By Andrea Garber, PhD, RD, and Daniel Le Grange, PhD
Eating Disorders Program, Departments of Pediatrics and Psychiatry
University of California, San Francisco
Reprinted from Eating Disorders Review
January/February Volume 26, Number 1
Adolescents with anorexia nervosa (AN) can rapidly become malnourished from caloric restriction, over-exercising, purging, and other weight-control behaviors. Restoring weight and nutritional status in the hospital or in outpatient settings is a crucial first step toward recovery.
Adequate weight gain during the early stages of refeeding predicts better long-term recovery.1-4 For medically unstable adolescents, the weight gained during hospitalization or upon hospital discharge (typically 2 to 3 weeks after admission) predicts weight recovery at 1 year.1-3 For those stable enough to begin outpatient psychotherapy, greater weight gain during the first 3 to 4 weeks (1.7 to 1.9 lb/wk) predicts full remission (both weight and cognitive recovery) at 1 year.4 These findings indicating that early weight gain sets the stage for long-term recovery underscore the pressing need to develop approaches to refeeding that safely optimize weight gain in adolescents with AN.
For decades, the recommendations for refeeding in AN have been quite conservative. For instance, in the U.S., the normal recommendations are to begin refeeding at around 1200 kcal per day, and then to advance slowly by adding about 200 kcal every other day.5-7 In Europe, the UK, and Australia, 8, 9 refeeding regimens starting with as little as 200 to 600 kcal per day have been recommended. These collective Lower Calorie Refeeding (LCR) approaches were intended to ensure patient safety by minimizing risk for the refeeding syndrome. This syndrome is characterized by rapid fluid and electrolyte shifts that can result in severe medical sequelae, including cardiac arrhythmias, cardiac arrest, muscle weakness, hemolytic anemia, delirium, seizures, coma, and even death.10 The refeeding syndrome was first documented in World War II prisoners of war and other starved populations, and is now understood to occur in response to influx of nutrients at the cellular level.
LCR became the standard of care for refeeding based on clinical consensus that nutrition should be reintroduced as slowly as possible to prevent the refeeding syndrome. Although several studies have now identified severely malnourished patients (<70% of expected weight) as being at the highest risk, 11 LCR has been applied broadly to safeguard all patients with AN. This approach has been generally safe: only a handful of cases of the refeeding syndrome have been reported in patients with AN.8,12-14 However, the results of recent studies indicate that LCR has contributed to the poor weight gain and longer hospital stays that have become expected as a normal part of the course of recovery in AN. For example, we reported that lower starting calorie regimens were associated with initial weight loss, slower weight gain, and longer hospital stays in adolescents with AN followed prospectively over the course of their hospital stay.15 Such findings have contributed to recognition of the so-called “underfeeding syndrome”14 and sparked an interest in Higher Calorie Refeeding (HCR).
HCR: As Yet, No Standard Definition
Due to insufficient evidence, there is currently no standard definition of HCR or recommendations for implementing it. HCR typically starts with between 1400 to 2400 kcal per day, and may advance anywhere from 0 to 200 kcal per day.16-18 These variations are likely to have an impact on the rate of weight gain and may explain inconsistent findings across studies.16, 18
There are also major differences in methods of delivery. Some programs use meals to deliver higher amounts of calories, 16,17 while others use enteral (tube) feeding alone, 19-21 and still others use a combination of both.22 A handful of studies using meal-based HCR in moderately malnourished adolescents have shown that it is feasible and produces better outcomes in hospitalized patients. Whitelaw et al. (2010) demonstrated satisfactory weight gain and no cases of the refeeding syndrome in 29 adolescents hospitalized with AN, by beginning refeeding with about 1900 kcal per day and increasing this rapidly by approximately 100 kcal per day for the first 5 days.9 In 2013, in a study of 56 adolescents, we reported nearly double the rate of weight gain and almost 6 days shorter hospitalization for the adolescents who were started on an average of 1775 kcal per day, compared to those started on about 1165 kcal per day.17 A concurrent large retrospective study of 310 adolescents by Golden et al. reported 3 days shorter hospital stay in adolescents when refeeding was started at an average of 1550 vs. 1165 kcal per day.17 These findings are quickly being translated into clinical practice despite gaps in the evidence.
