Interventions for Addressing Medical Complications Related to Outpatient Refeeding and Intake Regulation October 14, 2016 St. Joseph Mercy Health System Eating Disorder Conference Allison Laurie, PMHNP-BC

Overview/Objectives Define refeeding syndrome (RFS) Identify patients at risk for RFS Describe the pathophysiology of starvation Identify the main pathophysiologic features/clinical manifestations of RFS Discuss prevention of RFS Identify recommended treatment & standards of care Case review

Background Refeeding is the cornerstone of treatment for patients with anorexia nervosa Essential to prevent serious or even fatal medical complications of starvation Starvation induced cognitive deficits can preclude efficacy of psychotherapies Weight restoration is not without risk for the patient; must be balanced against the potentially fatal complications of the refeeding syndrome. Refeeding the anorexic patient is essential to achieving a successful treatment result. Literature indicates that one cannot effectively treat AN without first restoring body weight. Without adequate fuel, patients may face serious or even fatal medical complications of severe starvation. Additionally, without a concerted refeeding effort, no meaningful psychotherapy can take place, due to starvation induced cognitive deficits. Some literature suggests that the rate of weight gain predict long term outcomes. In a literature review conducted in 2015, pt’s well enough to be treated in Ambulatory settings, faster weight gain (0.43-0.86kg/week) during the first 3-4 weeks of outpatient psychotherapy predicts full remission (both weight and cognitive recovery) at 12 months. (Garber) However, weight restoration may be one of the most challenging and frustrating aspects of the recovery process for patients with AN. Additionally, the process of weight restoration is not without risk for the patient.

Refeeding Syndrome Overview Clinical complications that occur as a result of fluid and electrolyte shifts during nutritional rehabilitation of malnourished patients May result in cardiac arrhythmia, cardiac failure or arrest, hemolytic anemia, delirium, seizures, coma, and sudden death Garber, A. K., Sawyer, S. M., Golden, N. H., Guarda, A. S., Katzman, D. K., Kohn, M. R., Le Grange, D., Madden, S., Whitelaw, M. & Redgrave,  G. W. (2016). A systematic review of approaches to refeeding in patients with anorexia nervosa. International Journal of Eating Disorders.

Risk Factors Directly related to the amount of weight loss during the current episode, and the rate of weight restoration. Patients at <70 percent of IBW, or those who have lost weight most rapidly, are at greatest risk for the syndrome. Inpatient hospitalization recommended if patient has <70 percent of IBW for initial stage of nutritional replenishment. Other risk factors: low phosphate, potassium, or magnesium prior to refeeding; little to no nutritional intake for previous 5 to 10 days. Highest risk within first 2 weeks of refeeding. Risk progressively dissipates over the next few weeks. Mehanna, H. M., Moledina, J., & Travis, J. (2008). Refeeding syndrome: what it is, and how to prevent and treat it. Bmj, 336(7659), 1495-1498.

Pathogenesis of Starvation Starvation/malnutrition Insulin concentrations decrease, glucagon increases Gluconeogenesis, protein and fat catabolism (for glucose synthesis) Weight loss Water, vitamin, and mineral depletion With starvation, levels of glucose begin to fall within 24 to 72 hrs. This results in the release of the peptide hormone glucagon, and a reduction in insulin secretion. The net result of metabolic and hormonal changes in early starvation is that the body switches from using carbohydrate to using fat and protein as the main source of energy, and the basal metabolic rate decreases significantly (as much as 25%). Glucose levels are maintained by glycogenolysis- but glycogen stores rarely last more than 72 hrs. Glucose homeostasis is essential b/c certain tissues, such as brain, erythrocytes, and cells of the renal medulla are obligate glucose users. Demands are met by the process of gluconeogenesis by which non carbohydrate sources are metabolized to glucose. In addition, fatty acid oxidation in liver hepatocytes generates ketone bodies. Further energy production occurs from lactate and pyruvate (the products of glycolysis) as well as amino acids. In summary, metabolic adaptation occurs to ensure survival on fat fuel economy. There is a resultant loss of body fat and protein, and an accompanying depletion of potassium, phosphate and magnesium. Homeostatic mechanisms maintain serum concentrations of these ions at the expense of intracellular stores. Serum levels may remain normal despite a marked reduction in total body levels. During the period of prolonged starvation, several intra cellular minerals become severely depleted. However, serum concentrations of these minerals (including phosphate) may remain normal. This is because these minerals are mainly in the intracellular compartment, which contract during starvation.

