Refeeding syndrome with enteral nutrition in children: a case report, literature review and clinical guidelines

Clinical Nutrition (2002) 21(6): 515–520 r 2002 Elsevier Science Ltd. All rights reserved. doi:10.1054/clnu.2002.0586, available online at http://www.idealibrary.com on

ORIGINAL ARTICLE

Refeeding syndrome with enteral nutrition in children: a case report, literature review and clinical guidelines N. A. AFZAL, S. ADDAI, A. FAGBEMI, S. MURCH, M. THOMSON, R. HEUSCHKEL Centre for Paediatric Gastroenterology, Royal Free Hospital, Hampstead, London, UK (Correspondence to: NAA, Centre for Pediatric Gastroenterology, Royal Free Hospital, Pond Street, Hampstead, London, NW3 2QG, UK)

AbstractFRefeeding syndrome is a potentially fatal complication of the nutritional management of severely malnourished patients. The syndrome almost always develops during the early stages of refeeding. It can be associated with a severe derangement in electrolyte and £uid balance, and result in signi¢cant morbidity and mortality. It is most often reported in adults receiving total parenteral nutrition (TPN), although refeeding with enteral feeds can also precipitate this syndrome. We report what we believe to be the first case of refeeding syndrome in an adolescent with newly diagnosed Crohn’s disease. This developed within a few days of starting exclusive polymeric enteral nutrition. A systematic literature review revealed 27 children who developed refeeding syndrome after oral/enteral feeding. Of these, nine died as a direct result of complications of this syndrome. We discuss the implications of this syndrome on clinical practice and propose evidence-based guidelines for its management. r 2002 Elsevier Science Ltd. All rights reserved.

Crohn’s disease was made (1), and the standard treatment with polymeric enteral nutrition (2) and aminosalicylates was planned. The patient was commenced on Mesalazine 1 g BD (Pentasas). Prior to the commencement of enteral nutrition and before biopsy results were known 7 days later, the patient had lost a further 2.7 kg. She had a pulse rate of 120 min 1. She was prescribed 2500 kcal/day of a caseinbased polymeric enteral feed (Nestle´, Clinical Nutrition) of identical electrolyte composition to the commercially available Modulen IBDs (see Table 2). This is based on our established practice over the past 20 years of using 110–120% of total calorie requirements/day for a period of 8 weeks. In view of some initial vomiting, anti-emetics were also prescribed. Within 72 h the patient had lost a further 1.8 kg. Feeds were then administered by a nasogastric tube. Over the next 48 h the patient developed a fever but remained haemodynamically stable; pulse 150 min 1 and blood pressure 120/70 mmHg. Abdominal X-ray and ultrasound were normal. In view of a low haemoglobin (Table 1) and continuing disease, the patient was transfused and intravenous Metronidazole and Ciprofloxacin were added to the treatment. Over the next 2 days there was a dramatic decrease in phosphate levels to 0.23 mmol/l, despite a standard daily phosphate supplementation of 1.25 mmol/kg/day in the feed. A diagnosis of refeeding syndrome was made. Her weight had increased by 2.9–41 kg. An ECG was done with a normal corrected QT interval of 0.44 s (normal range: 0.35–0.45 s). An echocardiogram showed normal cardiac function.

Key words: refeeding syndrome; enteral nutrition; Crohn’s disease

Case report A 14-year-old girl presented with a 2-month history of diarrhoea. She had no significant past medical history until she began passing three to four loose stools per day, with associated mucous but no blood. She became lethargic, had recurrent abdominal pains and lost her appetite. She also complained of generalized aches and pains, but particularly arthralgia of her wrists and ankles. Over the previous 8 weeks she had lost 7 kg in weight. On examination, she weighed 41.6 kg (weight for age = 14.8th centile, z = 1.05) and was 168.2 cm tall (height for age = 88.6th centile, z = +1.2). She was pale, afebrile and had no oral ulcers. Her pulse was 90 beats/ min and abdominal examination revealed mild tenderness in the right iliac fossa. Perianal examination was entirely normal. Musculoskeletal examination did not reveal any focal joint disease. She had raised inflammatory markers, low albumin with normal phosphate levels (Table 1). Her colonoscopy revealed moderate-to-severe ulceration in the transverse and ascending colon, caecum and terminal ileum. Histology confirmed a patchy increase in chronic inflammatory cells and neutrophils in the lamina propria with occasional crypt abscesses. Barium meal and follow through showed a normal proximal small bowel, but significant ileal distortion. No strictures were identified. A diagnosis of ileo-colonic 515

