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CRITICAL ANALYSIS AND SYNTHESIS (CE ACTIVITY)
A Systematic Review of Approaches to Refeeding in
Patients with Anorexia Nervosa
Andrea K. Garber, PhD, RD1*
Susan M. Sawyer, MBBS, MD,
FRACP2
Neville H. Golden, MD3
Angela S. Guarda, MD4
Debra K. Katzman, MD, FRCPC5
Michael R. Kohn, MBBS, FRACP6
Daniel Le Grange, PhD7,1
Sloane Madden, MBBS (Hons),
PhD FRANZCP, CAPCert8
Melissa Whitelaw,
BAppSc(PhysEd),
AppSc(HlthSc), BNutrDiet,
APD2,9
Graham W. Redgrave, MD4
ABSTRACT
Objective: Given the importance of
weight restoration for recovery in patients
with anorexia nervosa (AN), we examined
approaches to refeeding in adolescents
and adults across treatment settings.
Methods: Systematic review of PubMed,
PsycINFO, Scopus, and Clinical Trials databases (1960-2015) using terms refeeding,
weight restoration, hypophosphatemia,
anorexia nervosa, anorexia, and anorexic.
Results: Of 948 screened abstracts, 27
met these inclusion criteria: participants
had
AN;
reproducible
refeeding
approach; weight gain, hypophosphatemia or cognitive/behavioral outcomes.
Twenty-six studies (96%) were observational/prospective or retrospective and performed in hospital. Twelve studies
published
since
2010
examined
approaches starting with higher calories
than currently recommended (1400
kcal/d). The evidence supports 8 conclusions: 1) In mildly and moderately malnourished
patients,
lower
calorie
refeeding is too conservative; 2) Both
meal-based approaches or combined
nasogastric+meals can administer higher
calories; 3) Higher calorie refeeding has
not been associated with increased risk
Resumen
Objetivo: Objetivo: Dada la importancia
de la restauraci
on del peso en la recuperaci
on de pacientes con anorexia nervosa
(AN), examinamos los abordajes para la
realimentaci
on de adolescentes y adultos
for the refeeding syndrome under close
medical monitoring with electrolyte correction; 4) In severely malnourished inpatients, there is insufficient evidence to
change the current standard of care; 5)
Parenteral nutrition is not recommended; 6) Nutrient compositions within
recommended ranges are appropriate; 7)
More research is needed in non-hospital
settings; 8) The long-term impact of different approaches is unknown;
Discussion: Findings support higher calorie approaches to refeeding in mildly
and moderately malnourished patients
under close medical monitoring, however
the safety, long-term outcomes, and feasibility outside of hospital have not been
established. Further research is also
needed on refeeding approaches in
severely malnourished patients, methods
of delivery, nutrient compositions and
treatment settings.
Keywords: anorexia nervosa; refeeding; weight restoration; nutritional
rehabilitation; refeeding syndrome;
hypophosphatemia; medical complications; medical stability; length of
stay
a lo largo de los diferentes entornos de
tratamiento.
M
etodos: Se hizo una revisi
on sistem
atica de PubMed, PsycINFO, Scopus, y Bases de datos de ensayos
Accepted 30 August 2015
*Correspondence to: Andrea K. Garber, Department of Pediatrics, Division of Adolescent and Young Adult Medicine, University of California, San Francisco, Benioff Children’s Hospital. E-mail: [email protected]
This article was published online on 12 December 2015. An error was subsequently identified. This notice is included in the online
and print versions to indicate that both have been corrected on 21 December 2015.
1
Department of Pediatrics, Division of Adolescent and Young Adult Medicine, University of California, San Francisco, Benioff Children’s
Hospital
2
Director, Centre for Adolescent Health, Royal Children’s Hospital; Geoff and Helen Handbury Chair of Adolescent Health, Department
of Paediatrics, The University of Melbourne; and Researcher, Murdoch Childrens Research Institute
3
Department of Pediatrics, Division of Adolescent Medicine, Stanford University School of Medicine
4
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine
5
Department of Pediatrics, Division of Adolescent Medicine, Research Institute, Hospital for Sick Children, and University of Toronto
School of Medicine
6
Department of Adolescent Medicine, Sydney Children’s Hospital Network, Westmead and the University of Sydney
7
Department of Psychiatry, University of California, San Francisco
8
Department of Psychological Medicine, Sydney Children’s Hospital Network, The University of Sydney
9
Department of Nutrition and Food Services, The Royal Children’s Hospital, Melbourne
Published online 12 December 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/eat.22482
C 2015 Wiley Periodicals, Inc.
V
International Journal of Eating Disorders 49:3 293–310 2016
293
GARBER ET AL.
clınicos (1960-2015) utilizando los
t
erminos realimentaci
on, recuperaci
on de peso, hipofosfatemia, anorexia nervosa, anorexia y anor
exico.
Resultados: De 948 res
umenes revisados, 27 reunieron los siguientes criterios
de inclusi
on: participantes tenıan AN;
abordaje de realimentaci
on reproducible;
resultados en ganancia de peso,
hipofosfatemia y cognitivo/conductuales.