Consequences of Starvation Decreased insulin and increased glucagon secretion. Switch from glucose toward ketone bodies as a source of energy. Glycogen stores used BMR decreases Brain adapts to using ketones Atrophy of all organs Reduced lean body mass Abnormal liver function

Refeeding Syndrome The reintroduction of nutrition to a starved or fasted individual results in rapid decline in both gluconeogenesis and anaerobic metabolisms. This is mediated by the rapid increase in serum insulin that occurs on refeeding. Insulin stimulates the movement of extracellular potassium, phosphate, and magnesium to the intracellular compartment. Depleted intracellular stores and a large concentration gradient ensure a rapid fall in the extracellular concentration of these ions. Osmotic neutrality must be maintained, resulting in the retention of sodium and water. Reactivation of carbohydrate-dependent metabolic pathways increases demand for thiamine, a cofactor required for cellular enzymatic reactions. The deficiencies of phosphate, Mag, K and thiamine occur to varying degrees and have different effects in different patients. This explains why RFS is not defined by a clear set of signs and symptoms, but is considered an arbitrary term referring to a wide spectrum of biochemical abnormalities and clinical consequences.

Clinical Manifestations Symptoms of RFS are variable and may be unpredictable. Nausea/vomiting Lethargy Respiratory insufficiency Cardiac failure Hypotension Arrhythmias Delirium Coma Fatality Mehanna, H. M., Moledina, J., & Travis, J. (2008). Refeeding syndrome: what it is, and how to prevent and treat it. Bmj, 336(7659), 1495-1498.

Clinical Manifestations of Electrolyte Abnormalities Associated with RFS Phosphate Potassium Magnesium Sodium Vitamins/Thiamine Mehanna, H. M., Moledina, J., & Travis, J. (2008). Refeeding syndrome: what it is, and how to prevent and treat it. Bmj, 336(7659), 1495-1498.

Phosphate Pathogenesis: Begins with depletion of stores during starvation Upon intake of glucose with refeeding, release of insulin triggers cellular uptake of phosphate Insulin additionally causes cells to produce a variety of depleted molecules that require phosphate (ATP), which further deplete body’s stores of phosphate. Lack of phosphate results in tissue hypoxia and resultant myocardial dysfunction, respiratory failure, etc. Hypophosphatemia is the hallmark/predominant cause of RFS Phosphorus is a predominantly intracellular mineral. It is essential for all intracellular processes and for the structural integrity of cell membranes. Many enzymes and second messengers are activated by phosphate binding. Required for energy storage in the for of adenosine triphosphate (ATP) Regulates the affinity of hemoglobin for oxygen and thus regulates oxygen delivery to tissues. Important in renal acid-base buffer system Even small decreases in serum phosphorus may lead to widespread dysfunction of cellular processes affecting almost every physiological system.

Clinical Manifestations of Hypophosphatemia - Normal range: 0.8-1.45 mmol/l - Cardiovascular: heart failure, arrhythmia, hypotension, cardiomyopathy, shock, death. - Renal: acute tubular necrosis, metabolic acidosis - Skeletal: rhabdomyolysis, weakness, myalgia, diaphragm weakness. - Neurologic: delirium, coma, seizures, tetany - Endocrine: hyperglycemia, insulin resistance, osteomalacia - Hematologic: hemolysis, thrombocytopenia, leukocyte dysfunction

Potassium Pathogenesis: Also depleted in starvation Serum concentration may be normal With the change to anabolism upon refeeding, potassium is taken up into cells as they increase in volume and number, and as a direct result of insulin secretion Result is hypokalemia Causes derangements in the electrochemical membrane potential.

Clinical Manifestations of Hypokalemia - Normal Range 3.5-5.1 mmol/l Cardiovascular: hypotension, ventricular arrhythmias, cardiac arrest, bradycardia, or tachycardia Respiratory: hypoventilation, respiratory distress, respiratory failure Skeletal: weakness, fatigue, muscle twitching GI: diarrhea, nausea, vomiting, anorexia, paralytic ileus, constipation Metabolic: metabolic acidosis

Magnesium Another predominantly intracellular cation Important cofactor for must enzyme systems including oxidative phosphorylation and ATP production Necessary for structural integrity of DNA, RNA, and ribosomes. Affects membrane potential, deficiency can lead to cardiac dysfunction & neuromuscular complications.