516

REFEEDING SYNDROME WITH ENTERAL NUTRITION IN CHILDREN

Table 1 Flow chart of laboratory investigations. Refeeding syndrome diagnosed on day 5 Ref range

Admission

D2

D4

D5

11.5–15.8 140–400 0–5 0–20 35–50 0.87–1.45 2.1–2.6 135–145 3.5–5 0.7–1 3–6.5 48–128 11.5–17

8.3 646 193

7.4 579 156

10.3 (Post Tx) 404 145 18 0.63 2.3 132 3.9

9.0 351 166 9 16 0.23 2.28 125 5.0

3.5

2.5

Hb (g/dl) Plat (  109/l) CRP (mg/l) ESR (mm/h) Albumin (g/l) Phos (mmol/l) Ca (mmol/l) Na (mmol/l) K (mmol/l) Mg (mmol/l) Urea (mmol/l) Selenium (mg/l) Zinc (mmol/l)

21 0.98 2.43 134 3.6 0.81 3.0 28.8 5.8

21 0.84 2.34

D7

43 18 1.19 2.33 133 4.1

D12

Follow up

10.1 788 10 12 22 1.48 2.49 137 4.7 0.93 3.1 46.4 11.3

11.8 331 1 7 41 1.36 2.48 0.85

Post Tx=Post transfusion Table 2 Major constituents in the polymeric feed Values Energy density (kcal/l) Protein (g/l) Carbohydrates (g/l) Na (mg/l) K (mg/l) Cl (mg/l) Ca (mg/l) P (mg/l) Ca/P Mg (mg/l) Mn (mg/l)

1000 40 110 600 1400 930 800 550 1.5 250 1000

Her enteral intake was reduced by 25% to 1800 ml (1800 kcal/day), and phosphate supplements were increased to 5 mmol/kg/day. Within 48 h her phosphate rose to 1.19 mmol/l. Intravenous azathioprine 125 mg (3 mg/kg/day) was added to her treatment (3) and was changed to the oral route 5 days later. There was gradual improvement and she was discharged home a week later, taking full volumes of her feed, i.e. 2500 kcal/day by nasogastric tube. On discharge her weight was 39.7 kg (weight for age = 9.4th centile, z = 1.3). See Table 1 for blood results. At 3 weeks follow-up her inflammatory markers were normal (Table 1) and her weight had increased to 41.5 kg (weight for age 13.4th centile, z = 1.1). A repeat colonoscopy performed 8 weeks after diagnosis showed a marked macroscopic and histological improvement. There was only mild crypt distortion in the colon with slight infiltration of neutrophils. Her weight had increased to 45.4 kg. Presently, 3 months after diagnosis she has gained 13.4 kg (52.3 kg; weight for age = 54.5th centile, z = 0.11 and height for age = 85.2th centile, z = +1.05) since start of treatment. She feels well and has started attending regular school again. She remains on oral azathioprine and mesalazine. Systematic review For review of the current literature a combination of hand-searching and computer-based techniques was

