Refeeding Syndrome: Recognition Is the Key to Prevention and Management

RESEARCH Practical Solutions

Refeeding Syndrome: Recognition Is the Key to Prevention and Management JONATHAN TRESLEY; PATRICIA M. SHEEAN, PhD, RD

R

efeeding syndrome is a life-threatening constellation of cardiovascular, pulmonary, hepatic, renal, neuromuscular, metabolic, and hematological abnormalities following inappropriate alimentary resuscitation in severely malnourished or starved individuals. Clinical observations of refeeding syndrome were originally described and reported around the time of World War II when prisoners of war and semi-starved war protestors experienced cardiac failure following nutrition repletion (1,2). Today, anorexia nervosa is one of the more frequent clinical presentations at risk of refeeding syndrome; however, malnourished elderly patients, oncology patients receiving chemotherapy, and postoperative patients may also be at risk. Recognizing individuals prone to refeeding syndrome and understanding the compensatory physiologic mechanisms and resulting nutritional implications are crucial to avoiding the morbidity and mortality associated with this phenomenon. PATHOPHYSIOLOGY OF STARVATION Within the first 24 to 72 hours of fasting, blood glucose levels begin to decline. Insulin concentrations decrease while glucagon levels increase, resulting in mobilization of glucose stores primarily from glycogen. Because of the lack of glucose-6-phosphatase and Glut-2 transporters, skeletal muscle glycogen can only supply glucose to the myocytes, whereas liver glycogen is catabolized and provides glucose for the entire body (3). This initial change aids in the supply of glucose for glucose-dependent tissues (eg, brain, renal medulla, and red blood cells) (4). However, after 72 hours of starvation, when glycogen stores from the liver and the skeletal muscle are fully and partial depleted, respectively, glucose synthesis occurs predominantly from lipid and protein breakdown products (5). Specifically, release of large quantities of fatty

J. Tresley is a medical student, Feinberg School of Medicine, and P. M. Sheean is an instructor, Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL. Address correspondence to: Patricia M. Sheean, PhD, RD, Department of Preventive Medicine, Northwestern University, Feinberg School of Medicine, Suite 1102 [D335], 680 North Lake Shore Drive, Chicago, IL 606114402. E-mail: [email protected] Manuscript accepted: June 25, 2008. Copyright © 2008 by the American Dietetic Association. 0002-8223/08/10812-0016$34.00/0 doi: 10.1016/j.jada.2008.09.015

© 2008 by the American Dietetic Association

acids and glycerol from adipose tissue and amino acids from skeletal muscle are observed. Hepatic fatty acid ␤-oxidation results in the formation of ketone bodies (acetoacetate, ␤-hydroxybutyrate and acetone) which can be reconverted to acetyl-coenzyme A to produce energy via the Krebs cycle. Energy in the form of glucose is also synthesized from endogenous glycerol, the gluconeogenic amino acids (primarily alanine and glutamine) and lactate and pyruvate produced by glycolysis via the Cori cycle (5). Overall, this adaptation to altered sources of energy can result in profound fat and muscle wasting, in addition to total body depletion of electrolytes, magnesium, potassium, and phosphate. PATHOPHYSIOLOGY OF REFEEDING SYNDROME AND CLINICAL MANIFESTATIONS Clinical manifestations of refeeding syndrome predominate when carbohydrate is reintroduced. The sudden swing from fat and protein catabolism to carbohydrate metabolism stimulates a catastrophic increase in insulin production. This increase in insulin secretion results in intracellular shifts of glucose with obligatory cellular uptakes of phosphate, magnesium, and potassium. In addition, this sudden introduction of carbohydrate can reduce water and sodium excretion, resulting in expansion of the extracellular fluid compartment and fluid overload, pulmonary edema and/or cardiac decompensation (5). Several additional clinical features may also be observed during this time, including hypophosphatemia, hypokalemia, hypomagnesemia, hyperglycemia, and thiamin deficiency. Hypophosphatemia (eg, serum phosphorus concentration ⬍1.0 to 1.5 mg/dL [0.3 to 0.5 mmol/L]), a characteristic feature of refeeding syndrome, can lead to cardiac arrhythmias, respiratory failure, rhabdomyolysis, and confusion (6-13). Severe hypokalemia (eg, serum potassium concentration ⬍2.5 mEq/L [⬍2.5 mmol/L]) can result in paralysis, respiratory compromise, rhabdomyolysis, muscle necrosis, and changes in myocardial contraction and signal conduction. Moderate to severe hypomagnesemia (eg, serum magnesium concentration ⬍1.0 mg/dL [⬍0.5 mmol/L]) can produce electrocardiographic changes, tetany, convulsions, and seizures (4). Depending on the route and rate of carbohydrate infusion, hyperglycemia from insufficient insulin secretion may also result. Finally, water-soluble vitamin deficiencies may be present because of depleted stores from prolonged, inadequate intake. In the face of carbohydrate refeeding, Wernicke’s encephalopathy, characterized by mental status changes, ocular dysfunction, and gait ataxia, is most often identified due to inadequate thiamin reserves and thiamin’s role as a cofactor in carbohydrate metabolism

