Refeeding Syndrome in Anorexia Nervosa

Anorexia nervosa (AN) is an illness commonly diagnosed in adolescence with low recovery
rates and high healthcare costs. The major medical complication of AN is malnutrition.
Caloric restriction, purging and other weight control behaviors can lead to medical
instability (abnormal vital signs) requiring hospitalization. The primary goal of
hospitalization is to restore medical stability by reintroducing nutrition, or "refeeding".
Within 12 mo of discharge, 43% of patients will require medical rehospitalization. This
results in a costly course of recovery, given that eating disorders are the most expensive
among primary mental health diagnoses requiring hospitalization. Several lines of inquiry
seeking to identify characteristics or short-term outcomes that may predict better recovery
in AN point to rapid short-term weight gain as a strong predictor of long-term outcomes.
Greater weight gain in hospital predicts weight recovery at 12 moand, in psychotherapeutic
trials, greater weight gain during the first 3-4 wk (1.7-1.9 lb/wk) predicts full remission
at 12 mo. Unfortunately, the currently recommended approach, Lower Calorie Refeeding (LCR),
is associated with slow weight gain and prolonged hospital stay. Treatment is now moving
sporadically toward Higher Calorie Refeeding (HCR) in the hope of improved recovery.
However, no study to date has directly compared these two approaches.] Since the refeeding
syndrome, characterized by rapid electrolyte shifts, delirium and cardiac arrest in response
to the influx of nutrients was first described around WWII, refeeding has been approached
with caution. Following documentation of this syndrome in patients with AN, conservative,
consensus-based recommendations for LCR were developed to ensure safety. LCR typically
begins around 1200 kilocalories (kcal) per day and advances by 200 kcal every other day. The
investigators found that patients initially lose weight on this "start low and go slow"
approach and require prolonged hospitalizations to achieve medical stability. This finding
contributed to recognition of the "underfeeding syndrome". In subsequent studies, the
investigators demonstrated that HCR produced faster weight gain and shorter hospitalization.
While no increased risk of refeeding syndrome has been reported using HCR, the variety of
electrolyte supplementation protocols being used to manage risk have not been examined.

Findings from these observational and retrospective studies have been rapidly accepted by
many clinicians and insurers and HCR is now being integrated into practice in many
hospitals. However, there are major gaps in the evidence necessary to adopt HCR as the new
standard of care. These gaps are: 1.) It is not known if HCR impacts clinical remission,
which is typically defined as the combination of weight and cognitive recovery at 12 mo. 2.)
The safety of HCR has not been confirmed. The hallmark electrolyte imbalances of refeeding
syndrome occur frequently and still have not been systematically examined on differing
refeeding protocols. 3.) The relative cost-effectiveness of the two approaches has not been
established.

The investigators propose to conduct a randomized controlled trial (RCT) at two sites to
directly compare HCR and LCR for refeeding in AN. To accomplish the following aims, 120
adolescents will be enrolled upon admission to hospital for malnutrition secondary to AN and
randomized 1:1 to HCR (beginning with 2000 kcal and advanced 200 kcal/d) or LCR (beginning
at 1400 kcal/d and advanced 200 kcal every other day) until medical stability is restored.
Participants will be followed for 12 mo after randomization: Daily while in hospital and at
follow-up [10 dy],1 mo, 3 mo, 6 mo, and 12 mo after randomization.

Inclusion Criteria:

- Adolescents hospitalized for medical instability secondary to malnutrition will be
eligible as follows.

Inclusion criteria:

1. diagnosis of AN, atypical AN

2. age 12-24 years

3. no hospital admissions for the previous six months

4. meet hospitalization criteria (daytime HR < 50 bpm or night time HR < 45 bpm, BP
<90/45 mmHg, temperature < 36? C or orthostasis defined by increase in HR > 20 bpm or
decrease in systolic BP > 20 mmHg or decrease in diastolic BP > 10 mmHg from lying to
standing)

Exclusion Criteria:

1. diagnosis of bulimia nervosa [DSM-5]

2. current pregnancy

3. admission for food refusal without malnutrition

4. chronic disease (e.g. immune/endocrine disorders,pulmonary, cardiac, or renal
disease)

5. current suicidality or psychosis.