used. Original articles were identified from the MEDLINE database (1966–May 2001) via PubMeds for all reports of children developing refeeding syndrome while receiving enteral nutrition. A combination of the MeSH terms ‘enteral nutrition’, ‘hypophosphataemia’, ‘phosphate, low’ ‘feeding, parenteral’, ‘nutritional disorders’ as well as the terms ‘refeeding syndrome’ and ‘refeeding’ were used in the search. References of all articles published after 1966 were reviewed and relevant earlier references obtained in full. Twenty-seven children (o18 years) are reported in the world literature that developed refeeding syndrome after enteral feeding (Table 3). Universally, they had a prolonged hospital admission needing intensive care and nine children died as a result of refeeding complications. All of them had poor nutritional status (weight range 45–75% of ideal weight for height); seven had kwashiorkor (4, 5) and four anorexia nervosa (6–9). We have not included the report by Waterlow et al., who described 53 children with kwashiorkor and low serum phosphate, as refeeding syndrome was not conclusively diagnosed in this study (10). In all 27 children, a diagnosis of refeeding syndrome was made by fall in phosphate levels after the onset of enteral refeeding. High calorie feeds were being given to almost all cases at the time of diagnosis, and two girls were binge eating (6, 9). Three children remained asymptomatic with a low serum phosphate (9, 11). Cardiac complications (4, 6, 7) were noted in six patients which included cardiac arrest, cardiac failure, pericardial effusion, hypotension and bradycardia. Cardiac failure was treated with diuretics and digoxin. One patient with bradycardia required insertion of a cardiac pace maker. Three patients had delirium associated with disorientation that lasted several days (7, 8). This complication was noted to develop a week after refeeding. One patient developed haemolytic anaemia and rhabdomyolysis secondary to a low serum phosphate (11). In most patients a mild elevation of liver enzymes was noted. Along with a low serum phosphate, a wide range of electrolyte disturbances (Ca, Mg, K, Na) were also seen.

CLINICAL NUTRITION

517

Table 3 Cases of refeeding syndrome reported with enteral nutrition in children Author

Year

No. of pts

Age range

Underlying diagnosis

Clinical Features

Patrick et al. (4)

1977

6

11–28 months

Kwashiorkor

5 1 1 2

6 months–19 yr 16 yr 16 yr 12–13 yr

Not recorded Anorexia nervosa Anorexia nervosa Anorexia nervosa

1998

3

3–12 yr

1998 2000

8 1 27

o10 yr 16 yr 6 months–19 yr

Cardiac arrest Cardiac failure Not recorded Low phosphate only Delirium Cardiac arrest Delirium on day 7 Haemolysis, rhabdomyolysis Low phosphate only Phosphates o0.32 mmol/l Hypotension and bradycardia

Mezoff et al. (45) Kaysar et al. (9) Beumont et al. (8) Kohn et al. (7)

1989 1991 1992 1998

Worley et al. (11) Manary et al. (5) Fisher et al. (6) Total

Neurological disease child neglect Kwashiorkor Anorexia nervosa

In most instances, the refeeding syndrome was treated with a reduction in volume and caloric density of the feeds. All diets were subsequently supplemented with phosphate and vitamins. The management of many of these children with refeeding syndrome reveals a consistent practice of reducing calories and fluids to 50–75% of daily requirements (6, 9).

Pathophysiology The pathophysiology of refeeding syndrome remains poorly understood. The derangement in serum phosphate is best understood, although this may not be the most important. Eighty percent of body phosphate stores are present in bone and total amount ranges from 19 to 29 mmol in an adult (12). In order to maintain plasma phosphate above 0.8 mmol/l, adults require an intake of 12.9 mmol/day (with a bioavailability of 60%) (13). Starvation leads to a loss of water, minerals and lean muscle mass. There are several mechanisms that maintain the serum phosphate during starvation (14). Overall phosphate requirements are decreased during starvation, and serum levels are initially maintained by mobilizing bone reserves. A poor phosphate intake suppresses secretion of parathyroid hormone (PTH), which increases tubular phosphate re-absorption to more than 80%. Phosphate deficiency also leads to renal PTH resistance, thus preventing further phosphaturia. When a malnourished patient starts receiving nutritional support, there is a rapid reversal in insulin, thyroid and adrenergic axes, with metabolism shifting toward anabolism (15). Carbohydrates stimulate insulin release, which in turn increases the cellular uptake of phosphate, glucose and water, as well as stimulating protein synthesis; in addition it increases renal tubular sodium and water reabsorption (16). Severely malnourished children tend to increase their total body sodium (17), yet without developing obvious