Finding Safe Levels
Safety is an urgent question as clinical practice moves forward with HCR. The justifiable concern that higher levels of nutrients introduced more rapidly would increase risk for the refeeding syndrome has not been substantiated by recent studies of HCR. However, several limitations preclude establishing HCR as a safe approach at this time. First, no study to date has had (and perhaps no future study will have) a sufficiently large sample to examine the full spectrum of clinical features of the relatively rare occurrence of the refeeding syndrome. Studies thus far have focused on low serum phosphorus, the hallmark of the refeeding syndrome, shown to occur in 14% of adolescents with AN across multiple refeeding studies.23 However, the wide variety of electrolyte replacement approaches make it impossible to determine whether this hypophosphatemia occurs earlier or is greater in magnitude in patients on HCR. Another limitation inherent to the available retrospective and observational studies is systematic bias. Physicians may be more likely to prescribe lower calories and/or electrolyte replacement disproportionately to severely malnourished patients, knowing that they are at highest risk.11 These limitations underscore the need for randomized controlled trials (RCTs) to systematically compare and examine the safety of refeeding protocols.
In addition to the questions of medical safety, it is not known whether there are unintended psychological consequences associated with HCR. Whether increased anxiety related to HCR could negatively impact cognitive recovery is a particular concern, based on several studies demonstrating that mealtime anxiety increases in proportion to caloric load in AN patients.24-27 Increasing caloric loads of the same volume administered to AN patients via tube feeding (such that patients were unaware of the calories ingested) produced increased psychological and physiologic stress, including increases in energy expenditure and plasma cortisol and fear of becoming fat with higher calories. The possibility that increased meal-based anxiety on HCR accumulates to impede long-term cognitive recovery is not supported by the available data showing that greater weight gain in early psychotherapy predicts superior weight and cognitive recovery.28 However, an essential next step is to examine whether the caloric level and/or rate of refeeding (not just amount of weight gain) impacts the course of cognitive recovery.
The promising outcomes in hospitalized patients make it tempting to assume HCR would produce better long-term weight recovery; however, this has not been examined. In fact, several lines of evidence suggest HCR may not produce better weight gain over the long-term. In the only randomized control trial of refeeding in AN to date, Rigaud et al. compared two groups—one that received higher calories via tube feeding to a lower-calorie meal-based group, and found no difference in weight at 12 months.24
In our 2013 study, discharge weights were equal between HCR and LCR groups due to the shorter hospital stay among patients treated with HCR. Based on this finding, we would anticipate no difference in long-term weight recovery between groups, given that discharge weight is a strong predictor of weight recovery at one year.1 Earlier discharge was initially worrisome to clinicians who were accustomed to protracted hospitalizations for these patients. However, a recent large randomized control trial provides strong evidence that there is no benefit to extending hospitalization in adolescents with AN. Madden et al. (2014) compared short-term medical stabilization to longer-term weight recovery in hospitalized patients, both followed by family-based therapy, and found no difference in 12-month weight recovery although patients spent about 20 additional days in the hospital.29 Collectively, these findings suggest that the potential benefit of HCR may not be improved weight recovery but less time in the hospital.
Weighing the Possibility of Relapse with Shorter Hospital Stays
Any benefit of shorter hospitalization associated with HCR could be easily outweighed by an increase in the incidence of relapse. In addition to the historically long initial stay in the hospital, relapse contributes to the recognition of AN as among the top “common and costly” primary mental health diagnoses in pediatrics.30 Forty-three percent of patients require medical re-hospitalization within 12 months of first admission.31 Yet Rigaud et al.’s trial found delayed relapse in the higher-calorie group.20 Although this finding cannot be attributed to differing lengths of stay (the severely malnourished adult participants were hospitalized for equally extended periods of 2 months), there is, nevertheless, no indication that patients refed on HCR would require earlier or more frequent re-hospitalization to supplement the initially shorter stay.