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(5,14,15). Together these acute metabolic changes can lead to a variety of adverse clinical scenarios, including death (14,15). IDENTIFYING RISK FACTORS FOR REFEEDING SYNDROME It is generally believed that the most important factor in managing refeeding syndrome is prevention and, therefore, identification of patients who are at risk (4,6,8,16-18). Individuals who are aggressively fed orally, enterally, or parenterally after chronically poor nutritional intake for any reason are most likely to exhibit the signs and symptoms of refeeding syndrome. As a general rule, patients with weight loss of ⱖ10% within a 2- to 3-month period (eg, prolonged fasting, rapid weight loss after bariatric surgery, prolonged intravenous fluid use) or individuals who are ⬍70% of ideal body weight (eg, cancer patients, the elderly, third-world populations) are at greatest risk for refeeding syndrome (6,8,17). Optimal treatment generally includes a conservative approach to nutritional repletion, although no one technique has been reported to be superior. The clinical mantra of “start low and go slow” has been advocated (5). The following case presentation illustrates the importance of recognizing refeeding syndrome and highlights several approaches to treatment. Patient Profile CK is a previously healthy 15-year-old white male high school sophomore student with a history of an intentional 50 kg (110 lb) weight loss from June 2006 (102.7 kg [226 lb]) to July 2007 (52.7 kg [116 lb]). The majority of weight loss occurred from January 2007 to July 2007 as a result of excessive exercise (3-4 hours per day) and severe dietary restriction (self-reported 500 kcal/day), after his primary medical doctor encouraged him to lose weight. He denied laxative use, emesis, or eating sweets, pasta, or rice for 7 months and was obtaining weight-loss ideas from the Internet. He reported consuming carrots and apples for lunch and frozen dinners in the evenings. CK visited his pediatrician in June 2007, at which time he was instructed to maintain a 3,000-calorie diet to gain weight. CK attempted to adhere to this recommendation 1 week prior to his follow-up appointment with this pediatrician in July 2007. Upon follow-up, CK was found to have abnormal vital signs and was sent to an outside hospital emergency department. On presentation, his vital signs were notable for a temperature of 33.9°C (93.0°F), heart rate of 46 beats per minute, and blood pressure of 83/53 mm Hg. His physical exam noted a soft-spoken, interactive male with severe wasting, sunken eyes, bradycardia, muffled heart sounds, cool lower extremities with 1⫹ nonpitting edema, and dry, taut skin on his face and hands. To appreciate his cardiac exam, CK was asked to fold his arms across his chest to avoid protuberance of his spine and scapulas to allow the stethoscope to lay flat on his back. On admission, serum phosphate and serum magnesium were 3.7 mg/dL (1.2 mmol/L) and 2.5 mg/dL (1.0 mmol/L), respectively, with declines to 2.7 mg/dL (0.9 mmol/L) and 2.2 mg/dL (0.9 mmol/L), respectively, 8 hours later. CK was transferred to a pediatric hospital for admission secondary to an-

