The Art and Science of Infusion Nursing Sara E. Parli, PharmD Kathryn M. Ruf, PharmD, BCPS Barbara Magnuson, PharmD, BCNSP
Pathophysiology, Treatment, and Prevention of Fluid and Electrolyte Abnormalities During Refeeding Syndrome ABSTRACT Refeeding syndrome may occur after the reintroduction of carbohydrates in chronically malnourished or acutely hypermetabolic patients as a result of a rapid shift to glucose utilization as an energy source. Electrolyte abnormalities of phosphorus, potassium, and magnesium occur, leading to complications of various organ systems, and may result in death. Patients should be screened for risk factors of malnutrition to prevent refeeding syndrome. For those at risk, nutrition should be initiated and slowly advanced toward the patient’s goal over several days. Electrolyte disturbances should be aggressively corrected. Key words: electrolytes, enteral nutrition, hypokalemia, hypomagnesemia, hypophosphatemia, nutritional support, refeeding syndrome, starvation, total parenteral nutrition, water-electrolyte imbalance
R
efeeding syndrome (RS) is a group of complications that occur within 2 to 5 days of the reintroduction of enteral or parenteral nutrition in a starved or severely malnourished person.1 RS may present with neurologic, pulmonary, cardiac, neuromuscular, and/or hematologic Author Affiliations: Department of Pharmacy Services, UK HealthCare, Lexington, Kentucky (Drs Parli and Magnuson); and Department of Pharmacy Services, Jewish Hospital KentuckyOne Health, Louisville, Kentucky (Dr Ruf). Sara E. Parli, PharmD, is a critical care clinical pharmacist at UK HealthCare. She works primarily with the acute general surgery/ trauma team to provide comprehensive pharmaceutical care to patients, including intravenous therapy. She also provides adjunct assistance to the nutrition support service. Kathryn M. Ruf, PharmD, BCPS, is the critical care specialist at Jewish Hospital in Louisville, Kentucky. She has a special interest DOI: 10.1097/NAN.0000000000000038
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complications as a result of multiple metabolic alterations and significant fluid and electrolyte disturbances.2 In a review of case reports and cases series describing patients with RS, Skipper1 found that the complications of refeeding hypophosphatemia are not always consistent. However, hypophosphatemia is considered the hallmark sign of RS.2 The presentation ranges in severity and, in some, may result in death. The recognition of RS dates to the World War II era, when significant complications were observed after victims were restored to normal food and liquid intake after prolonged periods of malnutrition or starvation. Peripheral edema, hypertension, neurologic complications, and cardiac insufficiency were described.3-5 This article aims to describe the pathophysiology of starvation as it relates to RS and its associated electrolyte abnormalities. It will discuss the risk factors for the development of RS in modern clinical practice, as well as the prevention and management of RS, including electrolyte replacement.
PATHOPHYSIOLOGY OF STARVATION During the first 24 to 72 hours of starvation, the body uses glycogen stored by the liver as an energy source via glycogenolysis. During this time, skeletal in nutrition support therapies and has recently completed research focusing on refeeding syndrome in a heterogeneous intensive care unit population. Barbara Magnuson, PharmD, BCNSP, is the coordinator and clinical pharmacist on a multidisciplinary nutrition support service at UK HealthCare that promotes the maintenance or restoration of optimal nutritional therapy for patients, primarily in critical care areas, receiving parenteral and/or enteral nutrition. The authors of this article have no conflicts of interest to disclose. Corresponding Author: Barbara Magnuson, PharmD, BCNSP, Clinical Pharmacist, Nutrition Support, UK HealthCare, Lexington, KY ([email protected]).
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muscles break down to release amino acids for gluconeogenesis to supply necessary glucose to the brain, renal medulla, and red blood cells. After 72 hours, metabolic pathways shift to free fatty acid oxidation to protect skeletal muscles from protein catabolism.2 Adaptive mechanisms occur after prolonged starvation, including decreased liver gluconeogenesis, decreased basal metabolic rate, and increased use of free fatty acids by the brain. Hormonal changes also occur, such as decreased insulin secretion, increased growth hormone secretion, and increased cortisol secretion. Prolonged starvation leads to weight loss, decreased overall total cell mass, and electrolyte abnormalities, such as decreased serum phosphorus, potassium, and magnesium. Serum albumin is also decreased, leading to a reduction in oncotic pressure and increased extracellular water. Cardiac effects are also evident. Decreased cardiac mass and output are observed, as well as reduced total cardiac volume, end diastolic volume, and left ventricular mass.6,7
PATHOPHYSIOLOGY OF RS After prolonged malnutrition or starvation, the provision of parenteral or enteral nutrition support results in a sudden and dramatic shift back to glucose as a primary fuel. An increased demand for phosphorylated intermediates of glycolysis, such as adenosine triphosphate (ATP), results. Insulin levels also increase to drive glucose into cells for use. Increased insulin secretion results in rapid entrance of phosphorus, potassium, and magnesium into cells, exacerbating already-low levels of these electrolytes. Furthermore, insulin exerts an antidiuretic effect, leading to sodium and water retention that result in the expansion of the extracellular water compartment. Fluid overload may lead to pulmonary edema and, ultimately, respiratory failure. Ventricular volume also returns to normal, while left ventricular mass remains reduced. This may cause further fluid retention and exacerbate congestive heart failure.8,9 An essential cofactor for carbohydrate metabolism—thiamine—is also possibly decreased during starvation, and this may worsen during RS. Thiamine stores become quickly depleted with malnutrition, weight loss, alcoholism, malabsorptive syndromes, and chronic vomiting.10 Increased demand for thiamine after the reintroduction of carbohydrates will exacerbate already-low thiamine stores during RS.2 The sequelae and clinical impact of RS have been well described in the literature. A 1997 review by Hernandez-Aranda and colleagues11 described 148 patients with severe malnutrition who received enteral or parental nutrition support for at least 7 days. They found that 48% of patients had symptoms associated with RS; those with RS had a 10-day-longer hospital
length of stay. Furthermore, 15 patients who developed RS died.
