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Clinical Nutrition (2002) 21(6): 515520

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 malnour-
ished 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 signicant 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 Crohns
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.

Key words: refeeding syndrome; enteral nutrition; Crohns disease was made (1), and the standard
Crohns disease treatment with polymeric enteral nutrition (2) and
aminosalicylates was planned. The patient was com-
menced on Mesalazine 1 g BD (Pentasas).
Case report Prior to the commencement of enteral nutrition and
before biopsy results were known 7 days later, the
A 14-year-old girl presented with a 2-month history of patient had lost a further 2.7 kg. She had a pulse rate of
diarrhoea. She had no signicant past medical history 120 min 1. She was prescribed 2500 kcal/day of a casein-
until she began passing three to four loose stools per day, based polymeric enteral feed (Nestle, Clinical Nutrition)
with associated mucous but no blood. She became of identical electrolyte composition to the commercially
lethargic, had recurrent abdominal pains and lost her available Modulen IBDs (see Table 2). This is based on
appetite. She also complained of generalized aches and our established practice over the past 20 years of using
pains, but particularly arthralgia of her wrists and 110120% of total calorie requirements/day for a period
ankles. Over the previous 8 weeks she had lost 7 kg in of 8 weeks. In view of some initial vomiting, anti-emetics
weight. On examination, she weighed 41.6 kg (weight for were also prescribed. Within 72 h the patient had lost a
age = 14.8th centile, z = 1.05) and was 168.2 cm tall further 1.8 kg. Feeds were then administered by a
(height for age = 88.6th centile, z = +1.2). She was pale, nasogastric tube. Over the next 48 h the patient devel-
afebrile and had no oral ulcers. Her pulse was 90 beats/ oped a fever but remained haemodynamically stable;
min and abdominal examination revealed mild tender- pulse 150 min 1 and blood pressure 120/70 mmHg.
ness in the right iliac fossa. Perianal examination was Abdominal X-ray and ultrasound were normal. In view
entirely normal. Musculoskeletal examination did not of a low haemoglobin (Table 1) and continuing disease,
reveal any focal joint disease. She had raised inamma- the patient was transfused and intravenous Metronida-
tory markers, low albumin with normal phosphate levels zole and Ciprooxacin were added to the treatment.
(Table 1). Her colonoscopy revealed moderate-to-severe Over the next 2 days there was a dramatic decrease in
ulceration in the transverse and ascending colon, caecum phosphate levels to 0.23 mmol/l, despite a standard daily
and terminal ileum. Histology conrmed a patchy phosphate supplementation of 1.25 mmol/kg/day in the
increase in chronic inammatory cells and neutrophils feed. A diagnosis of refeeding syndrome was made. Her
in the lamina propria with occasional crypt abscesses. weight had increased by 2.941 kg. An ECG was done
Barium meal and follow through showed a normal with a normal corrected QT interval of 0.44 s (normal
proximal small bowel, but signicant ileal distortion. No range: 0.350.45 s). An echocardiogram showed normal
strictures were identied. A diagnosis of ileo-colonic cardiac function.

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 D7 D12 Follow up


Hb (g/dl) 11.515.8 8.3 7.4 10.3 (Post Tx) 9.0 10.1 11.8
Plat (  109/l) 140400 646 579 404 351 788 331
CRP (mg/l) 05 193 156 145 166 43 10 1
ESR (mm/h) 020 9 12 7
Albumin (g/l) 3550 21 21 18 16 18 22 41
Phos (mmol/l) 0.871.45 0.98 0.84 0.63 0.23 1.19 1.48 1.36
Ca (mmol/l) 2.12.6 2.43 2.34 2.3 2.28 2.33 2.49 2.48
Na (mmol/l) 135145 134 132 125 133 137
K (mmol/l) 3.55 3.6 3.9 5.0 4.1 4.7
Mg (mmol/l) 0.71 0.81 0.93 0.85
Urea (mmol/l) 36.5 3.0 3.5 2.5 3.1
Selenium (mg/l) 48128 28.8 46.4
Zinc (mmol/l) 11.517 5.8 11.3
Post Tx=Post transfusion