Veintis
eis estudios (96%) fueron observacionales/prospectivo o retrospectivo y
realizados en hospital. Doce estudios
publicados desde 2010 examinaron abordajes que iniciaron con m
as altos niveles
cal
oricos que los actualmente recomendados (1400kcal/d). La evidencia apoya
8 Conclusiones: 1) En pacientes con
desnutrici
on leve a moderada, la realimentaci
on con menos calorıas, es un
m
etodo muy conservador; 2) Pueden
aportarse m
as calorıas tanto con abordajes basados en comidas como con
combinaci
on
de
comidas 1 sonda
nasog
astrica; 3) Realimentaci
on alta en
calorıas, no ha sido asociada con riesgo
incrementado de sındrome de realimentaci
on, cuando es llevada a cabo
bajo estricto monitoreo m
edico y
correcci
on de niveles de electrolitos; 4)
Es insuficiente la evidencia que apoya
un cambio en los actuales protocolos
de atenci
on en pacientes hospitalizados severamente desnutridos; 5) No se
recomienda la alimentaci
on parenteral; 6) La composici
on de nutrientes
dentro de los rangos recomendados es
apropiada; 7) Se necesita m
as investigaci
on para abordajes no hospitalarios; 8) El impacto a largo plazo de los
diferentes esquemas de abordaje a
un
se desconoce;
A Systematic Review of Approaches to
Refeeding Patients with Anorexia
Nervosa
The primary goal of refeeding patients with anorexia nervosa (AN) is to reverse malnutrition and its
complications. Weight gain during refeeding is crucial, as it sets the stage for long-term recovery. In
hospitalized patients, faster weight gain1 and higher
weight upon discharge2,3 predict weight recovery at
1 year.1–3 Weight recovery is typically defined as
95% of the median Body Mass Index (%mBMI) per
CDC data4 and is associated with the reversal of
long-term medical complications, including amenorrhea.5,6 In patients well enough to be managed in
ambulatory settings, faster weight gain during the
first 3–4 weeks (0.43–0.86 kg week21) of outpatient
psychotherapy predicts full remission (both weight
and cognitive recovery) at 12 months.7 However,
the need for weight gain must be balanced against
the potentially fatal complications of the refeeding
syndrome, which can manifest in cardiac arrhythmia, cardiac failure or arrest, hemolytic anemia,
delirium, seizures, coma, and sudden death.8–12
These clinical sequelae are thought to occur as a
result of movements of glucose and electrolytes
from the extracellular to the intracellular space in
response to surges in insulin after nutrients are
reintroduced following starvation and depleted
hepatic glycogen stores.13
The current standard of care for refeeding
patients with AN is to commence at low caloric levels and advance slowly, with variable recommendations internationally. In the United States,
294
n: Los hallazgos apoyan los
Discusio
abordajes de realimentaci
on m
as altos
en calorıas, en pacientes leve y moderadamente desnutridos, con estricto
control m
edico, sin embargo, la seguridad, resultados a largo plazo y factibilidad de los mismos fuera del hospital,
no ha sido establecido. Tambi
en se
necesita m
as investigaci
on en abordajes de realimentaci
on para pacientes
con desnutrici
on severa, m
etodos de
administraci
on,
composici
on
de
nutrientes y lugares de tratamiento.
C 2015 Wiley Periodicals, Inc.
V
(Int J Eat Disord 2016; 49:293–310).
recommendations are to start around 1,200 calories
per day (kcal day21) and advance slowly by about
200 kcal every other day,14–16 whereas starting
caloric prescriptions as low as 200–600 kcal day21
are recommended in Europe and the United Kingdom.17 The purpose of such “start low and go slow”
approaches is to minimize the risk of refeeding syndrome. However, these lower calorie approaches
have recently been linked to poor weight gain and
prolonged hospitalization.18 Growing recognition
of the so-called “underfeeding syndrome”19 has
spurred renewed interest in more aggressive
approaches to refeeding.20 These approaches are
varied, but typically begin with higher calorie and/
or more rapid advancement and may be delivered
through meals alone or a combination of meals
with supplemental nasogastric (NG) feeding.
Refeeding may occur in a variety of settings,
including hospital, partial hospital and/or day
treatment, residential programs, and outpatient settings. Patients who are physiologically or psychologically unstable are admitted to hospital for
refeeding. Criteria for admission to hospital vary by
country, region, age (adolescents vs. adults), and
the type of treatment facility. However, published
positions and guidelines for adolescent and adult
care have suggested that hospital admission is warranted in the presence of vital sign abnormalities
(bradycardia, hypotension, orthostatic heart rate
and blood pressure, and hypothermia), failure to
respond to lower levels of care, suicidality, or other
severe psychiatric symptoms.15,20,21 Severe malnutrition alone, defined as BMI < 15 kg m22 in adults17
or <70% mBMI,21 may also warrant hospitalization.
International Journal of Eating Disorders 49:3 293–310 2016
REFEEDING IN PATIENTS WITH ANOREXIA NERVOSA
Panel 1: Inclusion and exclusion criteria applied during screening
REQUIRED FOR INCLUSION
Studies of approaches to refeeding adolescents and adults with AN, where:
#1: Refeeding protocol was defined such that it could be reproduced in other settings, by either calorie/nutrient level or mode of delivery
including rate and or concentration of formula.
–AND–
#2: Outcomes included weight gain, rate of hypophosphatemia or cognitive/behavioral improvements (including neurocognitive functioning
and/or long-term eating disorder cognitions and behaviors).
EXCLUSION CRITERIA
#1: Studies comparing malnourished to refed patients (where the feeding protocol was undefined and varied)
#2: Studies reporting other medical/nutritional outcomes (such as change in body composition but not weight recovery) and those reporting
neurological outcomes (such as brain structure or volume) but not neurocognitive functioning, cognitions or behaviors.
#3: Studies of refeeding where the protocol was not described*
* In cases where the paper met inclusion criteria with the exception that the refeeding protocol was not described, details of the refeeding protocols were procured by author communication.
The initial focus of refeeding is to restore physiological stability through weight gain. Bradycardia
normalizes more quickly during refeeding than other
signs, such as orthostatic changes, which may take
weeks.22 In adolescents in the United States, normalization of vital signs is commonly used as a discharge
criterion from medical inpatient units, which is why
some studies of refeeding have used length of hospital stay as a proxy for the time required to achieve
medical stability. In addition to physiological instability at presentation, patients are at risk of developing complications during the refeeding process itself.
Refeeding hypophosphatemia (RH) is used to indicate risk for the development of the refeeding syndrome23 and is more likely to occur in severely
malnourished patients.24 Studies of hospitalized
patients show that the risk of developing refeeding
syndrome is highest during the first week.25 However, there are no recommendations in place for electrolyte monitoring and correction with supplements,
with wide variations in clinical practice.26 For these
reasons, both the degree of malnutrition and electrolyte supplementation must be considered when evaluating studies of refeeding.
These findings underscore the need to identify
approaches to refeeding that simultaneously maximize weight recovery and minimize the associated
risks. In addition, they highlight the need to consider
how relatively short-term approaches to inpatient
refeeding may support the long-term goals of recovery, which include cognitive recovery and reduction
of eating disorder psychopathology. The purpose of
this review is to systematically examine published
studies on approaches to refeeding in adolescents
and adults with AN, with particular attention to the
approach to refeeding (including caloric level, methods of delivery, and nutrient content) and characteristics of the study population (including age and
degree of malnutrition). Pertinent medical outcomes
International Journal of Eating Disorders 49:3 293–310 2016
are weight gain and rate of RH; cognitive outcomes
include neurocognitive functioning and eating disorder thoughts and behaviors.
Method
Literature Search
We performed a comprehensive database search for
abstracts published in English from 1960 to March 15,
2015, in Pubmed, PsycINFO, Scopus, and Clinical Trials
databases. Search strategies combined controlled vocabulary terms (MeSH, Thesaurus) with keywords and
phrases for the following concepts: refeeding, weight restoration, hypophosphatemia, and anorexia nervosa.
Exclusion terms were: neoplasm(s) and cancer(s) and
tumor(s). References were exported to Endnote (version
X7), and duplicates were removed using Author, Year,
Title, and Reference Type as the comparison criteria.