ELECTROLYTE ABNORMALITIES ASSOCIATED WITH RS The insulin-driven intracellular movement of phosphorus, potassium, and magnesium that occurs after reintroduction of enteral or parenteral nutrition results in the electrolyte disturbances seen in RS. Hypophosphatemia, hypokalemia, and hypomagnesemia may result in severe clinical effects. Hypophosphatemia Phosphorus, a major intracellular anion, is critical for ATP and 2,3-diphosphoglycerate (2,3-DPG) production. Decreased ATP results in energy failure, while decreased 2,3-DPG increases hemoglobin affinity for oxygen, resulting in decreased oxygen delivery to cells. In an observational series of 19 trauma patients, hypophosphatemia and associated abnormalities were described in which 8 patients were inadvertently given parenteral nutrition without phosphate supplementation. Patients who developed hypophosphatemia were also found to have decreased levels of ATP and 2,3DPG. A significant correlation was observed between total calories administered and a fall in serum phosphorus concentration, as well as between the amount of phosphate administered and the increase in serum phosphorus concentration.12 The average consumption of phosphorus is 1000 to 1400 mg/d. Eighty percent of phosphorus is stored in the skeleton, with the remaining portion found in soft tissue and muscle. Phosphorus is absorbed in the jejunum and is primarily eliminated through the renal system. The normal serum value is 2.5 to 4.5 mg/dL. The degree of hypophosphatemia is correlated with symptoms and may be classified as moderate (1.5-2.2 mg/dL) or severe (less than 1.5 mg/dL).13,14 Physiologic manifestations of hypophosphatemia include neurologic, respiratory, cardiac, and immune function effects. Effects of moderate hypophosphatemia include weakness, confusion, disorientation, and hypotension. Severe hypophosphatemia may lead to seizures, coma, acute respiratory failure as a result of impaired diaphragm contractility, cardiac arrhythmias, increased pulmonary artery wedge pressure, volume overload, and death.7,15 Hypokalemia Potassium, the most abundant intracellular ion, regulates the electrical cellular membrane potential, cellular metabolism, and glycogen and protein synthesis. The average consumption of potassium is 4700 mg/d and is absorbed in the small intestine. Potassium elimination is
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complex and highly regulated at the distal tubule of the nephron.16 The normal serum value of potassium is 3.5 to 5.0 mEq/L. Similar to hypophosphatemia, the degree of hypokalemia is correlated with symptoms and may be classified as moderate (2.5-3.5 mEq/L) or severe (less than 2.5 mEq/L). Effects of moderate hypokalemia include nausea, vomiting, constipation, and weakness. Severe hypokalemia may lead to respiratory failure, rhabdomyolysis and muscle necrosis, electrocardiogram (ECG) changes, cardiac arrhythmias, and paralysis.17,18 Hypomagnesemia Magnesium, the second most abundant intracellular ion, is a cofactor for many biochemical reactions and enzymes and is essential for oxidative phosphorylation. The majority of magnesium is found in the bone; therefore, serum levels reflect neither the body’s total stores nor intracellular stores. Oral magnesium is only about 30% absorbed and is eliminated through the renal system. It also has a laxative effect that will further complicate its absorption in the presence of short bowel syndrome or other malabsorptive syndromes. The normal serum value of magnesium is 1.8 to 2.5 mg/dL. As with hypophosphatemia and hypokalemia, the degree of hypomagnesemia is correlated with symptoms and may be classified as mild to moderate (less than 1.5 mg/ dL) or severe (less than 1.0 mg/dL). Effects of mild to moderate hypomagnesemia include nausea, vomiting, diarrhea, weakness, altered mental status, and muscle twitching or tremor. Severe hypomagnesemia may lead to ECG changes, cardiac arrhythmias (including Torsades de Pointes and ventricular tachycardia), tetany, convulsions, seizures, coma, and death.19 Thiamine Deficiency Thiamine, vitamin B1, is a water-soluble vitamin with a recommended intake of 1.4 mg/d. It is absorbed in the small intestine and eliminated through the renal system. Thiamine deficiency may lead to confusion, ocular disturbance, short-term memory loss, ataxia, coma, and Wernicke’s encephalopathy/Korsakoff’s syndrome. Thiamine is required for the decarboxylation of pyruvate. In patients with thiamine deficiency, pyruvate is converted to lacate, contributing to lactic acidosis.2,10
RISK FACTORS FOR RS Risk factors for the development of RS include obvious protein and calorie malnutrition. Patients with edema and cachexia, body weight 85% less than ideal, anorexia nervosa, chewing or swallowing difficulties, residents admitted from skilled nursing facilities, and those with a history of excessive alcohol intake may be at risk for protein and calorie malnutrition. Patients with
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chronic diseases associated with under-nutrition— including cancer, chronic obstructive pulmonary disease, cirrhosis, poor oral intake seen in patients with headneck tumor or radiation, esophageal tumors or surgery, gastrointestinal fistulas, and high-output ileostomy drainage—are also susceptible to RS. Children with failure to thrive and those with prolonged vomiting or malabsorptive syndromes also should be observed carefully. There are also patients who may be at risk of RS but who may not fit these classically described risk factors. Whereas RS has been well described historically during parenteral nutrition administration, it is also observed during the provision of enteral nutrition.11,20,21 Furthermore, patients who are morbidly obese with recent rapid or massive weight loss, patients after major surgery with a prolonged preoperative starvation, and critically ill patients unable to be fed for 2 to 5 days may also be at increased risk of RS. Consideration also should be given to those with hypermetabolic states, such as patients after multiple-trauma and traumatic brain injury, as well as those with burns or sepsis, because of their increased susceptibility.2,22,23 In a review of 62 surgical and medical intensive care unit (ICU) patients with at least 48 hours of nothing by mouth and no history of malnutrition, 34% demonstrated refeeding hypophosphatemia, with 10% developing a phosphorus level less than 1 mg/dL. Patients who demonstrated refeeding hypophosphatemia were found to have both a prolonged ICU length of stay and duration of mechanical ventilation. Serum prealbumin was the only predictive factor in the development of RS in this population.20 Clinicians must adequately identify patients at risk of RS and recognize the magnitude of the risk. Although traditional risk factors associated with known malnutrition may contribute, many other factors, including those specific to critically ill patients, may be important as well. Failure to identify risk factors may result in failure to prevent or even recognize RS.
