66–200 nmol/l) as well as hypomagnesaemia (0.62 mmol/l). Thiamine (200 mg/day for 5 days) and magnesium supplements (20 mmol/day for 3 days) were given i.v. The hypotension resolved 3 h after the first dose, and after 12 h, there was improvement in his neurological symptoms, which had resolved completely by the time of his discharge 1 month later.
This case illustrates the importance of giving i.v. thiamine prophylactically to all alcoholic patients (200 mg i.v. on the first day, then 300 mg p.o. for 5 days) undergoing hospital treatment, especially when this is accompanied by nutritional support. Oral multivitamin supplements are inadequate to prevent critical falls in thiamine levels with refeeding. K+, PO42− and Mg2+ levels should also be monitored and supplemented appropriately.
Case 6: chronic diarrhoea and coeliac disease
A 65-year-old man with a 15-year history of coeliac disease who was being treated with steroids and a gluten-free diet presented with fatigue and increased thirst for the last month. For 2 months before admission, he had suffered from watery diarrhoea (15–20 stools daily) and weight loss of 12 kg. On admission, he appeared dehydrated and malnourished (BMI 17.5 kg/m2). Investigations showed Clostridium difficile in the stool, anaemia (Hb 9.1 g/dl) and hypoalbuminaemia (serum albumin 26 g/l). Hypokalaemia was present (2.4 mmol/l), but magnesium and phosphate concentrations were normal. After restoration of salt, water and potassium balance, parenteral nutrition (2500 ml/day, 360 g carbohydrate, 20 g nitrogen) was begun. Clostridium difficile infection was treated with metronidazole. After 3 days, his diarrhoea had improved, but his weight had increased by 4 kg (reflecting salt and water gain), with peripheral oedema and pleural effusions. He developed severe hypophosphataemia and hypokalaemia, but the serum magnesium was at the lower limit of normal. This was accompanied by generalized muscle weakness, thrombocytopaenia and gastrointestinal bleeding. Folate concentrations were normal (16.1 nmol/l). Following fluid restriction, temporary withdrawal of parenteral nutrition, i.v. phosphate supplements (20 mmol/day for 4 days), and transfusion with blood, platelets and fresh frozen plasma, these problems resolved and the patient recovered fully after 2 weeks.
Fluid, electrolyte and mineral loss from diarrhoea exacerbated the risk, due to malnutrition, of developing the refeeding syndrome, especially when parenteral nutrition was given in full amount immediately rather than being introduced slowly. Steroid treatment may also have added to negative nitrogen balance and potassium depletion. The development of muscle weakness, cardiac decompensation, thrombocytopaenia and gastrointestinal bleeding in this case could all be explained by phosphate depletion, although folate, selenium, magnesium and thiamine deficiency can develop in patients with coeliac disease and diarrhoea. These should, therefore, be monitored carefully. Hypophosphataemia can develop rapidly (within 3–4 days) and should be prevented by prophylactic supplements.
Case 7: cancer
A 49-year-old man with oesophageal cancer developed dysphagia, leading to weight loss (11 kg in 6 weeks) and malnutrition (BMI 16.3 kg/m2). Investigations showed anaemia (Hb 8.7 g/dl), hypoalbuminaemia (serum albumin 27 g/l), hypokalaemia (2.2 mmol/l) and a prolonged prothrombin time. A percutaneous endoscopic gastrostomy was inserted, and enteral feeding initiated at 4.2 MJ/day (Survimed, 1000 kcal/day), increasing by 1.0 MJ (250 kcal) daily up to 8.4 MJ/day (Survimed: 2000 kcal/day, micronutrients: 100% DRI). Moreover, vitamins and trace elements were supplemented with a multivitamin product (Supradyn one tablet/day: 100% of DRI). Radiotherapy and chemotherapy were begun. After 4 days, the patient complained of numbness and paraesthesiae in the hands and feet as well as abdominal cramps. Biochemical investigations showed classical features of the refeeding syndrome; with hypokalaemia (2.1 mmol/l), hypophosphataemia (0.43 mmol/l) and hypomagnesaemia (0.43 mmol/l). Following i.v. supplementation with K+ (60 mmol/day for 3 days), PO42− and Mg2+ (20 mmol/day of each for 3 days), the symptoms resolved.