Procedure for Screening for Eligible Studies
Inclusion and exclusion criteria are described in
Panel 1. Abstracts identified from the initial search were
screened in a secondary review process, and full text
papers were obtained of those meeting inclusion criteria.
Abstracts of review papers and case studies were
removed from this review but cataloged for further bibliography and referencing. In cases of uncertainty (e.g.,
the abstract was unavailable or contained insufficient
detail to determine if inclusion criteria were met), the
full-text of the paper was obtained and screened.
Methods for Assessing Study Quality
The quality of the selected studies was independently
assessed by three authors (AKG, SMS, and GR). We used the
diagram for flow of information from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) statement for systematic reviews as well as the
organizational structure from the PRISMA checklist,
295
GARBER ET AL.
FIGURE 1..
Flow chart of study selection.
including a detailed description of the eligibility criteria
(Panel 1) and the search and selection criteria for studies.27
The limited designs of the available studies did not allow
for a formal quality assessment or statistical methods to
evaluate the results (e.g., to compare or evaluate collective
effect sizes). The majority of studies of refeeding in AN are
retrospective and/or observational, and there is no empirically validated method to evaluate the quality of nutrient
date resulting from such study designs.28 These study
designs are known to be subject to several types of bias,
which are described and discussed in the text where
relevant.
Results
Studies Selected for Inclusion in Systematic
Review
A flow chart depicting the study selection process is shown in Figure 1. The initial search of elec296
tronic databases yielded 948 references. An
additional 17 abstracts were identified from bibliographies of relevant review papers. After removing 47 duplicates, 918 abstracts were included for
screening. Initial screening using the inclusion and
exclusion criteria led to the exclusion of 846
abstracts. Studies were most often excluded
because: they were not a study of refeeding (e.g., a
cross-sectional study comparing malnourished to
refed patients with AN), did not include patients
with AN, focused on pharmacotherapy, or utilized
animal models. This process yielded 72 abstracts.
The full texts of these abstracts were obtained and
evaluated again according to the inclusion and
exclusion criteria. Of these, 45 studies were
excluded primarily because the refeeding protocol
was not described in sufficient detail for it to be
reproduced in other study or treatment settings.
For example, several studies described refeeding
protocols designed to achieve a desired rate of
International Journal of Eating Disorders 49:3 293–310 2016
Study Design
Prospective
Retrospective
Obarzanek et al. 199439
Ornstein et al. 200325
3
4
Retrospective
Retrospective
10 Golden et al. 201342
11 Le Clerc et al. 201343
Observational
Inpt psych
Inpt psych
Inpt med
Inpt med
Inpt psych
Inpt CRC
Inpt CRC
Inpt med
Inpt med
Inpt med
Inpt CRC
Inpt med
Retrospective
Retrospective
Retrospective
Robb et al. 200246
Zuercher et al. 200347
Silber et al. 200448
2
3
4
Inpt
Res
Inpt
Combined approach with nasogastric feeding and oral intake
Retrospective
Inpt
1 Bufano et al. 199045
13 Redgrave et al. 201535
12 El Ghoch et al. 2014
Prospective
Observational
Observational
Hart et al., 201138
Garber et al. 201341
8
9
44
Observational
Retrospective
Retrospective
Garber et al. 2012
Gaudiani et al. 201237
Whitelaw et al. 201040
5
6
7
18
Observational
Solanto et al. 199436
2
Inpt psych
Study Settinga
Study Characteristics
155 NG1O
226 O
6 NG1O
8O
52 NG1Ox
48 O
9
361
50
29
310
247
56
35
25
29
69
10
22 L
31 H
10
Nb
Summary of refeeding studies, by refeeding approach
Meal-based approach to refeeding
Observational
1 Krahn 199332
TABLE 1.
Mean maximum of
2311 kcals/d
Target weight gain 1
kg wk21
Target weight gain
1–1.5 kg wk21
Target 35004000kcals/dwith IV
glucose in BMI<14
Meals
Meals
Meals
Meals
Target 2000 kcal/d
Meals
Meals
Meals; behavioral
contracts distinguish
groups
Meals
Meals
Method of
Delivery
Compare nocturnal
NG 1 oral to oral;
mean maximum kcals:
3255 (NG1O), 2508 (O)
25.7 NG1O 14.2 (1.7) NG10
Compare voluntary
25.2 O
15.7 (1.7) O
NG1meals to meals
13.8 NG
15.3 (1.7) NG1O
Compare nocturnal
1
17.4 (2.3) O
NG 1 oral to oral;
NRv
16.2 (2.2)
15.4 (1.6)
16.1 (1.8)
15.8 (0.5) Lq
16.6 (0.4) Hr
15.9 (2.2) L
16.1 (1.7) Hs
16.4 (1.7)t
16.3 (2.3)
13.1n
NRo
m
15.0 (1.5)l
NRk
15.0 (1.9) Aj
14.3 (1.6) B
NRh
14.8 NG1O 15.5 (1.7) NG1O
15.0 O
16.0 (1.8) O
NR
28.5
26.5
14.7
16.1
20.7
16.2
16.2
26.0
15.7
15.5
23.3
16.0 L
16.2 H
19–38
Age (yrs)c
Admission
BMId (SD/SE)
Participant Characteristics
NR
NR
NR
Oral 1 NG at 25% of
REEw
1200-1500
1,500
1205
990
1900; target 2200 by
day 3, 2700 by day 5
1500 kcal d21
1093 L
1764 H
1163 L
1557 H
1500
1200-1400
1105
1200; Target 3600
kcal/d after wk 2
1000-1200
300 kcal every 3 days
to goal
25% of target kcals on
day 1, 50% on day 2,
75% on day 3
600, 1080, 1200 on
first three days (NG),
oral kcals NR
250
(500 q 2–3 days)
75–250
(250 q 2 days)
NR
NR
986 L
1228 H
100–200
Advanced to mean of
2105 kcal/d during
first 15 days, then to
mean of 3216 during
next 53 days
100–200
(200 q 1–2 days)
100
NR
100–300
Increase 300 kcal/d
during wk 2
67–100
(200 q 2–3 days)
0.93 NG1O
0.83 O
2.12 NG1O
0.53 O
1.70 NG1O
0.76 O
1.92
1.98
NRu
0.62
0.98 L
1.90 H
1.52 L
1.56 H
1.7
0.88
NR
1.3p
NR
1.3
0.64 (0.32) A
1.15 (0.48) B
1.25
Rate of Weight
Gain (kg wk21)f
NRy
NR
NR
33.3%
18.5%
NR
18.2% L
14.9% H
3.5%
NR
45%
20%
45%
38%
27.5%
NR
NR
NRi
Rate
of RHg
Medical/Nutritional Outcomes
Starting Kcal d21 or
Nutrient Level
Caloric Advance
(Kcal d21)e
Refeeding Approach
Prospective (test-retest)
Retrospective
Retrospective
Hatch et al. 201033
Gentile et al. 201251
Agostino et al. 201352
7
8
9
Inpt med
Inpt
Inpt
Inpt
Inpt
Inpt nutr
Study Settinga
78
31 NG1O
134 O
10
37
33
41 NG1O
40 O
Nb
Approaches with altered nutrient content
Prospective
1 Forbes et al. 198454
CRC
5 Hii
7L
Combined approach with total parenteral nutrition and oral intake
Retrospective
Inpt psych
104 PNhh1O
1 Diamanti et al. 200853
94 O
Prospective cohort
Retrospective
Gentile et al. 201050
6
10 Madden et al. 201534
RCT
Study Design
Study Characteristics
Rigaud et al. 200749
Continued
5
TABLE 1.