PREVENTION AND MANAGEMENT OF RS The key to the management of RS is to prevent it. Once a patient with risk for the development of RS is identified, nutrition should be escalated slowly, and overfeeding must be avoided. The American Society of Parenteral and Enteral Nutrition (A.S.P.E.N.) guidelines recommend identifying patients at risk for RS and initiating nutrition support at 25% of the estimated goal.22,24 Therefore, initial nutrition support should provide only the minimal needs to prevent overfeeding. The minimum requirement of carbohydrates—for instance, 100 to 150 g/d for a 70-kg male—should be supplied. Carbohydrate administration will suppress gluconeogenesis, spare
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protein catabolism, and supply energy to the central nervous system.25,26 Protein should be provided on the basis of individual requirements, typically 1.5 g/kg/d or 2.0 g/kg/d, if the patient is severely underweight. Patients who require increased amounts of protein include those with trauma, head injury, burn, continuous renal replacement therapy (CRRT), hepatic dysfunction and cirrhosis, decubitus ulcers, and skin breakdown. Patients who require decreased amounts of protein include those with renal failure with uremia. Multivitamin and trace elements should be given once a day, along with daily thiamine supplementation. Nutrition should be slowly advanced over 3 to 5 days until the caloric goal is met. If the patient is severely malnourished, nutrition should be increased even more slowly and should be escalated over a 5- to 7-day period. Baseline electrolytes should be assessed and corrected before initiating nutrition support.27 Serum electrolytes and vital signs also should be carefully monitored after nutrition support is started.22,24
ELECTROLYTE REPLACEMENT Careful monitoring of key electrolytes, including phosphorus, potassium, and magnesium, is required for patients at risk of RS. Electrolyte abnormalities should be corrected before the initiation of nutrition support in patients at risk of RS. Both parenteral and enteral options are available for replacement regimens; however, special consideration must be given to the severity of the electrolyte disturbance when selecting a replacement regimen. Enteral replacement for mild or asymptomatic hypophosphatemia is reasonable. (See Table 1 for available enteral products.) Phosphorus tablets or powder packets can be given by mouth or through a feeding tube. However, enteral phosphorus products may cause an osmotic laxative effect in critically ill patients, which may worsen hypophosphatemia. Parenteral replacement is most effective for severe or symptomatic hypophosphatemia. (See Table 1 for parenteral phosphorus products.) Intravenous (IV) phosphorus products are available as either potassium or sodium salts. The choice of product should be considered carefully; a patient will receive 4.4 mEq of potassium for every 3 mmol of phosphorus delivered if the potassium salt is selected. The compatibilities of the specific formulation should also be checked before administration. The rate of potassium salt administration depends on the ability to monitor the patient and must account for potassium concentrations. Slower infusion time is required for non-ICU patient-monitoring areas. Central IV access is preferred.28 The combination of enteral and parenteral phosphorus may be given to allow for a faster phosphorus
TABLE 1
Enteral and Parenteral Phosphorus Replacement P (mmol)
Na+ (mEq)
K+ (mEq)
Skim milk per 8 oz (1 cup)
8
3
5
Potassium phosphate and sodium phosphate (K-Phos Neutral) tablet
8
13
1.1
Sodium phosphate (Fleet enema) solution per milliliter
4.15
4.82
0
Potassium phosphate (mL)
3
0
4.4
Sodium phosphate (mL)
3
4
0
Product Oral
Parenteral
3 mmol = 93 mg phosphorus (MW = 31) Abbreviations: P, phosphorus; Na+, sodium; K+, potassium; MW, molecular weight.
correction. The standard amount of phosphorus replaced depends on the serum level; however, weightbased replacement has also been evaluated.29 (Table 2 describes the treatment algorithm that was evaluated by Brown and colleagues.29) When this protocol was used, phosphorus levels were improved by day 2 and were within normal limits by day 3. Phosphorus should be rechecked 2 to 4 hours after each dose, and supplementation should be continued until the patient is asymptomatic and phosphorus is within normal limits. If the
TABLE 2
Weight-Based Phosphorus Replacement Phosphorus Level
Replacement Regimen
Mild 2.3-3 mg/dL
0.32 mmoL/kga
Moderate 1.6-2.2 mg/dL
0.64 mmoL/kga
Severe 1.5 mg/dL
1 mmoL/kga
Actual body weight, if ≤ 130% of ideal body weight (IBW). Adjust body weight if > 130% IBW. Adjusted body weight = [IBW + 0.25 (actual body weight − IBW)]. a
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patient is at risk for RS, phosphorus should be checked daily for the first week of nutrition support. Enteral supplementation for mild or asymptomatic hypokalemia is preferred. Although enteral potassium supplementation is safe and well absorbed, it is very irritating to the stomach and gastrointestinal tract and may cause severe cramping. For this reason, it’s recommended that enteral supplementation be taken with food and 4 to 6 ounces of water or juice. Enteral potassium products may cause an osmotic laxative effect in critically ill patients, which may cause difficulty in the correction of other electrolyte disorders. Parenteral replacement is preferred for severe or symptomatic hypokalemia. (See Table 3 for an example of a potassium replacement algorithm.) Special consideration must be given to patients with renal dysfunction because of potassium’s renal elimination. Generally, the replacement requirement for a patient with renal dysfunction is about half of that for a patient with normal renal function. An important exception would be patients requiring CRRT. Potassium is removed by varying degrees depending on the dialysis modality and will affect the amount required to correct a potassium deficit. The rate of administration and concentration depends on IV access type. Administration using peripheral lines should not exceed 10 mEq/h at a concentration of 40 to 80 mEq/L. When using central lines, the rate may be increased to a maximum of 40 mEq/h at a maximum concentration of 80 to 120 mEq/L. Potassium should never be given undiluted or as IV push in adult patients. The IV site should be monitored for possible extravasation and ECG may be required, especially if potassium is less than 2.5 mEq/L. Potassium should be rechecked 1 to 4 hours after dose, and supplementation should be continued until the patient is asymptomatic and potassium is within normal limits. If the patient is at risk for RS, potassium should be checked daily for the first week of nutrition support.
Unlike with hypophosphatemia and hypokalemia management, parenteral supplementation for hypomagnesemia is the preferred route for magnesium supplementation. Enteral magnesium oxide is available; however, it has a slow onset of action and poor absorption, with a laxative effect that may cause difficulty in the correction of other electrolyte disorders. Renal elimination is rapid, with about 50% of the magnesium dose excreted quickly. Rapid administration rates may simply increase urinary excretion of magnesium; therefore, total repletion may take several days. Magnesium has a slow equilibrium time between serum, intracellular space, and tissues.30 For nonemergent hypomagnesemia, 6 g of magnesium sulfate should be administered over 6 to 12 hours, with a maximum administration rate of 1 g over 1 hour. For severe symptomatic hypomagnesemia, aggressive dosing may be required in the acute care setting. Administration of 1 g over 30 minutes is preferred. However, the minimum infusion time in a monitored critical care setting is 7 minutes, as compared with 10 minutes for patients outside of this setting.31 Magnesium should be rechecked 12 to 24 hours after dose, and supplementation should be continued until the patient is asymptomatic and magnesium is within normal limits. If the patient is at risk for RS, magnesium should be checked daily for the first week of nutrition support. Parenteral supplementation is recommended for thiamine deficiency, followed by enteral supplementation until resolution of symptoms. Thiamine should be replaced before or while initiating nutrition support containing dextrose. Delaying thiamine replacement until initiation of nutrition support may increase the metabolic demand for thiamine and worsen the effects of deficiency. Thiamine is administered IV at 50 to 100 mg daily for 7 to 14 days, then is followed by enteral supplementation.2,10
CONCLUSION TABLE 3
Potassium Replacement Algorithm Replacement (Oral or IV)a
Potassium Mild 4.0 to 3.7 mEq/L
40 mEq
Moderate 3.6 to 3.4 mEq/L
60 mEq
Severe
REFERENCES
< 3.3 mEq/L a
80 mEq
If given orally, give in 2 divided doses.