In a study on malnourished cancer patients started on artificial nutritional support, the incidence of the refeeding syndrome, based on a phosphate concentration <0.41 mmol/l, was found to be 24.5%, and was even more frequent with enteral (37.5%) than with parenteral (18.5%) nutrition (Gonzalez Avila et al., 1996). In that study, 61.5% of patients who developed the refeeding syndrome did so within 72 h of starting feeding.
The seven cases illustrate the many contexts in which the refeeding syndrome may occur and highlight the rapidity of its onset, which may be within hours of commencing refeeding. Common factors include the severity of the underlying malnutrition, overaggressive nutritional support in the early stages without adequate supplements of phosphate, thiamine, potassium and magnesium, and associated conditions that exacerbate micronutrient, electrolyte and mineral deficiencies, for example alcoholism, gastrointestinal disorders and poor or eccentric diets.
Although phosphate is just one of the components affected, hypophosphataemia has far reaching consequences on the functioning of various organ systems. During starvation, phosphate and potassium are lost from the cell in proportion to the breakdown of glycogen and protein, potassium being the main intracellular cation balancing the negative charges on proteins. There is, therefore, no clinical deficiency of these electrolytes until catabolism is abruptly reversed and resynthesis of glycogen and protein begins, creating a sudden demand for inorganic phosphate for phosphorylation and adenosine triphosphate (ATP) synthesis and for potassium to balance the negative charges on protein and glycogen. Magnesium, being involved in ATP synthesis, is also taken up by the cells. Upon the introduction of carbohydrate, insulin is released into the blood stream and there is a shift of metabolism from fat to carbohydrate. Acute thiamine deficiency may be precipitated, especially in patients suffering from chronic alcoholism, since diminished thiamine reserves are rapidly used up, as carbohydrate metabolism is accelerated. Excessive infusion of glucose may also cause hyperglycaemia leading to osmotic diuresis, dehydratation and hyperosmolar non-ketotic coma (Crook et al., 2001). The production of fat from glucose due to lipogenesis can result in hypertriglyceridaemia and/or a fatty liver (Crook et al., 2001).
From a study of these cases, the published literature (Faintuch, 1990; Brooks and Melnik, 1995; Marik and Bedigian, 1996; Crook et al., 2001; Marinella, 2003; Hearing, 2004; Kraft et al., 2005) and recent guidelines on nutritional support (World Health Organisation, 1999; World Health Organisation, 2004; National Collaborating Centre for Acute Care, 2006), it is possible to suggest a protocol for the prevention and treatment of the refeeding syndrome (Tables 2 and 3) in which it is important to:
always be aware of the circumstances in which the syndrome is likely to develop,
refeed slowly and build up the macronutrient content of the feed over several days,
monitor the patient frequently,
anticipate the additional requirements, particularly of phosphate, potassium, magnesium and thiamine, and
minimize salt intake, unless the patient is salt depleted.
Fluid intake should also be minimized to that required to replace any deficit or to allow normal renal function. In a small, thin patient this may be as little as 1000–1200 ml/day. The present cases emphasize the need for:
thorough initial screening of such patients,
very cautious and slow introduction of refeeding,
anticipation of the problem with i.v. supplements,
careful and frequent monitoring in the early stages, and
early recognition and treatment of the condition if it develops.
Although there are no internationally validated guidelines for the treatment of the refeeding syndrome, on the basis of the published literature and expert opinion, we make the following recommendations for the prevention and management of the refeeding syndrome in adults (Table 3).
AB has been supported by grants from the Swiss Foundation for Nutrition Research and the Swiss Society for Internal Medicine.
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