Method of
Delivery
13–22
14.9 PN
1
15.2 O
14.8
14.9
23.9
15.1
NRjj
14.3 (0.2) PN1O
16.0 (0.2) O
20% vs. 10% kcal from
protein
Compare oral to
oral1TPN; both
groups start 40 kcal/
kg/d for 5 d then
increase to 60 kcal/kg/
d over 1 week
24–72 hr continuous
NG only, then nighttime NG 1 meals to
target weight gain rate
1 kg wk21
11.2 (0.7)
Concentrated continuous NG feed with IV
glucose for 24 hr and
oral intake, started at
1199 kcal increase to
2871 by day 90
16.6 (2.2) NG1O Compare continuous
16.7 (2.3) O
NG transitioning to
oral alone to oral
alone (historical
controls)
ff
NR
24-72 hr continuous
NG only, then nighttime NG 1 meals to
target 2400-3000
kcals/day
16.1 (0.93)cc
maximum kcals were
4350 (NG1O) and
3400 (O)
22.5 NG1O 12.1 (1.5) NG1O Compare 2-mo NG to
24.2 O
12.8 (2.0) O
NG 1 oral; target
weight gain rate 1 kg/
wk
22.8
11.3 (0.7)
30 with NG1O; 3 with
oral supplements and
IV glucose
14.9 O
Age (yrs)c
Admission
BMId (SD/SE)
Participant Characteristics
1,600–1,800 kcal
40 kcal/kg/day
72 hr NG (100 ml/hr),
then NG 1 1200-1400
meals
1500-1800 NG1O
1000-1200 O
1199
24–72 hr NG (100
ml hr21), then
NG 1 1,200–1,400
meals
1402
Based on REEz
400 kcal increments to
target wt gain of 1.0
kg wk21
Target 60 kcal/kg/day
at day 7
Variable, to attain
2400-3000 kcal/day
200
2508 by day 15; 2784
by day 30; 2935 by
day 60; 2871 by day
90
1895 by day 7; 2212
by day 15; 2510 by
day 30; 2683 by day
45; 3000 by day 60
Variable, to attain
2,400–3,000 kcal d21
600, 1080, 1200 on
first three days (NG),
oral kcals NR
Variable, to target
weight gain rate
0.22 H
0.17 L
0.71 PN1O
0.53 O
2.79 (wk 1)
1.34
(over 2.5 wk)
0.66 L
0.92 H
1.30
NR
0.63
1.36 NG1O
0.88 O
Rate of Weight
Gain (kg wk21)f
NR
3.8%
(PN1O only)
0%gg
3.6%ee
0%dd
NR
0%bb
0%aa
Rate
of RHg
Medical/Nutritional Outcomes
Starting Kcal d21 or
Nutrient Level
Caloric Advance
(Kcal d21)e
Refeeding Approach
Retrospective
Rigaud et al. 201056
3
Inpt nutr
Inpt psych
Study Settinga
7 PUFAkk
8 SFA
42 Nll
176 L
Nb
22.5 PUFA
17.7 SFA
22.1 N
23.3 L
Age (yrs)c
13.4 (1.1) PUFA
13.8 (1.8) SFA
13.8 (1.7) N
13.2 (1.2) L
Admission
BMId (SD/SE)
Participant Characteristics
Ad lib
NG1O
Meals
Method of
Delivery
Normal (4000–
4800 mg) vs. low
(1,600–2,000 mg) Na
diet
1,000 kcal
500 kcal increases to
goal of 1.2 kg wk21
Ad lib except for Na
b
1.4 PUFA
1.1 SFA
1.09 L; N was NR
Rate of Weight
Gain (kg wk21)f
NR
NR
Rate
of RHg
Medical/Nutritional Outcomes
Starting Kcal d21 or
Nutrient Level
Caloric Advance
(Kcal d21)e
Refeeding Approach
Inpt 5 inpatient; med 5 medicine; psych 5 psychiatry; CRC 5 clinical research center; outpt 5 outpatient; res 5 residential; nutr 5 nutrition.
For studies that included comparison groups, we report Ns separately for low-weight-gain (L) and high-weight-gain (H) interventions.
c
Age is presented as mean.
d
BMI5body mass index (kg/m2).
e
Rates of caloric advancement are calculated for some programs, who may not advance calories every day.
f
In some cases these rates are calculated rather than derived directly from the published reports, and not all patients stayed at least a week in all studies.
g
RH5refeeding hypophosphatemia.
h
NR5not reported; mean (SD) weight at admission was 39.9 (4.3) kg.
i
NR5not reported.
j
A and B refer to differing behavioral contracts (all participants started on same range of calories).
k
Mean (SD) % average body weight at the end of the baseline period (before refeeding began) was 63.8 (1.4).
l
Mean (SD) percent of ideal body weight was 72.7% (7.1).
m
Mean (SD) percent median BMI was 80.1 (11.5).
n
Mean (SD) percent ideal body weight was 62% (10).
o
Mean (SD) percent of ideal body weight was 72.9% (9.1).
p
Over the first two weeks of admission.
q
For studies that included comparison groups, Ns are reported separately for low-calorie (L) and high-calorie (H) interventions.
r
Mean (SD) percent median BMI was 77.6 (2.6) in the lower calorie group, 81.9 (1.8) in the higher calorie group.
s
Mean (SD) percent median BMI was 77.9 (9.6) in the lower calorie group, 78.7 (7.8) in the higher calorie group.
t
Mean (SD) percent ideal body weight was 75.8% (5.4).