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Although described as a historical phenomenon, RS is encountered frequently in modern clinical practice, with relatively poor recognition or understanding. Associated with significant morbidity and mortality, it includes abnormalities of electrolytes, fluid balance, and glucose. Its management includes aggressive monitoring and replacement of phosphate, potassium, and magnesium. Identifying patients at risk for RS is key for the implementation of prevention strategies, including methodical and slow reintroduction of both enteral and parenteral nutrition support over several days.
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1. Skipper A. Refeeding syndrome or refeeding hypophosphatemia: a systematic review of cases. Nutr Clin Pract. 2012;27(1):34-40.
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2. Kraft MD, Btaiche IF, Sacks GS. Review of the refeeding syndrome. Nutr Clin Pract. 2005;20(6):625-633. 3. Keys A, Brozek J, Henschel A, Mickelson O, Taylor HD, eds. The Biology of Human Starvation, Vol 1, 2. Minneapolis, MN: University of Minnesota Press; 1950. 4. Schnitker MA, Mattman PE, Bliss TL. A clinical study of malnutrition in Japanese prisoners of war. Ann Intern Med. 1951; 35(1):69-96. 5. Burger GCE, Sandstead HR, Drummond JC. Malnutrition and Starvation in Western Netherlands, September 1944 to July 1945. Part 1, 2. The Hague, Netherlands: General Printing Office; 1948. 6. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med. 1977;137(2):203220. 7. O’Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphatemia on myocardial performance in man. N Engl J Med. 1977;297(17):901-903. 8. DeFronzo RA, Cooke CR, Andres R, Faloona GR, Davis PJ. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest. 1975;55(4):845-855. 9. Guirao X, Franch G, Gil MJ, Garcia-Domingo MI, Girvent M, Sitges-Serra A. Extracellular volume, nutritional status, and refeeding changes. Nutrition. 1994;10(6):558-561. 10. Romanski SA, McMahon MM. Metabolic acidosis and thiamine deficiency. Mayo Clin Proc. 1999;74(3):259-263. 11. Hernandez-Aranda JC, Gallo-Chico B, Luna-Cruz ML, et al. Malnutrition and total parenteral nutrition: a cohort study to determine the incidence of refeeding syndrome. Rev Gastroenterol Mex. 1997;62(4):260-265. 12. Sheldon GF, Grzyb S. Phosphate depletion and repletion: relation to parenteral nutrition and oxygen transport. Ann Surg. 1975;182(6):683-689. 13. Gourley DR. The role of adenosine triphosphate in the transport of phosphate in the human erythrocyte. Arch Biochem Biophys. 1952;40(1):1-12. 14. Prankerd TA, Altman KI. A study of the metabolism of phosphorus in mammalian red cells. Biochem J. 1954;58(4):622-623. 15. Aubier M, Murciano D, Lecocguic Y, et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med. 1985;313(7):420-424. 16. Silva P, Brown RS, Epstein FH. Adaptation to potassium. Kidney Int. 1977;11(6):466-475. 17. Halperin ML, Kamel KS. Potassium. Lancet. 1998;352(9122):135140.
18. Freedman BI, Burkart JM. Endocrine crises. Hypokalemia. Crit Care Clin. 1991;7(1):143-153. 19. Rubiez GJ, Thill-Baharozian M, Hardie D, Carlson RW. Association of hypomagnesemia and mortality in acutely ill medical patients. Crit Care Med. 1993;21(2):203-209. 20. Marik PE, Bedigian MK. Refeeding hypophosphatemia in critically ill patients in an intensive care unit. A prospective study. Arch Surg. 1996;131(10):1043-1047. 21. Malone A, Seres D, Lord L. Complications of enteral nutrition. In: Mueller CM, ed. The A.S.P.E.N. Adult Nutrition Support Core Curriculum. 2nd ed. Silver Spring, MD: A.S.P.E.N.; 2012: 218-233. 22. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Enteral Nutr. 2009;33(3):277-316. 23. Mueller CM. The A.S.P.E.N. Adult Nutrition Support Core Curriculum. 2nd ed. Silver Spring, MD: A.S.P.E.N.; 2012. 24. Bankhead R, Boullata J, Brantley S, et al. Enteral nutrition practice recommendations. J Parenter Enteral Nutr. 2009;33(2):122-167. 25. Cahill GF Jr. Starvation in man. N Engl J Med. 1970;282(12):688675. 26. Miller SJ. Death resulting from overzealous total parenteral nutrition: the refeeding syndrome revisited. Nutr Clin Pract. 2008;23(2):166-171. 27. Lauts NM. Management of the patient with refeeding syndrome. J Infus Nurs. 2005;28(5):337-342. 28. Rosen GH, Boullata JI, O’Rangers EA, Enow NB, Shin B. Intravenous phosphate repletion regimen for critically ill patients with moderate hypophosphatemia. Crit Care Med. 1995;23(7): 1204-1210. 29. Brown KA, Dickerson RN, Morgan LM, Alexander KH, Minard G, Brown RO. A new graduated dosing regimen for phosphorus replacement in patients receiving nutrition support. J Parenter Enteral Nutr. 2006;30(3):209-214. 30. Rio A, Whelan K, Goff L, Reidlinger DP, Smeeton N. Occurrence of refeeding syndrome in adults started on artificial nutrition support: prospective cohort study. BMJ Open. 2013;3(1):1-9. http:// bmjopen.bmj.com/content/3/1/e002173.full.pdf+html. Accessed April 15, 2012. 31. Iannello S, Belfiore F. Hypomagnesemia: a review of pathophysiological, clinical and therapeutical aspects. Panminerva Med. 2001;43(3):177-209.