Table 2 Major constituents in the polymeric feed used. Original articles were identied from the MED-
Values
LINE database (1966May 2001) via PubMeds for all
reports of children developing refeeding syndrome while
Energy density (kcal/l) 1000
Protein (g/l) 40
receiving enteral nutrition. A combination of the MeSH
Carbohydrates (g/l) 110 terms enteral nutrition, hypophosphataemia, phos-
Na (mg/l) 600 phate, low feeding, parenteral, nutritional disorders
K (mg/l) 1400
Cl (mg/l) 930
as well as the terms refeeding syndrome and refeeding
Ca (mg/l) 800 were used in the search. References of all articles
P (mg/l) 550 published after 1966 were reviewed and relevant earlier
Ca/P 1.5
Mg (mg/l) 250
references obtained in full.
Mn (mg/l) 1000 Twenty-seven children (o18 years) are reported in the
world literature that developed refeeding syndrome after
enteral feeding (Table 3). Universally, they had a
Her enteral intake was reduced by 25% to 1800 ml
prolonged hospital admission needing intensive care
(1800 kcal/day), and phosphate supplements were in-
and nine children died as a result of refeeding
creased to 5 mmol/kg/day. Within 48 h her phosphate
complications. All of them had poor nutritional status
rose to 1.19 mmol/l. Intravenous azathioprine 125 mg
(weight range 4575% of ideal weight for height); seven
(3 mg/kg/day) was added to her treatment (3) and was
had kwashiorkor (4, 5) and four anorexia nervosa (69).
changed to the oral route 5 days later. There was gradual
We have not included the report by Waterlow
improvement and she was discharged home a week later,
et al., who described 53 children with kwashiorkor and
taking full volumes of her feed, i.e. 2500 kcal/day by
low serum phosphate, as refeeding syndrome was not
nasogastric tube. On discharge her weight was 39.7 kg
conclusively diagnosed in this study (10).
(weight for age = 9.4th centile, z = 1.3). See Table 1 for
In all 27 children, a diagnosis of refeeding syndrome
blood results.
was made by fall in phosphate levels after the onset of
At 3 weeks follow-up her inammatory markers were
enteral refeeding. High calorie feeds were being given to
normal (Table 1) and her weight had increased to
almost all cases at the time of diagnosis, and two girls
41.5 kg (weight for age 13.4th centile, z = 1.1).
were binge eating (6, 9).
A repeat colonoscopy performed 8 weeks after
Three children remained asymptomatic with a low
diagnosis showed a marked macroscopic and histologi-
serum phosphate (9, 11). Cardiac complications (4, 6, 7)
cal improvement. There was only mild crypt distortion
were noted in six patients which included cardiac arrest,
in the colon with slight inltration of neutrophils. Her
cardiac failure, pericardial eusion, hypotension and
weight had increased to 45.4 kg.
bradycardia. Cardiac failure was treated with diuretics
Presently, 3 months after diagnosis she has gained
and digoxin. One patient with bradycardia required
13.4 kg (52.3 kg; weight for age = 54.5th centile, z =
insertion of a cardiac pace maker.
0.11 and height for age = 85.2th centile, z = +1.05)
Three patients had delirium associated with disor-
since start of treatment. She feels well and has started
ientation that lasted several days (7, 8). This complica-
attending regular school again. She remains on oral
tion was noted to develop a week after refeeding.
azathioprine and mesalazine.
One patient developed haemolytic anaemia and rhab-
domyolysis secondary to a low serum phosphate (11).
Systematic review In most patients a mild elevation of liver enzymes was
noted. Along with a low serum phosphate, a wide range
For review of the current literature a combination of of electrolyte disturbances (Ca, Mg, K, Na) were also
hand-searching and computer-based techniques was seen.
CLINICAL NUTRITION 517

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

Author Year No. of pts Age range Underlying Clinical Features Deaths
diagnosis
Patrick et al. (4) 1977 6 1128 months Kwashiorkor Cardiac arrest 4
Cardiac failure
Mezo et al. (45) 1989 5 6 months19 yr Not recorded Not recorded 0
Kaysar et al. (9) 1991 1 16 yr Anorexia nervosa Low phosphate only 0
Beumont et al. (8) 1992 1 16 yr Anorexia nervosa Delirium 0
Kohn et al. (7) 1998 2 1213 yr Anorexia nervosa Cardiac arrest 0
Delirium on day 7
Worley et al. (11) 1998 3 312 yr Neurological disease child neglect Haemolysis, rhabdomyolysis 0
Low phosphate only
Manary et al. (5) 1998 8 o10 yr Kwashiorkor Phosphates o0.32 mmol/l 5
Fisher et al. (6) 2000 1 16 yr Anorexia nervosa Hypotension and bradycardia 0
Total 27 6 months19 yr 9