u
Weight gain goal was 0.45-0.68 kg/wk.
v
Mean (SD) body weight was 34.51 (4.48) kg.
w
REE5resting energy expenditure.
x
NG5nasogastric refeeding; O5oral refeeding.
y
“There were no cases of refeeding syndrome.” (p 417)
z
REE5resting energy expenditure.
aa
Patients with BMI < 12 received prophylactic phosphorous supplementation.
bb
Most patients received prophylactic phosphorous supplementation.
cc
Mean (SD) percent ideal body weight was 79.1% (5.8).
dd
Patients received prophylactic phosphorous supplementation.
ee
All 6 patients with hypophosphatemia were in the oral-only group; however, 90.3% of patients in the enteral feeding group were on prophylactic phosphorous supplementation.
ff
Mean (SD) % expected body weight 5 78.4 (6.5).
gg
Patients received prophylactic phosphorous supplementation.
hh
PN5parenteral nutrition; O5oral.
ii
H5high protein (20% of calories from protein); L5low protein (10% of calories from protein).
jj
Mean (SD) % ideal body weight 5 69.25 (8.3).
kk
PUFA5n3 polyunsaturated fatty acids; SFA5saturated fatty acids.
ll
N 5 Normal sodium diet; L 5 low sodium diet.
a
Prospective
Study Design
Study Characteristics
Mauler 200955
Continued
2
TABLE 1.
GARBER ET AL.
weight gain, however no method to determine or
estimate the study participants’ energy needs was
provided. Such feeding protocols would be difficult
to reproduce given the caloric requirements for
weight gain vary markedly across age and sex29 and
during stages of refeeding.30–32 In fewer cases,
studies were excluded because they did not include
the outcomes of interest (weight gain, rate of RH or
cognitive/behavioral measures). Seven studies25, 33–38
met eligibility based on initial screening, but details
of the refeeding protocols were missing; these
details were subsequently obtained via author communication. A total of 27 studies were included in
the final systematic review and are summarized in
Table 1.
Quality of Selected Studies
More than half of the studies meeting our selection
criteria were published since 2010. Among all of
the selected studies, 96% had retrospective or
observational/prospective study designs. As
expected with these designs, the most common
types of bias were selection bias and bias due to
differential loss to follow-up. Studies attempted to
minimize these sources of error in different ways.
For example, to avoid the potential effect of recent/
multiple episodes of refeeding, two studies41,42
enrolled participants on their first hospital admission, while two others treated multiple admissions
as statistically independent events.35,40 To limit the
confounding effect of weight at presentation on the
relationship between caloric level and rate of
weight gain or occurrence of RH, two studies
adjusted analyses for %mBMI at admission.41,42
Nevertheless, selection bias whereby high risk
patients (with medical complications, severe malnutrition, and/or chronic illness) are disproportionately assigned to lower calorie refeeding groups
could result in poor outcomes being overly attributed to the lower calorie refeeding approach. Selection bias could also result in disproportionate
phosphate supplementation in patients perceived
as high risk26 and must be considered when interpreting rates of RH as an outcome. Differential loss
to follow-up can be a problem in long-term studies
with open follow-up, whereby the characteristics of
the remaining patient population become increasingly skewed as patients are lost to follow-up.
Although this is a recognized problem in long-term
outcome studies of AN57 it is unlikely to have
affected the one long-term study included here,
since the authors report that “all” patients returned
for follow-up.49 However, it is a possible source of
300
bias in the two studies41,42 using length of stay as
an outcome. In many short-term inpatient programs, especially those with standardized approaches to care, length of stay is a proxy for time to
restore medical stability. However, medically complicated patients may remain in hospital longer for
a variety of reasons, regardless of refeeding
approach. Because of this potential bias, and the
challenge of interpreting different lengths of stay
across treatment settings and different countries,
we did not include length of stay as a key outcome
for the present review.
Meal-Based Refeeding
Thirteen studies described meal-based approaches
to refeeding where the caloric level was divided
into meals and snacks; any liquid supplements
were taken orally and NG feeding was only used for
acute food refusal.
Six studies in this group examined lower calorie
diets, starting around 1,200 kcal day21 and advancing by about 100 kcal day21.18,25,32,36,37,39 Weight
gain was reported in five of these six studies and
ranged from 0.62 to 1.30 kg week21. Solanto et al.
(1994)36 and Garber et al. (2012)18 reported that
adolescents who were refed starting at 1,000–1200
kcal day21 and advancing by about 100 kcal day21
initially lost weight and then slowly gained at a rate
of 0.68–0.88 kg week21. Garber et al. (2012)18 further demonstrated an association between lower
caloric prescription, poorer weight gain, and longer
hospital stay in mildly malnourished adolescents
(around 85% of mBMI). These findings may be
partly explained by the excessive metabolic cost of
weight gain in AN: both Krahn et al.32 and Obarzenak et al.39 demonstrated a large rise in Resting
Energy Expenditure that was disproportionate to
the amount of weight gained after 1 week of weight
stabilization on lower calories and followed by 1
week of daily caloric increases to a specified weight
or caloric goal. On the other hand, Gaudiani et al.
(2012)37 demonstrated the utility of lower calorie
refeeding in severely malnourished patients (<70%
mBMI or BMI < 15 kg m22). This study was notable
for its comprehensive examination of medical
complications. Seventy-seven percent of the cohort
had abnormal liver function tests (LFTs), however,
they peaked in the first 4 days and improved with
refeeding.
A group of seven studies,35,38,40–44 starting with
Whitelaw et al. (2010), examined higher calorie
meal-based approaches to refeeding in hospitalized adolescents with AN. These approaches
International Journal of Eating Disorders 49:3 293–310 2016
REFEEDING IN PATIENTS WITH ANOREXIA NERVOSA
started between 1,500 and 2,400 kcal day21 and
advanced by 67–250 kcal day21. Rates of weight
gain were reported in all studies except El Ghoch
et al. (2014)44 and ranged from 0.62 to 1.98
kg week21. Maximal caloric prescriptions achieved
before discharge ranged from 2,800 to 4,350
kcal day21. These studies established the feasibility
of higher calorie meal-based refeeding to promote
weight gain in hospitalized adolescents with AN.
Only two studies compared lower versus higher
meal-based refeeding protocols.41,42 In a prospective observational study of 56 adolescents, Garber
et al. (2013)41 reported faster weight gain and a
mean 5.7 days shorter hospital stay in higher mealbased refeeding protocols, and in a retrospective
study of 310 adolescents, Golden et al. (2013)42
reported a mean stay of 3.6 fewer days.
Among the studies of lower18,25,37 and
higher35,40–43 calorie meal-based approaches, a
total of eight studies examined RH as an outcome.