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Pathophysiology, Treatment, and Prevention of Fluid and Electrolyte Abnormalities During Refeeding Syndrome ABSTRACT Refeeding syndrome may occur after the reintroduction of carbohydrates in chronically malnourished or acutely hypermetabolic patients as a result of a rapid shift to glucose utilization as an energy source. Electrolyte abnormalities of phosphorus, potassium, and magnesium occur, leading to complications of various organ systems, and may result in death. Patients should be screened for risk factors of malnutrition to prevent refeeding syndrome. For those at risk, nutrition should be initiated and slowly advanced toward the patient’s goal over several days. Electrolyte disturbances should be aggressively corrected. Key words: electrolytes, enteral nutrition, hypokalemia, hypomagnesemia, hypophosphatemia, nutritional support, refeeding syndrome, starvation, total parenteral nutrition, water-electrolyte imbalance
R
efeeding syndrome (RS) is a group of complications that occur within 2 to 5 days of the reintroduction of enteral or parenteral nutrition in a starved or severely malnourished person.1 RS may present with neurologic, pulmonary, cardiac, neuromuscular, and/or hematologic Author Affiliations: Department of Pharmacy Services, UK HealthCare, Lexington, Kentucky (Drs Parli and Magnuson); and Department of Pharmacy Services, Jewish Hospital KentuckyOne Health, Louisville, Kentucky (Dr Ruf). Sara E. Parli, PharmD, is a critical care clinical pharmacist at UK HealthCare. She works primarily with the acute general surgery/ trauma team to provide comprehensive pharmaceutical care to patients, including intravenous therapy. She also provides adjunct assistance to the nutrition support service. Kathryn M. Ruf, PharmD, BCPS, is the critical care specialist at Jewish Hospital in Louisville, Kentucky. She has a special interest DOI: 10.1097/NAN.0000000000000038
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complications as a result of multiple metabolic alterations and significant fluid and electrolyte disturbances.2 In a review of case reports and cases series describing patients with RS, Skipper1 found that the complications of refeeding hypophosphatemia are not always consistent. However, hypophosphatemia is considered the hallmark sign of RS.2 The presentation ranges in severity and, in some, may result in death. The recognition of RS dates to the World War II era, when significant complications were observed after victims were restored to normal food and liquid intake after prolonged periods of malnutrition or starvation. Peripheral edema, hypertension, neurologic complications, and cardiac insufficiency were described.3-5 This article aims to describe the pathophysiology of starvation as it relates to RS and its associated electrolyte abnormalities. It will discuss the risk factors for the development of RS in modern clinical practice, as well as the prevention and management of RS, including electrolyte replacement.
PATHOPHYSIOLOGY OF STARVATION During the first 24 to 72 hours of starvation, the body uses glycogen stored by the liver as an energy source via glycogenolysis. During this time, skeletal in nutrition support therapies and has recently completed research focusing on refeeding syndrome in a heterogeneous intensive care unit population. Barbara Magnuson, PharmD, BCNSP, is the coordinator and clinical pharmacist on a multidisciplinary nutrition support service at UK HealthCare that promotes the maintenance or restoration of optimal nutritional therapy for patients, primarily in critical care areas, receiving parenteral and/or enteral nutrition. The authors of this article have no conflicts of interest to disclose. Corresponding Author: Barbara Magnuson, PharmD, BCNSP, Clinical Pharmacist, Nutrition Support, UK HealthCare, Lexington, KY ([email protected]).
NUMBER 3 | MAY/JUNE 2014 Copyright © 2014 Infusion Nurses Society Copyright © 2014 Infusion Nurses Society. Unauthorized reproduction of this article is prohibited.
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muscles break down to release amino acids for gluconeogenesis to supply necessary glucose to the brain, renal medulla, and red blood cells. After 72 hours, metabolic pathways shift to free fatty acid oxidation to protect skeletal muscles from protein catabolism.2 Adaptive mechanisms occur after prolonged starvation, including decreased liver gluconeogenesis, decreased basal metabolic rate, and increased use of free fatty acids by the brain. Hormonal changes also occur, such as decreased insulin secretion, increased growth hormone secretion, and increased cortisol secretion. Prolonged starvation leads to weight loss, decreased overall total cell mass, and electrolyte abnormalities, such as decreased serum phosphorus, potassium, and magnesium. Serum albumin is also decreased, leading to a reduction in oncotic pressure and increased extracellular water. Cardiac effects are also evident. Decreased cardiac mass and output are observed, as well as reduced total cardiac volume, end diastolic volume, and left ventricular mass.6,7
PATHOPHYSIOLOGY OF RS After prolonged malnutrition or starvation, the provision of parenteral or enteral nutrition support results in a sudden and dramatic shift back to glucose as a primary fuel. An increased demand for phosphorylated intermediates of glycolysis, such as adenosine triphosphate (ATP), results. Insulin levels also increase to drive glucose into cells for use. Increased insulin secretion results in rapid entrance of phosphorus, potassium, and magnesium into cells, exacerbating already-low levels of these electrolytes. Furthermore, insulin exerts an antidiuretic effect, leading to sodium and water retention that result in the expansion of the extracellular water compartment. Fluid overload may lead to pulmonary edema and, ultimately, respiratory failure. Ventricular volume also returns to normal, while left ventricular mass remains reduced. This may cause further fluid retention and exacerbate congestive heart failure.8,9 An essential cofactor for carbohydrate metabolism—thiamine—is also possibly decreased during starvation, and this may worsen during RS. Thiamine stores become quickly depleted with malnutrition, weight loss, alcoholism, malabsorptive syndromes, and chronic vomiting.10 Increased demand for thiamine after the reintroduction of carbohydrates will exacerbate already-low thiamine stores during RS.2 The sequelae and clinical impact of RS have been well described in the literature. A 1997 review by Hernandez-Aranda and colleagues11 described 148 patients with severe malnutrition who received enteral or parental nutrition support for at least 7 days. They found that 48% of patients had symptoms associated with RS; those with RS had a 10-day-longer hospital
length of stay. Furthermore, 15 patients who developed RS died.