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Table 1. Anthropometric data and estimated macronutrient needs for a 15-year-old patient admitted with disordered eating patterns related to self-restriction and excessive exercise

Height Admission body weight Usual body weight Body mass indexa IBWb Estimated energy needsde Estimated protein needsdf Estimated fluid needsg

Value

Percentile

172 cm (68 in) 54.2 kg (118 lb) 102.7 kg (226 lb) 18.31 59.1 kg (130 lb) 2,935 kcal/day 73-110 g/day 3,700 cc/day

50-75 25-50 ⬎95 10-25 91% IBWc

a

Calculated as kg/m2. IBW⫽ideal body weight. Height in inches/39.372⫻2.205⫻20.1⫻6.35/14. c % IBW⫽actual body weight/IBW⫻100. d Adapted from the Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine, National Academies (25). e Estimated energy requirement (kcal/day)⫽88.5⫺[61.9⫻age (years)]⫹physical activity coefficient⫻[(26.7⫻weight (kg)⫹(903⫻height (m)]⫹25. f Representing 10% to 15% of total energy or 1.4 to 2.0 g pro/kg/day. g Represents total water from food, beverages, and drinking water (26). b

orexia nervosa, hypothermia, sinus bradycardia, hypotension, sick euthyroid syndrome, and to rule out refeeding syndrome. It was evident that CK had disordered eating patterns (Nutrition Behavior-Environmental Domain 1.5) related to self-restriction and excessive exercise as evidenced by his physical exam and biochemical abnormalities. His mother reported that the entire family struggles with overweight and that they “did not want to admit that their son had a problem.” Anthropometric data are presented in Table 1, with sequential laboratory findings from his in-patient admission presented in Table 2. Serum electrolytes including phosphate, magnesium, potassium, and calcium along with body weight were recorded daily. Heart sounds were monitored throughout the day by intermittent physical exams and the patient was monitored by telemetry. Intervention Laboratory abnormalities were corrected, fluids were restricted to 1 L/day and calories were initiated slowly. It was estimated that ⬃2,900 kcal were required daily for growth and weight repletion; however, the patient was advised to consume approximately half of his total calorie needs initially to prevent refeeding syndrome. A diabetictype diet was ordered to provide consistent carbohydrates with three meals (90 g carbohydrate each) and two snacks (30 g carbohydrate each) per day. No vitamin supplements were given and no sodium restrictions were ordered. After the patient’s first nutrition consultation, he expressed full understanding of the goals of his treatment. However, he became preoccupied with counting grams of carbohydrates per meal and grew worried that he would gain fat as opposed to muscle mass, spending ⬎2 hours with his menus each day. Psychiatry was consulted and CK was diagnosed with Axis I: anorexia nervosa⫺restricting type and Axis II: positive for obses-

Table 2. Daily hospital laboratory values, body weights, and average blood pressures from admission (day 1) to discharge (day 9) for a 15-year-old patient at risk for refeeding syndrome Value (reference range)

Day 1

Day 2

Day 3

Sodium (136-146 mEq/L) Potassium (3.5-5.0 mEq/L) Chloride (98-106 mEq/L) Bicarbonate (22-29 mEq/L) BUN (7-18 mg/dL)a Creatinine (0.5-1.0 mg/dL)b Phosphorus (2.9-5.4 mg/dL)c Magnesium (1.5-2.3 mg/dL)e Ionized calcium (4.80-4.92 mg/dL)f Glucose (70-105 mg/dL)g Weight (kg) Mean daily systolic blood pressure (⬍113 mm Hg)h Mean daily diastolic blood pressure (⬍64 mm Hg)h