Deaths 4 0 0 0 0 0 5 0 9

tissue oedema (18). Albina et al. have shown that refeeding with TPN results in a reduction of sodium and water excretion in humans, while concurrent sodium ingestion contributes to the rapid expansion of extracellular fluid volume (19). Glucose refeeding in fasted subjects minimizes weight loss and urinary sodium loss, whereas an exclusive protein-feed leads to continued weight loss and increased urinary sodium excretion (20). Potassium and magnesium also become depleted during starvation (21). On refeeding, potassium (22) and magnesium are then deposited intracellularly and serum levels may fall without supplementation (23, 24). Refeeding can decrease serum phosphate levels to below 0.3 mmol/l within hours. Untreated, hypophosphataemia leads to depletion of phosphorylated compounds (ATP, 2,3 DPG, G-3PD) (25, 26) and may result in cardiac, neuromuscular, haematological and respiratory compromise. Rarely, rhabdomyolysis due to ATP depletion with subsequent renal failure may occur (27). Cardiac arrest has been reported as a complication of refeeding syndrome in patients presenting at less than 70% of prior body weight (7). Prolonged starvation results in a reduced cardiac mass and output. Heymsfield et al. demonstrated a reduced total cardiac volume, end diastolic volume and left ventricular mass in severely malnourished patients (28). During the refeeding syndrome, ventricular volume returns to normal while left ventricular mass remains reduced (28). This may lead to fluid retention and congestive cardiac failure. Phosphate deficiency may also lead to decreased sarcomere contractility (29) and cause direct myocardial damage (30). Nitrogen should be given together with carbohydrates as gluconeogenesis alone is unable to meet requirements following starvation (31). Experience with feeding malnourished children has shown clinically significant milk intolerance to be rare (32). If a milk-based feed induces diarrhoea with positive faecal reducing substances, a hydrolysate may be used. This may improve in intestinal permeability and mucosal regeneration more rapidly than whole protein feeds (33, 34).

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REFEEDING SYNDROME WITH ENTERAL NUTRITION IN CHILDREN

Mattioli et al. reported a case of an adult male with ulcerative colitis who, following an emergency colectomy, developed Wernicke’s encephalopathy during refeeding with TPN. He died on the 18th post-operative day from neurological complications and coma. An autopsy suggested thiamine deficiency and thus the authors recommend thiamine administration to all patients during refeeding (35). Platelet and leukocyte dysfunction, as well as haemolytic anaemia (36) are reported following the refeeding of malnourished patients (37–39).

Discussion Refeeding syndrome is defined as ‘the occurrence of severe fluid and electrolyte shifts (especially, but not exclusively, of phosphate) and their associated complications in malnourished patients undergoing enteral/ parenteral refeeding (31)’. Marik et al. defined refeeding syndrome as a fall in phosphate levels by more than 0.16 mmol/l to below 0.65 mmol/l (40). Refeeding syndrome is not uncommon and severe hypophosphataemia (o0.35 mmol/l) has been reported in 0.8% of all hospitalized adult patients (41). Starvation for as little as 48 h may predispose to refeeding syndrome, with a low serum pre-albumin level (o110 g/l) predicting hypophosphataemia (40). Marik et al. showed that 81% (17/21) of patients developing refeeding syndrome had a pre-albumin level of less than 110 g/l; yet similar levels were also found in 30% of patients who did not develop refeeding syndrome. Not all malnourished patients without mineral supplementation develop the classic electrolyte and fluid shifts, or their consequences, during refeeding (31). The reasons for this are not clear. Initial reports of refeeding syndrome were made following the refeeding of adult survivors of concentration camps in 1945 (42). Oral feeding of starved victims resulted in cardiac insufficiency and neurological complications such as coma and convulsions. The syndrome was also seen in refeeding of healthy volunteers who had undergone starvation for 6 months (43). In the 1970s, the refeeding syndrome was reported following the introduction of TPN (31). Silvis et al. reported a patient with Crohn’s disease treated with TPN developing neurological complications of the refeeding syndrome that included paresthesiae, weakness and seizures (44). Our patient clearly had aggressive Crohn’s disease. The dramatic weight loss, although not unusual per se at first presentation, had occurred over a matter of weeks, and not months. As a result of this severe disease, nutritional stores had been depleted more rapidly than normal. The constellation of active inflammation, malabsorption and profound anorexia thus led to this episode of refeeding syndrome during conventional treatment with enteral nutrition.