ELECTROLYTE ABNORMALITIES ASSOCIATED WITH RS The insulin-driven intracellular movement of phosphorus, potassium, and magnesium that occurs after reintroduction of enteral or parenteral nutrition results in the electrolyte disturbances seen in RS. Hypophosphatemia, hypokalemia, and hypomagnesemia may result in severe clinical effects. Hypophosphatemia Phosphorus, a major intracellular anion, is critical for ATP and 2,3-diphosphoglycerate (2,3-DPG) production. Decreased ATP results in energy failure, while decreased 2,3-DPG increases hemoglobin affinity for oxygen, resulting in decreased oxygen delivery to cells. In an observational series of 19 trauma patients, hypophosphatemia and associated abnormalities were described in which 8 patients were inadvertently given parenteral nutrition without phosphate supplementation. Patients who developed hypophosphatemia were also found to have decreased levels of ATP and 2,3DPG. A significant correlation was observed between total calories administered and a fall in serum phosphorus concentration, as well as between the amount of phosphate administered and the increase in serum phosphorus concentration.12 The average consumption of phosphorus is 1000 to 1400 mg/d. Eighty percent of phosphorus is stored in the skeleton, with the remaining portion found in soft tissue and muscle. Phosphorus is absorbed in the jejunum and is primarily eliminated through the renal system. The normal serum value is 2.5 to 4.5 mg/dL. The degree of hypophosphatemia is correlated with symptoms and may be classified as moderate (1.5-2.2 mg/dL) or severe (less than 1.5 mg/dL).13,14 Physiologic manifestations of hypophosphatemia include neurologic, respiratory, cardiac, and immune function effects. Effects of moderate hypophosphatemia include weakness, confusion, disorientation, and hypotension. Severe hypophosphatemia may lead to seizures, coma, acute respiratory failure as a result of impaired diaphragm contractility, cardiac arrhythmias, increased pulmonary artery wedge pressure, volume overload, and death.7,15 Hypokalemia Potassium, the most abundant intracellular ion, regulates the electrical cellular membrane potential, cellular metabolism, and glycogen and protein synthesis. The average consumption of potassium is 4700 mg/d and is absorbed in the small intestine. Potassium elimination is
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complex and highly regulated at the distal tubule of the nephron.16 The normal serum value of potassium is 3.5 to 5.0 mEq/L. Similar to hypophosphatemia, the degree of hypokalemia is correlated with symptoms and may be classified as moderate (2.5-3.5 mEq/L) or severe (less than 2.5 mEq/L). Effects of moderate hypokalemia include nausea, vomiting, constipation, and weakness. Severe hypokalemia may lead to respiratory failure, rhabdomyolysis and muscle necrosis, electrocardiogram (ECG) changes, cardiac arrhythmias, and paralysis.17,18 Hypomagnesemia Magnesium, the second most abundant intracellular ion, is a cofactor for many biochemical reactions and enzymes and is essential for oxidative phosphorylation. The majority of magnesium is found in the bone; therefore, serum levels reflect neither the body’s total stores nor intracellular stores. Oral magnesium is only about 30% absorbed and is eliminated through the renal system. It also has a laxative effect that will further complicate its absorption in the presence of short bowel syndrome or other malabsorptive syndromes. The normal serum value of magnesium is 1.8 to 2.5 mg/dL. As with hypophosphatemia and hypokalemia, the degree of hypomagnesemia is correlated with symptoms and may be classified as mild to moderate (less than 1.5 mg/ dL) or severe (less than 1.0 mg/dL). Effects of mild to moderate hypomagnesemia include nausea, vomiting, diarrhea, weakness, altered mental status, and muscle twitching or tremor. Severe hypomagnesemia may lead to ECG changes, cardiac arrhythmias (including Torsades de Pointes and ventricular tachycardia), tetany, convulsions, seizures, coma, and death.19 Thiamine Deficiency Thiamine, vitamin B1, is a water-soluble vitamin with a recommended intake of 1.4 mg/d. It is absorbed in the small intestine and eliminated through the renal system. Thiamine deficiency may lead to confusion, ocular disturbance, short-term memory loss, ataxia, coma, and Wernicke’s encephalopathy/Korsakoff’s syndrome. Thiamine is required for the decarboxylation of pyruvate. In patients with thiamine deficiency, pyruvate is converted to lacate, contributing to lactic acidosis.2,10
RISK FACTORS FOR RS Risk factors for the development of RS include obvious protein and calorie malnutrition. Patients with edema and cachexia, body weight 85% less than ideal, anorexia nervosa, chewing or swallowing difficulties, residents admitted from skilled nursing facilities, and those with a history of excessive alcohol intake may be at risk for protein and calorie malnutrition. Patients with
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chronic diseases associated with under-nutrition— including cancer, chronic obstructive pulmonary disease, cirrhosis, poor oral intake seen in patients with headneck tumor or radiation, esophageal tumors or surgery, gastrointestinal fistulas, and high-output ileostomy drainage—are also susceptible to RS. Children with failure to thrive and those with prolonged vomiting or malabsorptive syndromes also should be observed carefully. There are also patients who may be at risk of RS but who may not fit these classically described risk factors. Whereas RS has been well described historically during parenteral nutrition administration, it is also observed during the provision of enteral nutrition.11,20,21 Furthermore, patients who are morbidly obese with recent rapid or massive weight loss, patients after major surgery with a prolonged preoperative starvation, and critically ill patients unable to be fed for 2 to 5 days may also be at increased risk of RS. Consideration also should be given to those with hypermetabolic states, such as patients after multiple-trauma and traumatic brain injury, as well as those with burns or sepsis, because of their increased susceptibility.2,22,23 In a review of 62 surgical and medical intensive care unit (ICU) patients with at least 48 hours of nothing by mouth and no history of malnutrition, 34% demonstrated refeeding hypophosphatemia, with 10% developing a phosphorus level less than 1 mg/dL. Patients who demonstrated refeeding hypophosphatemia were found to have both a prolonged ICU length of stay and duration of mechanical ventilation. Serum prealbumin was the only predictive factor in the development of RS in this population.20 Clinicians must adequately identify patients at risk of RS and recognize the magnitude of the risk. Although traditional risk factors associated with known malnutrition may contribute, many other factors, including those specific to critically ill patients, may be important as well. Failure to identify risk factors may result in failure to prevent or even recognize RS.