Clinical Manifestations of Hypomagnesemia Normal Range: 0.77-1.33mmol/l Cardiovascular: arrhythmias, T wave alternans Respiratory: hypoventilation, respiratory distress, respiratory failure Neuromuscular: weakness, fatigue, muscle cramps, ataxia, vertigo, paresthesia, hallucinations, depression, convulsions GI: abdominal pain, diarrhea, vomiting, loss of appetite, constipation Hypocalcemia *Many cases of hypomagnesemia do not manifest until late - T wave alternans (TWA) is a periodic beat-to-beat variation in the amplitude or shape of the T wave in an electrocardiogram (ECG or EKG

Sodium Pathogenesis: Changes in carbohydrate metabolism have a profound effect on sodium and water balance Introduction of carbohydrate to a diet leads to a rapid decrease in renal excretion of sodium and water. If fluid repletion is instituted to maintain a normal urine output, pts may rapidly develop fluid overload.

Clinical Manifestations of Hyponatremia Normal Range: 136-145 mmol/l Cardiovascular: heart failure, arrhythmia Respiratory: respiratory failure, pulmonary edema Renal: renal failure Skeletal: muscle cramps, fatigue, fluid retention, swelling (edema). ©2015

Vitamins/Thiamine Thiamine is an essential coenzyme in carbohydrate metabolism. Deficiencies can result in Korsakoff’s syndrome: Retrograde and anterograde amnesia, confabulation Wernicke’s encephalopathy: Ocular abnormalities, ataxia, confusion, hypothermia, coma Particular concern in alcoholism * Vitamin deficiencies may also result in CHF, lactic acidosis, beriberi disease, and muscle weakness. ©2015

Cardiovascular Complications Most fatalities occur due to cardiac complications Impaired contractility, decreased stroke volume, heart failure, and arrhythmias Atrophy of the heart during starvation results in heightened vulnerability for fluid overload and heart failure. Sodium and fluid retention can lead to volume overload Echo, ECG, and cardiology consult as indicated by pt’s clinical status ©2015

Preventing RFS Identification of high risk patients One or more of the following (NICE guidelines): Little to no intake for >10 days Body mass index (kg/m2) <16 Weight loss of >15% in the past three to six months Low levels of potassium, phosphate, or magnesium before feeding Mehanna, H. M., Moledina, J., & Travis, J. (2008). Refeeding syndrome: what it is, and how to prevent and treat it. Bmj, 336(7659), 1495-1498. ©2015

Preventing RFS Identification of high risk patients: Or the patient has two or more of the following: Body mass index <18.5 Unintentional weight loss >10% in the past 3 to 6 months Little or no nutritional intake for >5 days History of alcohol misuse or drugs including insulin, chemotherapy, antacids or diuretics. Recommendations are based on low grade evidence- mainly cohort studies and case series, and consensus expert opinion To ensure adequate prevention, the NICE guildlines recommend thorough nutritional assessment before refeeding is started. weight change over time, nutrition, alcohol intake, plasma electrolytes (especially phosphate, sodium, potassium, and magnesium) and glucose should be measured at baseline before feeing and any deficiences corrected during feeding with close monitoring. Mehanna, H. M., Moledina, J., & Travis, J. (2008). Refeeding syndrome: what it is, and how to prevent and treat it. Bmj, 336(7659), 1495-1498. ©2015

Preventing RFS Patients are at highest risk for RFS in the first two weeks of nutritional replenishment and weight gain. Historically, the standard of care for refeeding patients with AN is to initiate at low caloric levels, and advance slowly. Example: Start at 1,200 calories per day (kcal/day) and advance by about 200 calories every other day. Purpose of these conservative approaches was to minimize the risk of pts developing the RFS. It could be argued that this was successful, as only a few cases of RFS have been reported during the decades since lower calorie approaches became the standard of care for refeeding in AN. However, lower calorie refeeding has also been linked to poor weight gain, and prolonged hospital stays. Increasing recognition that low and go slow approach may lead to poor outcomes has contributed to a growing interest in higher calorie refeeding in clinical practice and research. Since 2010, ten studies have reported approaches to refeeding beginning with 1400 calories per day or more through meals alone. ©2015

When to Hospitalize? Criteria for admission vary by region, age, and the type of treatment facility. Some published positions and guidelines have suggested that hospital admission is warranted in the presence of: Vital sign abnormalities (bradycardia, hypotension, orthostatic HR/BP, and hypothermia) Failure to respond to lower levels of care, suicidality, or other severe psychiatric symptoms Severe malnourishment (BMI<15kg/m2) ©2015