137 5.4 101 28 35 0.9 3.7 2.5

136 3.6 103 27 30 0.9 2.7 2.2

79 54.2 80 40

52.4 103 59

139 3.9 103 31 26 0.8 2.1d 2.1 5.2 56 51.2 107 57

Day 4 4.0 18 3.2 2.1 5.0 50.3 106 62

Day 5

Day 6

Day 7

Day 8

Day 9

138 4.0 100 31 23 0.8 3.7 1.9 5.32 76 50.3 105 64

137 3.7 102 28 18 0.7 3.2 1.9

136 3.8 102 28 23 0.7 3.8 1.9 5.28 78 51.8 112 70

139 4.6 105 29 17 0.6 3.7 2.0 5.4 84 51.9 114 62

138 4.2 102 29 16 0.5 3.6 2.1 5.4 74 52.1 112 57⬎

50.6 107 64

a

BUN⫽blood urea nitrogen. To convert mg/dL BUN to mmol/L, multiply mg/dL by 0.357. To convert mmol/L BUN to mg/dL, multiply mmol/L by 2.8. BUN of 11.2 mg/dL⫽4.00 mmol/L. Cr⫽creatinine. To convert mg/dL Cr to ␮mol/L, multiply mg/dL by 88.4. To convert ␮mol/L Cr to mg/dL, multiply ␮mol/L by 0.01. Cr of 0.5 mg/dL⫽44.2 ␮mol/L. Phos⫽phosphorus. To convert mg/dL Phos to mmol/L, multiply mg/dL by 0.323. To convert mmol/L Phos to mg/dL, multiply mmol/L by 3.1. Phos of 3.2 mg/dL⫽1.03 mmol/L. d Because serum phosphorus levels were trending downward, a PM level was ordered and was 1.9 mg/dL (0.61 mmol/L); intravenous K-phos was supplemented. e Mg⫽magnesium. To convert mg/dL Mg to mmol/L, multiply mg/dL by 0.411. To convert mmol/L Mg to mg/dL, multiply mmol/L by 2.4. Mg of 2.0 mg/dL⫽0.82 mmol/L. f iCa⫽ionized calcium. To convert mg/dL iCa to mmol/L, multiply mg/dL by 0.250. To convert mmol/L iCa to mg/dL, multiply mmol/L by 4.0. iCa of 5.0 mg/dL⫽1.25 mmol/L. g Glu⫽glucose. To convert mg/dL Glu to mmol/L, multiply mg/dL by 0.0555. To convert mmol/L Glu to mg/dL, multiply mmol/L by 18.0. Glu of 108 mg/dL⫽6.0 mmol/L. h Adapted from the fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents (27). b c

sive compulsive personality disorder traits. He was restricted to only 20 minutes per menu. During his hospitalization, CK received regular consultations with registered dietitians, psychiatrists, and pastoral care, revealing the desire “to do everything right.” In addition, oral supplements providing 1 kcal/cc were initiated on day 4 to provide an additional 250 kcal/day with instructions to continue consumption for weight repletion after discharge (eg, two cans per day for an additional 500 kcal/day.) A 500-mg phosphorus supplement was given initially four times daily and gradually decreased to 250 mg three times daily, pending normal serum phosphate levels. Caloric intake was increased gradually throughout hospitalization with a goal of 200-g weight gain per day. No gastrointestinal side effects were noted upon refeeding. Initially, CK expressed concern about not returning home immediately after discharge, but the importance of enrolling in an outpatient hospitalization program for continued therapy was impressed upon him. The patient was transferred 8 days after admission to an outpatient hospitalization eating disorder program. DISCUSSION The incidence of refeeding syndrome is not known and is likely recognized after its occurrence when morbid alterations have occurred and reactive treatment has begun. Once a patient presents with refeeding syndrome, standard of care mandates immediate admission, cautious resuscitation of intravascular volume and correction of blood electrolytes, particularly phosphorus due to the potential to cause respiratory compromise or respiratory failure (4,6-8,17,19). Feeding must then be initiated slowly and increased gradually (19-21). Currently, it is