PREVENTION AND MANAGEMENT OF RS The key to the management of RS is to prevent it. Once a patient with risk for the development of RS is identified, nutrition should be escalated slowly, and overfeeding must be avoided. The American Society of Parenteral and Enteral Nutrition (A.S.P.E.N.) guidelines recommend identifying patients at risk for RS and initiating nutrition support at 25% of the estimated goal.22,24 Therefore, initial nutrition support should provide only the minimal needs to prevent overfeeding. The minimum requirement of carbohydrates—for instance, 100 to 150 g/d for a 70-kg male—should be supplied. Carbohydrate administration will suppress gluconeogenesis, spare
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protein catabolism, and supply energy to the central nervous system.25,26 Protein should be provided on the basis of individual requirements, typically 1.5 g/kg/d or 2.0 g/kg/d, if the patient is severely underweight. Patients who require increased amounts of protein include those with trauma, head injury, burn, continuous renal replacement therapy (CRRT), hepatic dysfunction and cirrhosis, decubitus ulcers, and skin breakdown. Patients who require decreased amounts of protein include those with renal failure with uremia. Multivitamin and trace elements should be given once a day, along with daily thiamine supplementation. Nutrition should be slowly advanced over 3 to 5 days until the caloric goal is met. If the patient is severely malnourished, nutrition should be increased even more slowly and should be escalated over a 5- to 7-day period. Baseline electrolytes should be assessed and corrected before initiating nutrition support.27 Serum electrolytes and vital signs also should be carefully monitored after nutrition support is started.22,24
ELECTROLYTE REPLACEMENT Careful monitoring of key electrolytes, including phosphorus, potassium, and magnesium, is required for patients at risk of RS. Electrolyte abnormalities should be corrected before the initiation of nutrition support in patients at risk of RS. Both parenteral and enteral options are available for replacement regimens; however, special consideration must be given to the severity of the electrolyte disturbance when selecting a replacement regimen. Enteral replacement for mild or asymptomatic hypophosphatemia is reasonable. (See Table 1 for available enteral products.) Phosphorus tablets or powder packets can be given by mouth or through a feeding tube. However, enteral phosphorus products may cause an osmotic laxative effect in critically ill patients, which may worsen hypophosphatemia. Parenteral replacement is most effective for severe or symptomatic hypophosphatemia. (See Table 1 for parenteral phosphorus products.) Intravenous (IV) phosphorus products are available as either potassium or sodium salts. The choice of product should be considered carefully; a patient will receive 4.4 mEq of potassium for every 3 mmol of phosphorus delivered if the potassium salt is selected. The compatibilities of the specific formulation should also be checked before administration. The rate of potassium salt administration depends on the ability to monitor the patient and must account for potassium concentrations. Slower infusion time is required for non-ICU patient-monitoring areas. Central IV access is preferred.28 The combination of enteral and parenteral phosphorus may be given to allow for a faster phosphorus
TABLE 1
Enteral and Parenteral Phosphorus Replacement P (mmol)
Na+ (mEq)
K+ (mEq)
Skim milk per 8 oz (1 cup)
8
3
5
Potassium phosphate and sodium phosphate (K-Phos Neutral) tablet
8
13
1.1
Sodium phosphate (Fleet enema) solution per milliliter
4.15
4.82
0
Potassium phosphate (mL)
3
0
4.4
Sodium phosphate (mL)
3
4
0
Product Oral
Parenteral
3 mmol = 93 mg phosphorus (MW = 31) Abbreviations: P, phosphorus; Na+, sodium; K+, potassium; MW, molecular weight.
correction. The standard amount of phosphorus replaced depends on the serum level; however, weightbased replacement has also been evaluated.29 (Table 2 describes the treatment algorithm that was evaluated by Brown and colleagues.29) When this protocol was used, phosphorus levels were improved by day 2 and were within normal limits by day 3. Phosphorus should be rechecked 2 to 4 hours after each dose, and supplementation should be continued until the patient is asymptomatic and phosphorus is within normal limits. If the
TABLE 2
Weight-Based Phosphorus Replacement Phosphorus Level
Replacement Regimen
Mild 2.3-3 mg/dL
0.32 mmoL/kga
Moderate 1.6-2.2 mg/dL
0.64 mmoL/kga
Severe 1.5 mg/dL
1 mmoL/kga
Actual body weight, if ≤ 130% of ideal body weight (IBW). Adjust body weight if > 130% IBW. Adjusted body weight = [IBW + 0.25 (actual body weight − IBW)]. a
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patient is at risk for RS, phosphorus should be checked daily for the first week of nutrition support. Enteral supplementation for mild or asymptomatic hypokalemia is preferred. Although enteral potassium supplementation is safe and well absorbed, it is very irritating to the stomach and gastrointestinal tract and may cause severe cramping. For this reason, it’s recommended that enteral supplementation be taken with food and 4 to 6 ounces of water or juice. Enteral potassium products may cause an osmotic laxative effect in critically ill patients, which may cause difficulty in the correction of other electrolyte disorders. Parenteral replacement is preferred for severe or symptomatic hypokalemia. (See Table 3 for an example of a potassium replacement algorithm.) Special consideration must be given to patients with renal dysfunction because of potassium’s renal elimination. Generally, the replacement requirement for a patient with renal dysfunction is about half of that for a patient with normal renal function. An important exception would be patients requiring CRRT. Potassium is removed by varying degrees depending on the dialysis modality and will affect the amount required to correct a potassium deficit. The rate of administration and concentration depends on IV access type. Administration using peripheral lines should not exceed 10 mEq/h at a concentration of 40 to 80 mEq/L. When using central lines, the rate may be increased to a maximum of 40 mEq/h at a maximum concentration of 80 to 120 mEq/L. Potassium should never be given undiluted or as IV push in adult patients. The IV site should be monitored for possible extravasation and ECG may be required, especially if potassium is less than 2.5 mEq/L. Potassium should be rechecked 1 to 4 hours after dose, and supplementation should be continued until the patient is asymptomatic and potassium is within normal limits. If the patient is at risk for RS, potassium should be checked daily for the first week of nutrition support.
Unlike with hypophosphatemia and hypokalemia management, parenteral supplementation for hypomagnesemia is the preferred route for magnesium supplementation. Enteral magnesium oxide is available; however, it has a slow onset of action and poor absorption, with a laxative effect that may cause difficulty in the correction of other electrolyte disorders. Renal elimination is rapid, with about 50% of the magnesium dose excreted quickly. Rapid administration rates may simply increase urinary excretion of magnesium; therefore, total repletion may take several days. Magnesium has a slow equilibrium time between serum, intracellular space, and tissues.30 For nonemergent hypomagnesemia, 6 g of magnesium sulfate should be administered over 6 to 12 hours, with a maximum administration rate of 1 g over 1 hour. For severe symptomatic hypomagnesemia, aggressive dosing may be required in the acute care setting. Administration of 1 g over 30 minutes is preferred. However, the minimum infusion time in a monitored critical care setting is 7 minutes, as compared with 10 minutes for patients outside of this setting.31 Magnesium should be rechecked 12 to 24 hours after dose, and supplementation should be continued until the patient is asymptomatic and magnesium is within normal limits. If the patient is at risk for RS, magnesium should be checked daily for the first week of nutrition support. Parenteral supplementation is recommended for thiamine deficiency, followed by enteral supplementation until resolution of symptoms. Thiamine should be replaced before or while initiating nutrition support containing dextrose. Delaying thiamine replacement until initiation of nutrition support may increase the metabolic demand for thiamine and worsen the effects of deficiency. Thiamine is administered IV at 50 to 100 mg daily for 7 to 14 days, then is followed by enteral supplementation.2,10
CONCLUSION TABLE 3
Potassium Replacement Algorithm Replacement (Oral or IV)a
Potassium Mild 4.0 to 3.7 mEq/L
40 mEq
Moderate 3.6 to 3.4 mEq/L
60 mEq
Severe
REFERENCES
< 3.3 mEq/L a
80 mEq
If given orally, give in 2 divided doses.