Ornstein et al. (2003)25 were the first to explore
the rate of RH with caloric intake. This retrospective chart review found that 27.5% of mildly to
moderately malnourished adolescents hospitalized
with AN developed RH on a lower calorie refeeding approach starting at 1,200–1,400 kcal day21
and increasing by 200 kcal every 24–48 h. In addition, low percent of ideal body weight upon
admission was significantly associated with serum
phosphorus nadir during refeeding. This study
identified low admission BMI (or %mBMI) as a
risk factor for the development of RH in mildly to
moderately malnourished participants, an association confirmed by subsequent studies in this
group, including Whitelaw et al. (2010),40 Golden
et al. (2013),42 and Redgrave et al. (2015).35 On the
other hand, in severely malnourished/critically ill
patients, Gaudiani et al. (2012)37 did not find that
admission BMI predicted RH. The elevated transaminases commonly occurring in this study population (as mentioned above) were also not
predictive of RH; however they were associated
with the occurrence of hypoglycemia. Variable
approaches to electrolyte correction must be considered when interpreting these findings. For
example, Garber et al. (2013)41 reported that 36%
of adolescents received electrolyte correction, similar to Whitelaw et al. (2010).40 In contrast, Le
Clerc et al. (2013) reported that only one of thirty
patients required electrolyte replacement for low
serum phosphorus.43 All of the studies in this
group reported replacing phosphate as needed to
treat low or declining levels, and none reported
side effects of phosphate supplementation.
International Journal of Eating Disorders 49:3 293–310 2016
Four studies examined the association between
caloric intake or rate of weight gain and RH and
found no association. Golden et al. (2013)42
observed that 15.8% of adolescents developed RH,
and that RH was associated with lower BMI on
admission but not caloric intake. Consistent with
this, Garber et al. (2013)41 did not find differences
in electrolyte abnormalities between patients refed
using higher and lower calorie protocols. RH
occurred in 18.5% of a primarily adult cohort of
patients in the study by Redgrave et al. (2015)35
and was associated with admission BMI rather
than with rate of weight gain. Findings in severely
malnourished patients were consistent: Gaudiani
et al. (2012)37 found no association between caloric
intake and RH in the first 2–6 days of refeeding.
Only two studies of higher calorie meal-based
approaches have had sufficient sample sizes to
examine a subsample of severely malnourished
patients. In a study of 461 admissions for refeeding,
Redgrave et al. (2015)35 analyzed 135 adolescents
and adults with BMI < 15 kg m22 refed with meals
starting between 1,200 and 1,500 kcal, advancing
rapidly by 500 kcal every 2–3 days, supported by continuous intravenous (IV) 5% dextrose at 75 mL h21
and close medical monitoring until postprandial
blood glucose normalized. Weight gain was comparable to the higher BMI participants, but rates of RH
were higher (32.4% vs.18.5% in the whole sample).
Similarly, using a higher calorie refeeding approach
with careful medical supervision but without IV dextrose, Golden et al. (2013)42 compared a subsample
of severely malnourished adolescents (%mBMI 65%)
who were fed higher (N 5 31) vs. lower (N 5 18) calorie diets. Comparable weight gain was reported in
both groups. The rate of RH was higher in the
severely malnourished subsample than in the total
sample but did not differ by caloric prescription.
Only one study44 of meal-based refeeding reported
psychological outcomes, using a meals-only approach
to refeeding. El Ghoch (2014) assessed 50 adults with
chronic AN (mean length of illness of 8.7 6 6.7 years)
and severe malnutrition. The refeeding intervention
took place over 20 weeks (13 weeks inpatient and 7
weeks partial hospitalization) and began with 1,500
kcal to 2,500 kcal day21 for 3 weeks with subsequent
dietary intake aimed at achieving a weight gain goal of
0.45–0.68 kg week21. Participants also received intensive psychological treatment and cognitive behavioral
therapy for eating disorders. At the mean maximal
BMI achieved [19.6(0.8) kg m22], eating disorder
thoughts and behaviors [measured by the Eating Disorder Examination58] had improved significantly.
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GARBER ET AL.
Combined Approach with Nasogastric
Plus Oral Refeeding
Ten studies meeting inclusion criteria described
approaches to refeeding using NG feeding in combination with oral feeding. Five of these studies
began with a combination of supplemental NG
feeding and oral intake upon admission46,48–51;
three studies began with NG feeding only and then
introduced meals33,34,52; and one study began with
meals for 3 days, followed by 3 days of exclusive
NG tube feeding, followed by transition back to
meals only.45 NG feeding approaches were used to
deliver both lower and higher calorie loads. Rate of
weight gain was reported in all but one study33 and
ranged from 0.63 kg week21 in a study purposely
designed to deliver lower caloric loads to severely
malnourished/critically ill patients, to 2.79 kg week21
in a study of adolescents who were, on average,
moderately malnourished on average.34
Four studies in this group reported using lower
calorie approaches. Gentile et al. (2010, 2012)
focused on severely underweight adolescents and
adults with AN, with purposefully low weight gain
goals (0.5–1 kg week21) to minimize potential complications in these higher risk patients.50,51 Similar to
Gaudiani et al. (2012),37 biochemical and hematological parameters tended to improve during refeeding. This included LFTs, which were high in 43–48%
of participants at onset and improved after 30 and
60 days of refeeding.50 Robb et al. (2002) and Silber
et al. (2004) compared supplemental nocturnal NG
feeding in hospitalized adolescents to historical controls fed with meals alone.46,48 The rate of NG feeding was set to bring the total starting kcal level
(including meals) to 1,200 kcal day21 and was then
increased to support a consistent weight gain rate of
1–2 kg week21. With this method, Robb et al. (2002)
reported that the total mean calorie intake was
greater and weight gain was faster in the supplemental NG Group (3,255 kcal day21; 1.7 kg week21)
compared to those fed meals alone (2,508
kcal day21; 0.76 kg week21), with no difference in
the length of stay among 100 females.46 Silber et al.
(2004) confirmed this finding in 14 males.48
Three studies reported higher calorie approaches.