Preventing RFS Monitoring the patient clinically and biochemically during the refeeding process. Proactive correction of electrolyte abnormalities (particularly phosphorus levels) Monitoring for and treating cardiovascular complications. Electrolyte deficiencies that are present in pts with AN should be corrected prior to initiating the refeeding process This typically requires no more than 12-24 hours (no randomized trials have studied this issue). ©2015

When Not to Hospitalize For some patients, weight restoration can be achieved successfully outside of the hospital. Alternative treatment settings include partial hospitalization, residential programs, intensive outpatient programs. Non-inpatient settings are cost-effective for long-term nutritional rehabilitation. Particularly true for adolescents. One large scale RCT reported that aftera 3 week admission to achieve medical stabilization, day tx was not inferior to prolonged hospitalization at acheving wt restoration at 12 months in adolescents presenting for their first admission for AN. Cost effective ©2015

How to Refeed In mild and moderately malnourished patients, lower calorie refeeding is too conservative. In severely malnourished patients, there is insufficient evidence to support changing the current standard of care for refeeding. Standard recommendations for the macronutrient composition of refeeding is 25- 35% fat, 15-20% protein, 50-60% carbohydrate. The large proportion of adolescents hospitalized are mildly to moderately malnourished with relatively acute onset of AN. Studies have linked lower calorie refeeding to poor outcomes in this patient population, including poor wt gain and prolonged hospital stay. It is unknown whether such critically ill pts could tolerate higher caloric loads, and what level of medical management this might require. In theory, lowering the glucose load of the diet could attenuate risk for RFS; lower carbohydrate or lower glycemic load meals could provide benefit. Garber, A. K., Sawyer, S. M., Golden, N. H., Guarda, A. S., Katzman, D. K., Kohn, M. R., Le Grange, D., Madden, S., Whitelaw, M. & Redgrave,  G. W. (2016). A systematic review of approaches to refeeding in patients with anorexia nervosa. International Journal of Eating Disorders. ©2015

Treating RFS Reduce nutritional support Correct hypophosphatemia, hypokalemia, and hypomagnesemia. Patients with marked edema, or a serum phosphorus <2mg/dL should be hospitalized to intravenously correct electrolyte deficiencies, and for close monitoring. Continuous telemetry may be needed to monitor cardiopulmonary physiology. Garber, A. K., Sawyer, S. M., Golden, N. H., Guarda, A. S., Katzman, D. K., Kohn, M. R., Le Grange, D., Madden, S., Whitelaw, M. & Redgrave,  G. W. (2016). A systematic review of approaches to refeeding in patients with anorexia nervosa. International Journal of Eating Disorders. ©2015

Case Review A 40-year-old woman with a history of anorexia had suffered several complications of the condition in the past, including electrolyte disorders, arrhythmias, amenorrhea, osteoporosis, depression and progressive social isolation. Before admission, she had lost further weight to 40 kg (BMI 13.5 kg/m2). Prior to admission, she resumed eating several large meals a day. On admission, she had ankle edema and hypotension (95/70 mm Hg). Serum concentrations of phosphate, magnesium and potassium were low and the ECG showed sinus bradycardia (51 b.p.m.) and a prolonged QT interval (490 ms). Within 4 h of admission and continuation of oral nutrition and, despite oral supplements of vitamins and electrolytes, she developed muscle weakness and drowsiness. The ECG showed short runs of ventricular tachycardia. i.v. supplementation of electrolytes and minerals was started and the serum electrolyte concentrations returned to normal within 2 days, with resolution of the muscle weakness and the ventricular tachycardia. However, the QT interval remained prolonged at 460 ms. ©2015

Key Points Severe anorexia nervosa with a very low BMI is a common cause of the refeeding syndrome in hospital practice. In this case, refeeding was begun by the patient herself and was continued after hospital admission. In severe and prolonged malnutrition, there may be cardiac atrophy as well as electrolyte abnormalities, including sinus bradycardia and a prolonged QT interval (Heymsfield et al., 1978; Powers, 1982). These changes make the heart more vulnerable to hypophosphatemia and hypokalemia with ventricular arrhythmias and sudden death (Isner et al., 1985; Beumont and Large, 1991), especially, if the QT interval exceeds 470 ms (Cooke et al., 1994). It should also be remembered that the concomitant abuse of diuretics, laxatives and alcohol by anorectic patients may exacerbate electrolyte and vitamin deficiencies. It is, therefore, important to be alert to the danger of the refeeding syndrome in patients with these problems. ©2015

Questions? ©2015