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Although described as a historical phenomenon, RS is encountered frequently in modern clinical practice, with relatively poor recognition or understanding. Associated with significant morbidity and mortality, it includes abnormalities of electrolytes, fluid balance, and glucose. Its management includes aggressive monitoring and replacement of phosphate, potassium, and magnesium. Identifying patients at risk for RS is key for the implementation of prevention strategies, including methodical and slow reintroduction of both enteral and parenteral nutrition support over several days.
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1. Skipper A. Refeeding syndrome or refeeding hypophosphatemia: a systematic review of cases. Nutr Clin Pract. 2012;27(1):34-40.
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2. Kraft MD, Btaiche IF, Sacks GS. Review of the refeeding syndrome. Nutr Clin Pract. 2005;20(6):625-633. 3. Keys A, Brozek J, Henschel A, Mickelson O, Taylor HD, eds. The Biology of Human Starvation, Vol 1, 2. Minneapolis, MN: University of Minnesota Press; 1950. 4. Schnitker MA, Mattman PE, Bliss TL. A clinical study of malnutrition in Japanese prisoners of war. Ann Intern Med. 1951; 35(1):69-96. 5. Burger GCE, Sandstead HR, Drummond JC. Malnutrition and Starvation in Western Netherlands, September 1944 to July 1945. Part 1, 2. The Hague, Netherlands: General Printing Office; 1948. 6. Knochel JP. The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med. 1977;137(2):203220. 7. O’Connor LR, Wheeler WS, Bethune JE. Effect of hypophosphatemia on myocardial performance in man. N Engl J Med. 1977;297(17):901-903. 8. DeFronzo RA, Cooke CR, Andres R, Faloona GR, Davis PJ. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest. 1975;55(4):845-855. 9. Guirao X, Franch G, Gil MJ, Garcia-Domingo MI, Girvent M, Sitges-Serra A. Extracellular volume, nutritional status, and refeeding changes. Nutrition. 1994;10(6):558-561. 10. Romanski SA, McMahon MM. Metabolic acidosis and thiamine deficiency. Mayo Clin Proc. 1999;74(3):259-263. 11. Hernandez-Aranda JC, Gallo-Chico B, Luna-Cruz ML, et al. Malnutrition and total parenteral nutrition: a cohort study to determine the incidence of refeeding syndrome. Rev Gastroenterol Mex. 1997;62(4):260-265. 12. Sheldon GF, Grzyb S. Phosphate depletion and repletion: relation to parenteral nutrition and oxygen transport. Ann Surg. 1975;182(6):683-689. 13. Gourley DR. The role of adenosine triphosphate in the transport of phosphate in the human erythrocyte. Arch Biochem Biophys. 1952;40(1):1-12. 14. Prankerd TA, Altman KI. A study of the metabolism of phosphorus in mammalian red cells. Biochem J. 1954;58(4):622-623. 15. Aubier M, Murciano D, Lecocguic Y, et al. Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med. 1985;313(7):420-424. 16. Silva P, Brown RS, Epstein FH. Adaptation to potassium. Kidney Int. 1977;11(6):466-475. 17. Halperin ML, Kamel KS. Potassium. Lancet. 1998;352(9122):135140.
18. Freedman BI, Burkart JM. Endocrine crises. Hypokalemia. Crit Care Clin. 1991;7(1):143-153. 19. Rubiez GJ, Thill-Baharozian M, Hardie D, Carlson RW. Association of hypomagnesemia and mortality in acutely ill medical patients. Crit Care Med. 1993;21(2):203-209. 20. Marik PE, Bedigian MK. Refeeding hypophosphatemia in critically ill patients in an intensive care unit. A prospective study. Arch Surg. 1996;131(10):1043-1047. 21. Malone A, Seres D, Lord L. Complications of enteral nutrition. In: Mueller CM, ed. The A.S.P.E.N. Adult Nutrition Support Core Curriculum. 2nd ed. Silver Spring, MD: A.S.P.E.N.; 2012: 218-233. 22. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter Enteral Nutr. 2009;33(3):277-316. 23. Mueller CM. The A.S.P.E.N. Adult Nutrition Support Core Curriculum. 2nd ed. Silver Spring, MD: A.S.P.E.N.; 2012. 24. Bankhead R, Boullata J, Brantley S, et al. Enteral nutrition practice recommendations. J Parenter Enteral Nutr. 2009;33(2):122-167. 25. Cahill GF Jr. Starvation in man. N Engl J Med. 1970;282(12):688675. 26. Miller SJ. Death resulting from overzealous total parenteral nutrition: the refeeding syndrome revisited. Nutr Clin Pract. 2008;23(2):166-171. 27. Lauts NM. Management of the patient with refeeding syndrome. J Infus Nurs. 2005;28(5):337-342. 28. Rosen GH, Boullata JI, O’Rangers EA, Enow NB, Shin B. Intravenous phosphate repletion regimen for critically ill patients with moderate hypophosphatemia. Crit Care Med. 1995;23(7): 1204-1210. 29. Brown KA, Dickerson RN, Morgan LM, Alexander KH, Minard G, Brown RO. A new graduated dosing regimen for phosphorus replacement in patients receiving nutrition support. J Parenter Enteral Nutr. 2006;30(3):209-214. 30. Rio A, Whelan K, Goff L, Reidlinger DP, Smeeton N. Occurrence of refeeding syndrome in adults started on artificial nutrition support: prospective cohort study. BMJ Open. 2013;3(1):1-9. http:// bmjopen.bmj.com/content/3/1/e002173.full.pdf+html. Accessed April 15, 2012. 31. Iannello S, Belfiore F. Hypomagnesemia: a review of pathophysiological, clinical and therapeutical aspects. Panminerva Med. 2001;43(3):177-209.
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