Review articleRefeeding syndrome: Treatment considerations based on collective analysis of literature case reports
Introduction
Refeeding syndrome (RFS) represents a group of clinical symptoms and signs commonly observed in severely malnourished and cachectic patients. Symptoms of RFS occur from fluid and electrolyte imbalances resulting from nutritional supplementation via oral, enteral, or parenteral routes following a period of adaption to a prolonged starvation or malnourishment. Multiple organ systems including cardiac, respiratory, neurologic, and hematologic can be affected and may lead to multisystem organ failure and death in the most severe of cases. The most common cause of death is cardiac arrhythmias (Table 1). The hallmark findings in RFS are fluid and electrolyte dysregulation including hypophosphatemia, hypokalemia, hypomagnesemia, abnormalities in glucose metabolism, vitamin (importantly thiamine), and trace element deficiencies. RFS can be viewed as a spectrum disorder where symptoms range from mild to severe depending on the degree of starvation or malnourishment and the form of management employed.
One of the earliest accounts of RFS was in the 1940s when Brozek and colleagues documented cardiovascular failure in semi-starved patients, after they were abruptly fed a normal diet [1]. After World War II, Schnitker and colleagues documented that following liberation, 21% of chronically starved Japanese prisoners died despite the provision of “adequate diet” that included vitamin supplementation [2]. The term “refeeding syndrome” was coined and brought to attention by Weinsier and Krumdieck in 1981 when they reported the untimely death of two malnourished patients who were fed “overzealously” [3].
The predisposing conditions in patients at risk for developing RFS are listed in Table 2. Nutritional depletion is a common denominator and hallmark finding in patients with RFS. In prolonged starvation (weeks to months), glycogen stores are expended while proteins are conserved for intracellular enzymatic and structural functions, leaving fats as the predominant source of energy. During this time absolute size and volume of cells of the liver, heart, brain, and more importantly muscle decreases probably due to a combination of an energy deficient state, loss of intracellular storage macromolecules such as protein and glycogen, and adaptation to fat metabolism. For example, the brains of anorexia nervosa patients have significantly tropic changes and decreased hippocampal volume [4], [5]. Without replacement, intracellular and extracellular ions including PO43−, K+, Mg2+, and Na+ are lost over time, although their measured concentrations may remain falsely normal mainly because of concurrent loss of total body water that also accompanies malnourishment. Importantly, the falsely normal concentration of these ions is not simply due to excess total body water, since they may occur in normally hydrated individuals or individuals with only mild water retention. Once adaptation has occurred, survival can be effectively sustained for months, the exact duration being variable among individuals and proportional to amount of available fat stores [6]. Sudden introduction of seemingly adequate nutrition during this time can be interpreted by the body as “stressful.” Dormant enzymes are suddenly activated in the context of relative nutrient and cofactor deficiency. This deficiency of micro- and macromolecules is enhanced at the onset of increased enzymatic activity, precipitating signs and symptoms of RFS. The hemodynamic and metabolic sequelae that transpires is described below [6], [7], [8], [9]:
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Hypophosphatemia results from cellular uptake of phosphorus (P) and inorganic phosphates (PO43−) under the influence of insulin for the synthesis of ATP, DNA, RNA, proteins, and 2,3-diphosphoglycerate, and from the increased phosphorylation of glucose. Regulation of cellular function such as leukocyte chemotaxis, phagocytosis, and platelet clot formation requires PO43− and contributes to its depletion. Anabolic processes such as cell membrane formation by phospholipids, and cellular growth and replication by nucleoproteins and nucleic acids, further deplete PO43−. Lack of red cell PO43− leads to hemolysis, anemia, susceptibility to infections, inadequate oxygen delivery to tissues, generalized ischemia, diminished cellular regulation, and growth, which may cause multiple organ failure and death. A pathophysiological diagram is provided (Fig. 1).
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Hyperglycemia results from glucose introduction into a starved system adapted to fat metabolism. Infections become more common as hyperglycemia disrupts neutrophilic function, leading to a functional neutropenic state. Hyperosmosis from hyperglycemia may lead to coma and death.
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Hypomagnesemia results from cellular uptake of magnesium (Mg) after feeding. Mg is essential for many cellular process and all cellular processes involving ATP. Hypomagnesemia is an important mediator of both hypocalcemia and hypokalemia.