Our patient had a persistent tachycardia during the early stages of her refeeding. While this may partly have been due to active inflammation and/or bacteraemia, several other factors may have contributed. The patient may have mounted a compensatory tachycardia in view of early fluid overload, and this may have been exacerbated by her low serum albumin. However, clinical oedema was not documented. Significant hypophosphataemia may also have had a direct effect on cardiac contractility and output, although a normal cardiac echo was performed after the diagnosis was made. Reports of this syndrome are rare and, in the developed world, are usually associated with anorexia nervosa. As a result, physicians are unlikely to encounter this in their working life, and hence it may frequently go unrecognized (45). There have been very few reports of children with refeeding syndrome (Table 3), and no reports of it occurring during the management of Crohn’s disease

Table 4 Guidelines for the prevention of refeeding syndrome Refeeding syndrome should be considered as a potential complication in any patient recovering from a period of sub-optimal nutrition. The greatest caution is required during the first week after commencing nutritional support (50) (A) Monitoring Before initiating refeeding by any route, and during the first 3–5 days of feeding, careful assessment of the following is required 1. Hydration and nutritional state (15) Early weight gain may be secondary to fluid retention (50) 2. Serum electrolytes (15,31) Initial glucose and albumin (pre-albumin) Daily sodium, potassium, urea, creatinine, phosphate, Mg and calcium 3. Cardiac status (15) Pulse (compensatory tachycardia), ECG 7 Echo (B) Oral feeding regimen 1. Initial volume and calories (32) In more severe cases an initial starting volume of 75% of total daily requirements has been used o7 years oldF80–100 kcal/kg/day 7–10 yearsF75 kcal/kg/day 11–14 yearsF60 kcal/kg/day 15–18 yearsF50 kcal/kg/day If the initial food challenge is tolerated, this may be increased over 3–5 days (31,51). Each requirement should be tailored to an individual’s need and the above values may need to be adjusted by as much as 30%. Frequent small feeds are recommended (32) Feeds should provide minimum of 1 kcal/ ml to minimize volume overload. 2. Protein If a milk-based feed induces diarrhoea with positive faecal reducing substances, a hydrolysate may be used An initial regimen for malnourished children suggests 0.6–1 g/kg/day (15). The feed should be rich in essential amino acids and gradually increased as an intake of 1.2–1.5 g/kg/ day is needed for anabolism to occur (32, 50) 3. Supplements NaF1 mmol/kg/day, KF4 mmol/kg/day, MgF0.6 mmol/kg/day (32) Phosphate up to 1 mmol/ kg/ day intravenously and oral supplements up to 100 mmol/ day for children over 5 years of age. Hypocalcaemia may occur during phosphate supplementation (52) Thiamine (53), folic acid, riboflavin, ascorbic acid, pyridoxine, as well as the fat-soluble vitamins A, D, E and K should be supplemented. Trace elements, including Selenium, may also be deficient (32)

CLINICAL NUTRITION

with enteral nutrition. Exclusive enteral nutrition continues to be a potent primary therapy in newly diagnosed Crohn’s disease in children (2, 46). Despite its use in children with Crohn’s disease for over 25 years, this complication has never been reported. Although there are very few complications associated with the use of enteral nutrition, we report this case to highlight the need for continued caution in certain clinical circumstances. This instance of refeeding syndrome is very unlikely to be related to the type of formula. Adequate enteral nutrition is an important part of the management of all patients, irrespective of their disease. Malnourished patients have poorer clinical outcomes, with more infections and other complications, and use more resources than well-nourished patients (47–49). There are no accepted guidelines for the management of refeeding syndrome. We make recommendations after discussion with leading authorities in the field, and review of the published literature, including the WHO guidelines for the feeding of malnourished children (Table 4). Refeeding syndrome remains an important complication that may occur early in the refeeding of malnourished patients. It is vital to identify the patients at risk, and take appropriate measures to prevent the significant morbidity and even mortality that may ensue.

Acknowledgements The authors gratefully acknowledge Professor MH Golden, Dept of Child Health and Dr BE Golden, Dept of Child Health, University of Aberdeen, Foresterhill, UK for their helpful advice in the preparation of the guidelines.

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