In most instances, the refeeding syndrome was treated tissue oedema (18). Albina et al. have shown that
with a reduction in volume and caloric density of the refeeding with TPN results in a reduction of sodium and
feeds. All diets were subsequently supplemented with water excretion in humans, while concurrent sodium
phosphate and vitamins. The management of many of ingestion contributes to the rapid expansion of extra-
these children with refeeding syndrome reveals a cellular uid volume (19).
consistent practice of reducing calories and uids to Glucose refeeding in fasted subjects minimizes weight
5075% of daily requirements (6, 9). loss and urinary sodium loss, whereas an exclusive
protein-feed leads to continued weight loss and in-
creased urinary sodium excretion (20).
Potassium and magnesium also become depleted
Pathophysiology during starvation (21). On refeeding, potassium (22)
and magnesium are then deposited intracellularly and
The pathophysiology of refeeding syndrome remains serum levels may fall without supplementation (23, 24).
poorly understood. Refeeding can decrease serum phosphate levels to
The derangement in serum phosphate is best under- below 0.3 mmol/l within hours. Untreated, hypopho-
stood, although this may not be the most important. sphataemia leads to depletion of phosphorylated com-
Eighty percent of body phosphate stores are present in pounds (ATP, 2,3 DPG, G-3PD) (25, 26) and may result
bone and total amount ranges from 19 to 29 mmol in cardiac, neuromuscular, haematological and respira-
in an adult (12). In order to maintain plasma tory compromise. Rarely, rhabdomyolysis due to ATP
phosphate above 0.8 mmol/l, adults require an intake depletion with subsequent renal failure may occur (27).
of 12.9 mmol/day (with a bioavailability of 60%) (13). Cardiac arrest has been reported as a complication of
Starvation leads to a loss of water, minerals and lean refeeding syndrome in patients presenting at less than
muscle mass. There are several mechanisms that 70% of prior body weight (7). Prolonged starvation
maintain the serum phosphate during starvation (14). results in a reduced cardiac mass and output. Heyms-
Overall phosphate requirements are decreased during eld et al. demonstrated a reduced total cardiac volume,
starvation, and serum levels are initially maintained by end diastolic volume and left ventricular mass in
mobilizing bone reserves. A poor phosphate intake severely malnourished patients (28).
suppresses secretion of parathyroid hormone (PTH), During the refeeding syndrome, ventricular volume
which increases tubular phosphate re-absorption to returns to normal while left ventricular mass remains
more than 80%. Phosphate deciency also leads to reduced (28). This may lead to uid retention and
renal PTH resistance, thus preventing further phospha- congestive cardiac failure. Phosphate deciency may
turia. also lead to decreased sarcomere contractility (29) and
When a malnourished patient starts receiving nutri- cause direct myocardial damage (30).
tional support, there is a rapid reversal in insulin, Nitrogen should be given together with carbohydrates
thyroid and adrenergic axes, with metabolism shifting as gluconeogenesis alone is unable to meet requirements
toward anabolism (15). Carbohydrates stimulate insulin following starvation (31). Experience with feeding
release, which in turn increases the cellular uptake of malnourished children has shown clinically signicant
phosphate, glucose and water, as well as stimulating milk intolerance to be rare (32). If a milk-based feed
protein synthesis; in addition it increases renal tubular induces diarrhoea with positive faecal reducing
sodium and water reabsorption (16). substances, a hydrolysate may be used. This may
Severely malnourished children tend to increase their improve in intestinal permeability and mucosal regen-
total body sodium (17), yet without developing obvious eration more rapidly than whole protein feeds (33, 34).
518 REFEEDING SYNDROME WITH ENTERAL NUTRITION IN CHILDREN