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Hypokalemia results from cellular uptake of potassium (K), induced by insulin produced in response to the nutritional load.
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Fluid overload occurs from the sodium (Na) retention effects of hyperglycemia and hyperinsulinemia.
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Vitamin deficiency results from the rapid depletion of vitamins after onset of refeeding due to their role in various biochemical functions. For example, thiamine is necessary for glucose metabolism but its stores are depleted during starvation. Sudden introduction of glucose drives already depleted thiamine stores to a nadir, precipitating Wernicke's encephalopathy and lactic acidosis.
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Trace element deficiency also results from increased enzymatic activity during the anabolic process. For example, the importance of trace elements such as zinc and selenium as functional components of many enzymes involved in DNA/RNA metabolism and oxidative-reduction processes is well known.
Anorexia nervosa is the modern prototypical predisposing condition [10]. Other notable conditions are malabsorptive syndromes [11], [12], cancer [13], chronically uncontrolled diabetes mellitus [14], alcoholism [15], [16], status post surgery [17], and infirmities of advanced age [18] (Table 2) .
The incidence of RFS in severely malnourished patients who are being refed is 48% [19]. It is found in 34% of all ICU patients [20], 9.5% of patients hospitalized for malnutrition from gastrointestinal fistulae [21], and 25% of cancer inpatients [22]. Not all patients at risk will experience symptoms of RFS [23].
Until recently, because of the difficulty in its recognition, the management of RFS was based on clinical experience. Numerous cases have been reported since the syndrome was first recognized. Some authors have provided management recommendations based on the clinical outcomes [24]. Some hospitals and communities have centralized guidelines for managing the malnourished or cachectic patient [25], [26], although they may be intended for regional use and may not have widespread application. They also fail to provide guidelines for vitamin and trace element supplementation, which is part and parcel of managing the malnourished patient. In the absence of guidelines based on a collection of reported clinical cases, we have reviewed English literature case reports and highlighted the appropriate management of patients at risk for developing RFS. We have also illustrated how management of the cachectic patient has evolved over time and provided practical clinical guidelines based on the sum of experience documented in the case reports to supplement the guidelines mentioned above.
Section snippets
Methods and materials
English language case reports of RFS from January 1966 to September 2008 of children and adults were searched using the PubMed database and the following keywords: “refeeding syndrome,” “refeeding complications,” “refeeding case report,” and “refeeding hypophosphatemia.” Cases that did not clearly demonstrate complications as a result of nutritional supplementation were excluded. Fifty-four individual case reports from 36 authors were included in our review ranging from 1969 to 2008. To
Case 1—Pontine myelinolysis as a complication of RFS
A 23-y-old female with a past medical history of anorexia nervosa was found unresponsive in her bed. She had been vomiting for 2 wk, and her presenting signs and symptoms were seizures, hyponatremia, hypokalemia, and alkalemia with a pH of 7.62. She was given parenteral nutrition and her Na levels were corrected from 108 mM/L to 130 mM/L within 12 h. Her neurologic symptoms improved rapidly by 24 h but showed signs of neurologic deterioration. She became confused, ataxic, mute, bedridden, and
Insight from analyses of case reports
Where values were reported, hypophosphatemia was present in 100% (49/49) of cases, a finding consistent with previous discussions of the syndrome. Of the cases reported, anorexia nervosa was the most common predisposing diagnosis for the RFS (21/54; 39%), followed by malabsorptive syndromes (12/54; 22%), dysphagia (7/54; 13%), and alcoholism (7/54; 13%). Females were twice as likely as men (36/54; 67% versus 18/54; 33%) to develop RFS owing in part to the propensity of anorexia nervosa in young
Recommendations based on collective analyses of case reports
Given its non-specific presentation and presumed rarity, diagnosing RFS can be an arduous task for the physician. The reported incidence is likely an underestimate of the true value and thus clinicians must foremost be educated to recognize this syndrome [14]. In case 1, the patient had a clear psychiatric diagnosis of anorexia nervosa. When she became unable to eat, her caretakers wrongfully interpreted it as “refusing to eat,” which effectively delayed her diagnosis and treatment. Severe
Conclusion
RFS remains an important cause of morbidity and mortality in the severely malnourished or cachectic patient and deserves clinical attention. It affects all age groups and the symptoms occur early during refeeding especially with TPN. Despite all the available case reports and adequate advancements in understanding the pathophysiology, symptoms and death from RFS remain high. These symptoms can be successfully prevented and treated easily when recognized in a timely manner. Patients at risk must
References (89)
- et al.