Hatch et al. (2010) and Madden et al. (2015)33,34
started with 24–72 h of continuous NG feeding in
adolescents that began at 2,400 kcal day21 and then
transitioned to a combination of NG feeding and
meals for a total of 2400–3,000 kcals day21 to achieve
a target rate of weight gain of 1 kg week21 (author
communication).33,34 This approach resulted in the
largest weight gain (2.79 kg in week 134) reported
among all of the studies included in the present
302
review. Agostino et al. (2013) utilized a similar NG
feeding approach, but began with a slightly lower
caloric level of 1,500 or 1,800 kcal day21 depending
on age. Weight gain was greater in the group that
received continuous NG feeding for 7 days and then
transitioned to include meals, as compared to historical controls who received only meals.52
The majority of studies in this group reported
using prophylactic phosphate supplementation.33,34,46,49–52 One used supplementation for all
participants with BMI< 12 kg m22,49 and another
supplemented all patients on NG but not mealsonly feeding.52 Among these studies reporting RH,
rates ranged from 0 to 3.6%.34,49–52 By contrast, in a
study where prophylactic phosphate was not used,
RH occurred in one-third of participants.45
The only study in this group to examine changes
in cognition and eating disorder psychopathology
was Hatch et al. (2010).33 At the end of the admission (12.7 weeks), participants showed significant
improvements in cognitive processing speed in sensorimotor tasks and cognitive inhibition and less
distractibility on memory tasks. The study did not
report improvement in eating disorder cognitions
measured by the Eating Disorder Inventory III or
obsessionality as measured by the Maudsley Obsessive Compulsive scale following weight restoration,
however there were significant improvements in
depression, anxiety, and stress as measured by the
Depression, Anxiety and Stress Scale.
Two studies in this group stand out due to differences in study setting and design. Zuercher et al.
(2003) was the only study meeting criteria for the
present review that was performed in a nonhospital setting.47 This study compared participants in a residential setting who elected to receive
supplemental NG feeding to those who chose
meals only and reported greater caloric intake and
weight gain in the NG group however no differences in eating disorder psychopathology (per the
Eating Disorder Inventory-2). Selection bias must
be considered when interpreting this finding since
NG feeding was voluntary and the group opting for
NG refeeding had significantly lower BMI upon
admission and stayed in the program longer.
Indeed, rates of weight gain were similar between
groups in statistical analyses adjusting for these
variables.
A second study worth mentioning due to differing
design was the only RCT comparing different
approaches to refeeding. Rigaud et al. (2007)49 compared 70 days of NG feeding twice daily plus meals
to meals alone in chronically ill young adults with a
duration of illness of 3–4 years, at least one prior
International Journal of Eating Disorders 49:3 293–310 2016
REFEEDING IN PATIENTS WITH ANOREXIA NERVOSA
hospitalization, and BMI >11 kg m22.49 The groups
were separated in time, so that patients on the unit
all received the same treatment; patients randomized to a treatment that was not active at the time of
randomization waited up to 3 months for admission. Calorie levels in both groups were adjusted
based on REE to produce a 1 kg week21 weight gain.
Patients were not restricted to bed, and there was little monitoring of activity levels during treatment.
Consistent with the other studies described
here,46,48, 52 the NG group consumed more calories
and gained more weight. Assessment of tolerance of
the NG feeds indicated that any emotional distress
occurred during the early phase of refeeding.
Patients required an average of two tube changes
over the 70-day course of treatment. No serious
physical complications were reported. There was no
difference in weight and eating disorder psychopathology at 1-year follow-up, however relapse was
delayed by 7 weeks in the NG-fed group.
Parenteral Refeeding
Only one study meeting our inclusion criteria
examined total parenteral nutrition (TPN). Diamanti et al. (2008) reported that TPN in combination with oral feeding resulted in a greater rate of
weight gain than oral feeding alone.53 The authors
recommended that the rate of initial parenteral
refeeding be limited to 600–800 kcal per day and
the amount of protein be limited to 2 g kg21 of
body weight to avoid development of refeeding
syndrome. Weekly weight gain rates were low in
both groups (<1 kg week21), and TPN treated
patients gained on average only 183 g week21 faster
than those fed orally. Various complications of TPN
were reported, including elevated transaminases,
lower extremity edema, and hypophosphatemia.
Refeeding with Altered Nutrient
Content
Three studies described refeeding protocols with
a nutrient content that differed significantly from
current dietary guidelines [such as the 2010 US
Dietary Guidelines for Americans,29 the 2006
Nutrient Reference Values in Australia and New
Zealand,59 and the United Kingdom Nutrient Reference Values60]. First, Forbes et al. (1984)54 compared diets beginning at higher caloric levels but
with lower and higher protein contents (10 vs.
20% of calories from protein) among 12 patients
with AN admitted to a CRC for up to 4 weeks.
They found no difference in rate of overall weight
International Journal of Eating Disorders 49:3 293–310 2016
gain, lean mass, or REE and concluded that a
high protein diet does not benefit body composition during refeeding. Second, Mauler et al.
(2009)55 performed a controlled (but not randomized) feeding study in 25 participants with AN in
an inpatient psychiatry unit comparing a diet
higher in omega-3 polyunsaturated fatty acid (X3) content to a diet with an equal proportion of
calories from saturated fat. No differences in
weight gain or serum leptin concentrations were
observed, lending no support to the hypothesis
that high X-3 diets may produce greater weight
gain through attenuated leptin levels. The third
and final study in this group was by Rigaud et al.
(2010),56 who compared a low-sodium (1,600–
2,000 mg) to a normal-sodium diet (4,000–
4,800 mg) in a non-randomized study among
severely malnourished adults with AN.56 Weight
gain and peripheral edema were greater on the
normal- compared to low-sodium diet, suggesting that reducing the sodium content of the
refeeding diet may be useful in managing fluid
shifts, especially in adults with a BMI < 15
kg m22.
We examined the studies included in the mealbased group (above) to determine if any conclusions could be drawn about the effect of nutrient
content on refeeding outcomes. Six of the thirteen
studies reported nutrient content of the refeeding
diet18,40–44; the nutrient information for an additional four studies was obtained by author communication.25,35–37 Within these 10 studies, the
macronutrient distribution of the diets was consistent with currently recommended29,59,60 ranges
(about 25–35% of calories from fat, 15–20% protein
and 50–60% carbohydrate). As a result, no association between differing nutrient content and refeeding outcome could be determined. Some refeeding
approaches reported using IV glucose35,50,51 due to
concerns of post-prandial hypoglycemia and the
risk of RH during the initial phase of refeeding.13,61
Gentile et al. (2012) described a protocol for refeeding severely malnourished adults (mean BMI 11.3
kg m22) that initially supplemented oral refeeding
with 10% glucose intravenously. As mentioned earlier, Redgrave et al. (2015) used a similar approach,
using 5% dextrose in severely malnourished
patients.35
Discussion
For many years, a low calorie approach to refeeding hospitalized patients with AN has been recommended, beginning around 1,200 kcal day2114–17 or
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GARBER ET AL.