Considering the Real Cost of AN
If the same weight recovery can indeed be achieved with less time spent in the hospital, this would be a potentially major benefit of HCR, with important implications for the treatment and prognosis of adolescents with AN. Madden et al. (2014) estimated the difference in treatment times between medical stabilization and weight recovery groups amounted to $80,000 in the U.S. healthcare system.29 These sizeable savings do not even begin to cover what is perhaps the larger “cost” of AN — the cost of missed school and work, lost relationships, and decreased quality of life. Future studies should strive to examine these direct and indirect costs to determine the true effectiveness of HCR. However, cost-effectiveness and other potential benefits of HCR cannot be fully realized until the risks are better understood. Future studies are needed to establish the safety and elucidate the possible unintended consequences of HCR so any risks can be weighed against the promise of rapid weight recovery. Only then can clinicians, families, and patients embrace HCR as the new standard of care.
About the Authors
Dr. Garber is Associate Professor of Pediatrics, Division of Adolescent & Young Adult Medicine, at the Benioff Children’s Hospital, University of California, San Francisco.
Dr. Le Grange is Benioff UCSF Professor in Children’s Health, Departments of Psychiatry and Pediatrics, University of California, San Francisco.
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- Le Grange D, Accurso EC, Lock J, et al. Early weight gain predicts outcome in two treatments for adolescent anorexia nervosa. Int J Eat Disord. 2014; 47:124.
- Practice guideline for the treatment of patients with eating disorders (revision). American Psychiatric Association Work Group on Eating Disorders. Am J Psychiatry. 2000;157 (1 Suppl):1.
- Treatment of patients with eating disorders,3rd ed. American Psychiatric Association. Am J Psychiatry. 2006;163(7 Suppl):4.
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- Whitelaw M, Gilbertson H, Lam PY, et al. Does aggressive refeeding in hospitalized adolescents with anorexia nervosa result in increased hypophosphatemia? J Adolesc Health. 2010; 46:577.
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- Kohn MR, Golden NH, Shenker IR. Cardiac arrest and delirium: presentations of the refeeding syndrome in severely malnourished adolescents with anorexia nervosa. J Adolesc Health. 1998; 22:239.
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- Golden NH, Keane-Miller C, Sainani KL, et al. Higher caloric intake in hospitalized adolescents with anorexia nervosa is associated with reduced length of stay and no increased rate of refeeding syndrome. J Adolesc Health. 2013; 53(5):573-578.
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- Kohn MR, Madden S, Clarke SD. Refeeding in anorexia nervosa: increased safety and efficiency through understanding the pathophysiology of protein calorie malnutrition. Curr Opin Pediatr. 2011;23:390.
- O’Connor G, Nicholls D. Refeeding hypophosphatemia in adolescents with anorexia nervosa: a systematic review. Nutr Clin Prac. 2013;28:358.
- Rigaud D, Verges B, Colas-Linhart N, et al. Hormonal and psychological factors linked to the increased thermic effect of food in malnourished fasting anorexia nervosa. J Clin Endocrinol Metab. 2007; 92:1623.
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- Van Wymelbeke V, Brondel L, Marcel Brun J, et al. Factors associated with the increase in resting energy expenditure during refeeding in malnourished anorexia nervosa patients. Am J Clin Nutr. 2004;80:1469.
- Birmingham CL, Hlynsky J, Whiteside L, et al. Caloric requirement for refeeding inpatients with anorexia nervosa: the contribution of anxiety exercise, and cigarette smoking. Eat Weight Disord. 2005;10:e6.
- Le Grange D, Accurso EC, Lock J, et al. Early weight gain predicts outcome in two treatments for adolescent anorexia nervosa. Int J Eat Disord. 2014;47:124.
- Madden S, Miskovic-Wheatley J, Wallis A, et al. A randomized controlled trial of in-patient treatment for anorexia nervosa in medically unstable adolescents. Psychol Med. 2014;14:1.
- Bardach NS, Coker TR, Zima BT, et al. Common and costly hospitalizations for pediatric mental health disorders. Pediatrics. 2014;133:602.
- Steinhausen HC, Grigoroiu-Serbanescu M, Boyadjieva S, et al. Course and predictors of rehospitalization in adolescent anorexia nervosa in a multisite study. Int J Eat Disord. 2008; 41:29.