Mattioli et al. reported a case of an adult male with Our patient had a persistent tachycardia during the
ulcerative colitis who, following an emergency colect- early stages of her refeeding. While this may partly have
omy, developed Wernickes encephalopathy during been due to active inammation and/or bacteraemia,
refeeding with TPN. He died on the 18th post-operative several other factors may have contributed. The patient
day from neurological complications and coma. An may have mounted a compensatory tachycardia in view
autopsy suggested thiamine deciency and thus the of early uid overload, and this may have been
authors recommend thiamine administration to all exacerbated by her low serum albumin. However,
patients during refeeding (35). clinical oedema was not documented. Signicant hypo-
Platelet and leukocyte dysfunction, as well as haemo- phosphataemia may also have had a direct eect on
lytic anaemia (36) are reported following the refeeding cardiac contractility and output, although a normal
of malnourished patients (3739). 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
Discussion nervosa. As a result, physicians are unlikely to
encounter this in their working life, and hence it may
Refeeding syndrome is dened as the occurrence of frequently go unrecognized (45).
severe uid and electrolyte shifts (especially, but not There have been very few reports of children with
exclusively, of phosphate) and their associated compli- refeeding syndrome (Table 3), and no reports of it
cations in malnourished patients undergoing enteral/ occurring during the management of Crohns disease
parenteral refeeding (31). Marik et al. dened refeeding
syndrome as a fall in phosphate levels by more than
0.16 mmol/l to below 0.65 mmol/l (40). Refeeding Table 4 Guidelines for the prevention of refeeding syndrome
syndrome is not uncommon and severe hypophospha- Refeeding syndrome should be considered as a potential complication in
taemia (o0.35 mmol/l) has been reported in 0.8% of all any patient recovering from a period of sub-optimal nutrition.
hospitalized adult patients (41). The greatest caution is required during the rst week after commencing
nutritional support (50)
Starvation for as little as 48 h may predispose to
refeeding syndrome, with a low serum pre-albumin level (A) Monitoring
Before initiating refeeding by any route, and during the rst 35 days
(o110 g/l) predicting hypophosphataemia (40). Marik of feeding, careful assessment of the following is required
et al. showed that 81% (17/21) of patients developing 1. Hydration and nutritional state (15)
refeeding syndrome had a pre-albumin level of less than Early weight gain may be secondary to uid retention (50)
2. Serum electrolytes (15,31)
110 g/l; yet similar levels were also found in 30% of Initial glucose and albumin (pre-albumin)
patients who did not develop refeeding syndrome. Not Daily sodium, potassium, urea, creatinine, phosphate, Mg and calcium
all malnourished patients without mineral supplementa- 3. Cardiac status (15)
Pulse (compensatory tachycardia), ECG 7 Echo
tion develop the classic electrolyte and uid shifts, or
their consequences, during refeeding (31). The reasons (B) Oral feeding regimen
1. Initial volume and calories (32)
for this are not clear. In more severe cases an initial starting volume of 75% of total daily
Initial reports of refeeding syndrome were made requirements has been used
following the refeeding of adult survivors of concentra- o7 years oldF80100 kcal/kg/day
710 yearsF75 kcal/kg/day
tion camps in 1945 (42). Oral feeding of starved victims 1114 yearsF60 kcal/kg/day
resulted in cardiac insuciency and neurological com- 1518 yearsF50 kcal/kg/day
plications such as coma and convulsions. The syndrome If the initial food challenge is tolerated, this may be increased over 35
days (31,51). Each requirement should be tailored to an individuals
was also seen in refeeding of healthy volunteers who had need and the above values may need to be adjusted by as much as
undergone starvation for 6 months (43). In the 1970s, 30%. Frequent small feeds are recommended (32)
the refeeding syndrome was reported following the Feeds should provide minimum of 1 kcal/ ml to minimize volume
overload.
introduction of TPN (31). Silvis et al. reported a patient 2. Protein
with Crohns disease treated with TPN developing If a milk-based feed induces diarrhoea with positive faecal reducing
neurological complications of the refeeding syndrome substances, a hydrolysate may be used
An initial regimen for malnourished children suggests 0.61 g/kg/day
that included paresthesiae, weakness and seizures (44). (15).
Our patient clearly had aggressive Crohns disease. The feed should be rich in essential amino acids and gradually
The dramatic weight loss, although not unusual per se at increased as an intake of 1.21.5 g/kg/ day is needed for anabolism to
occur (32, 50)
rst presentation, had occurred over a matter of weeks, 3. Supplements
and not months. As a result of this severe disease, NaF1 mmol/kg/day, KF4 mmol/kg/day, MgF0.6 mmol/kg/day (32)
nutritional stores had been depleted more rapidly than Phosphate up to 1 mmol/ kg/ day intravenously and oral supplements
up to 100 mmol/ day for children over 5 years of age. Hypocalcaemia
normal. The constellation of active inammation, may occur during phosphate supplementation (52)
malabsorption and profound anorexia thus led to this Thiamine (53), folic acid, riboavin, ascorbic acid, pyridoxine, as well
episode of refeeding syndrome during conventional as the fat-soluble vitamins A, D, E and K should be supplemented.
Trace elements, including Selenium, may also be decient (32)
treatment with enteral nutrition.
CLINICAL NUTRITION 519

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Submission date: 4 February 2002 Accepted: 9 July 2002