Death resulting from overzealous total parenteral nutrition: the refeeding syndrome revisited
Am J Clin Nutr
(1981) - et al.
Hippocampal volume and cognitive function in anorexia nervosa
Psychiatry Res
(2006) Survival in starvation
Am J Clin Nutr
(1998)- et al.
Cardiac abnormalities in cachectic patients before and during nutritional repletion
Am Heart J
(1978) - et al.
The importance of the refeeding syndrome
Nutrition
(2001) - et al.
Refeeding syndrome with enteral nutrition in children: a case report, literature review and clinical guidelines
Clin Nutr
(2002) - et al.
Refeeding syndrome in patients with gastrointestinal fistula
Nutrition
(2004) - et al.
Acute respiratory failure due to refeeding syndrome and hypophosphatemia induced by hypocaloric enteral nutrition
Nutrition
(2009) Management of severe hypophosphatemia
Nutrition
(2009)- et al.
Potentially life-threatening hypophosphatemia in anorexia nervosa
J Adolesc Health Care
(1983)
Severe hypophosphatemia in children with kwashiorkor is associated with increased mortality
J Pediatr
Gross fragmentation of cardiac myofibrils after therapeutic starvation for obesity
Lancet
Magnesium and phosphorus
Lancet
Clinical and biochemical aspects of thiamine treatment for metabolic acidosis during total parenteral nutrition
Nutrition
Thiamine deficiency and beriberi features in a patient with hyperemesis gravidarum
Nutrition
Anaphylaxis from intravenous thiamine—long forgotten?
Am J Emerg Med
Tricarboxylic acid cycle enzymes following thiamine deficiency
Neurochem Int
Vitamins and trace elements: practical aspects of supplementation
Nutrition
Cardiac arrest and delirium: presentations of the refeeding syndrome in severely malnourished adolescents with anorexia nervosa
J Adolesc Health
Refeeding procedures after 43 days of total fasting
Nutrition
Paresthesias, weakness, seizures, and hypophosphatemia in patients receiving hyperalimentation
Gastroenterology
Phosphate homeostasis and hypophosphatemia
Am J Med
Drastic food restriction; effect on cardiovascular dynamics in normotensive and hypertensive conditions
J Am Med Assoc
A clinical study of malnutrition in Japanese prisoners of war
Ann Intern Med
Relation of trophic changes in the central nervous system, measured by the width of cordical sulci, to the clinical course of anorexia nervosa (II)
Neuro Endocrinol Lett
Starvation in man
N Engl J Med
Forced treatment of patients with anorexia
Curr Opin Psychiatry
Refeeding syndrome in a patient with Crohn's disease
J Clin Gastroenterol
Refeeding syndrome in cancer patients
Int J Clin Pract
Much ado about refeeding
Pract Gastroenterol
Refeeding hypophosphataemia in anorexia nervosa and alcoholism
Br Med J (Clin Res Ed)
Severe hypophosphatemia. Pathophysiologic implications, clinical presentations, and treatment
Medicine (Baltimore)
Preliminary results of the duodenal switch
Obes Surg
Refeeding syndrome
Age Ageing
Malnutrition and total parenteral nutrition: a cohort study to determine the incidence of refeeding syndrome
Rev Gastroenterol Mex
Refeeding hypophosphatemia in critically ill patients in an intensive care unit. A prospective study
Arch Surg
Incidence of re-nourishment syndrome in patients with cancer who receive artificial nutrition treatments
Nutr Hosp
Refeeding syndrome in hospital patients referred for enteral and parenteral nutrition
J Hum Nutr Diet
Nutrition in clinical practice-the refeeding syndrome: illustrative cases and guidelines for prevention and treatment
Eur J Clin Nutr
Re-feeding syndrome
J Laryngol Otol
Central pontine myelinolysis as a complication of refeeding syndrome in a patient with anorexia nervosa
J Neuropsychiatry Clin Neurosci
Refeeding syndrome in early pregnancy. Case report
Minerva Anestesiol
Wernicke's encephalopathy during total parenteral nutrition: observation in one case
JPEN J Parenter Enteral Nutr
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