advised to begin feeding at 20 kcal/kg/day or about half of estimated needs with 1.0 to 1.5 g/kg/day protein and careful attention to correction of electrolyte abnormalities (4,6-8,16-20,22-24). A low-sodium diet and fluid restriction of 1 L/day may also help to prevent fluid overload (6,17,19,20). To detect fluid overload, daily weights, heart rate, and rhythm should be monitored. Once electrolytes are stable, it is appropriate to advance feeding by 200 to 250 kcal every 2 to 3 days, pending stable blood electrolytes. However, weight gain of more than 2 to 3 lb/week is indicative of fluid retention (8,17,18) and all of these clinical guidelines must be tailored to the individual case. CK experienced relatively favorable outcomes because of the timely recognition of risk factors for and early symptoms of refeeding syndrome. His initial oral diet could have cautiously provided fewer calories; however, variety and availability were emphasized in light of his reluctance to eat. In addition, his management could have been enhanced by the inclusion of a standard multivitamin or perhaps repletion levels of the B vitamins in particular, because multiple B-vitamin deficiencies were likely based on limited body stores and previous insufficient oral intake. Because his physical exam findings did not reveal the dermatologic, neurologic, hematologic, or oral changes that often accompany B-vitamin deficiencies, laboratory tests were not explored. Regardless, unlike previous case reports of refeeding syndrome, this case exemplifies the vitality of recognizing the dangers of inappropriately refeeding a chronically malnourished individual. In addition, this case reiterates that refeeding syndrome is a complex series of potentially negative sequelae that necessitate more than phosphorus repletion. Educating clinical professionals involved in patient care is paramount to prevention.

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14. Berg JM, Tymoczko JL, Stryer L. Biochemistry. New York, NY: WH Freeman and Company; 2002. 15. Ladage E. Refeeding syndrome. ORL Head Neck Nurs. 2003;21:18-20. 16. Dunn RL, Stettler N, Mascarenhas MR. Refeeding syndrome in hospitalized pediatric patients. Nutr Clin Pract. 2003;18:327-332. 17. Bermudez O, Beightol S. Questions and answers: What is refeeding syndrome. Eat Disord. 2004;12:251-256. 18. Mehler PS, Crews CK. Refeeding the patient with anorexia nervosa. Eat Disord. 2001;9:167-171. 19. Huang YL, Fang CT, Tseng MC, Lee YJ, Lee MB. Life-threatening refeeding syndrome in a severely malnourished anorexia nervosa patient. J Formos Med Assoc. 2001;100:343-346. 20. Melchior JC. From malnutrition to refeeding during anorexia nervosa. Curr Opin Clin Nutr Metab Care. 1998;1:481-485. 21. Golden NH, Meyer W. Nutritional rehabilitation of anorexia nervosa. Goals and dangers. Int J Adolesc Med Health. 2004;16:131-144. 22. Brooks MJ, Melnik G. The refeeding syndrome: An approach to understanding its complications and preventing its occurrence. Pharmacotherapy. 1995;15:713-726. 23. Fisher M, Simpser E, Schneider M. Hypophosphatemia secondary to oral refeeding in anorexia nervosa. Int J Eat Disord. 2000;28:181-187. 24. Miller SJ. Death resulting from overzealous total parenteral nutrition: The refeeding syndrome revisited. Nutr Clin Pract. 2008;23:166171. 25. Lucas BL, Feucht S. In: Krausse LM, Escott-Stump S, eds. Krause’s Food, Nutrition and Diet Therapy. 12th ed. St Louis, MO: Saunders Elsevier; 2008;222-245. 26. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for water, potassium, sodium, chloride and sulfate. Washington, DC: National Academies Press; 2004. 27. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(suppl):555-576.