lower17 and advancing slowly. The purpose of these
conservative approaches was to minimize the risk
of patients developing the refeeding syndrome. In
this respect, it could be argued that these
approaches have been successful, as only a few
cases of the refeeding syndrome have been
reported during the decades since lower calorie
approaches became the standard of care for refeeding in AN.9,62,63 However, lower calorie refeeding
has also been linked to poor weight gain18,36,41,42
and prolonged hospital stay.41,42 Increasing recognition that underfeeding leads to poor outcomes in
AN12 is contributing to a growing interest in higher
calorie refeeding in clinical practice and research,
as reflected in the results of the present systematic
review. Since 2010, ten studies have reported
approaches to refeeding beginning with 1,400
kcal day21 or more through meals alone35,40–44 or
from approaches that combine NG and oral feeding.33,34,52 Only two recent studies reported lower
calorie approaches, both in higher-risk (severely
malnourished) patients.37,51
We found marked heterogeneity in approaches
to higher calorie refeeding, with large variation in
starting calorie levels, rates of advancement, and
modes of delivery. The outcomes of interest were
likely influenced by these differences, in addition
to the effects of differences around length of stay,
approaches to electrolyte correction, type of program (medical or psychiatric), and level and duration of psychotherapy provided. For example, the
two available studies comparing groups on lower
and higher meal-based refeeding come from comparable adolescent medical in-patient units. However, the feeding protocols differed by both initial
calories and rate of energy advancement, which
may explain why one study reported a faster rate of
weight gain in the higher calorie group,41 and the
other did not.42 For these reasons, we did not
attempt to statistically quantify the relationship
between calories and weight gain across studies.
Nevertheless, our systematic review supports the
following evidence-based conclusions:
In Mild (%mBMI 80–90%) and
Moderately Malnourished (% mBMI
70–79%) Patients, Lower Calorie
Refeeding is Too Conservative
The large proportion of adolescents hospitalized in
medical stabilization units across the United
States,64 Canada,43 Australia,34,40 and the United
Kingdom65 are mildly to moderately malnourished
with relatively acute onset of AN. Studies have
304
linked lower calorie refeeding to poor outcomes in
this patient population, including poor weight gain
and prolonged hospital stay. Subsequent studies of
higher calorie refeeding in similar study populations, using either meals-only35,40–43 or NG feeding
in combination with meals,33,34,52 report similarly
good weight gain with wide variability in RH (see
below for a discussion of safety).
Meal-Based Approaches and
Combined Approaches Using NG
Feeding with Meals Can Be Used to
Administer Higher Calories to
Hospitalized Patients with AN
There is insufficient evidence at this time to determine the superiority of meal-based to nasogastric
plus meal-based refeeding approaches. This is
largely due to limitations in study design: studies
comparing supplemental enteral feeding to mealsonly approaches were not designed to determine
whether there was an independent effect of the
method of delivery. Instead, these studies collectively demonstrate that supplemental NG feeding is
useful for increasing the total caloric load.33,34,46–48
However, equally good weight gain has been
reported using meals-only approaches.35,40–44 Tolerance and/or acceptability could tip the balance in
favor of one approach over the other, however this
has not been sufficiently examined. One study of
higher calorie meal-based feeding reported that
patients could complete the higher calorie meals to
the same extent as those fed lower calorie meals,
and none required NG feeding41; other studies have
reported that 8%40 and 15%43 of adolescents on
higher calorie meal-based refeeding required supplemental NG feeding to meet caloric prescriptions.
In a study of supplemental NG feeding, patients
reported that it was acceptable when presented in
the context of a standardized protocol that is uniformly applied within a specialty program for the
treatment of AN.49 Acceptability of NG feeding is
supported by a large study in a residential setting47
and with qualitative research examining attitudes
among adolescents to an NG feeding protocol.66
Halse et al. reported that patients recognized the
medical rationale for placement of the tube but also
experienced some ambivalence towards the procedure, which may reflect a general resistance to
weight gain (rather than tube feeding per se).66 Prospective trials comparing meal-based with NG plus
meals are needed and should control for the number
of calories prescribed and carefully assess tolerance.
International Journal of Eating Disorders 49:3 293–310 2016
REFEEDING IN PATIENTS WITH ANOREXIA NERVOSA
Higher Calorie Refeeding Has Not
Been Associated with Increased Risk
for the Refeeding Syndrome under
Close Medical Monitoring with
Electrolyte Correction
No cases of refeeding syndrome were reported
within the studies of higher calorie refeeding.
Variable rates of RH, a sensitive marker of risk for
the refeeding syndrome,23 were reported without
incident. However, these aspects have not been
compared within a controlled trial, and there are
several limitations to the available evidence that
preclude a comparison of safety across
approaches to refeeding. First, sample sizes have
been generally small; a very large, multicenter
trial would be required to comprehensively
examine the full range of clinical features associated with the refeeding syndrome using various
refeeding approaches, since only a handful of
cases of cardiac arrest and death have been
reported in the AN literature.9,63,67 Second, while
patients with severe malnutrition are at highest
risk of RH24 they are not well represented in the
available studies. Third, the incidence of RH may
in fact be underrepresented by the current studies. This is due in part to the variety of
approaches to electrolyte correction that are currently used in clinical practice.26 RH has been
indicated by the lowest serum phosphorus level
during hospitalization, and it is possible that this
measure was obtained in participants who had
already begun receiving supplements (meaning
that a “true” nadir was never reached). Selection
bias could also contribute to the underestimation
of RH if more severely malnourished participants40 and/or those on higher calories were
more likely to receive phosphate supplementation.41 Fourth, the relative safety of different
methods of delivery has not been compared. The
hypothesis that continuous NG feeding (as
opposed to bolus feeds) ameliorates RH33,34,68
warrants examination. Finally, thresholds for low
serum phosphate levels vary among clinical laboratories and therefore there are likely differences
in dosing and timing of phosphate across studies.
Difference in these variables are likely to occur
even within clinical programs, related to differing
interpretation of and comfort level with borderline laboratory values. These limitations, together
with the gravity of the risk of the refeeding syndrome, underscore the need for close medical
monitoring when higher calorie approaches are
undertaken. Prospective studies using standardized protocols (for refeeding and electrolyte
International Journal of Eating Disorders 49:3 293–310 2016
replacement as well as admission and discharge
criteria) are needed.
In Severely Malnourished Inpatients
with an (BMI < 15 kg m22 in Adults or
mBMI < 70% in Adolescents), There is
Insufficient Evidence to Support
Changing the Current Standard of
Care for Refeeding
Greater caution continues to be used with more
severely malnourished, chronically ill, and/or
adult patients. A few recent studies have focused
on this population and uniformly demonstrated
improvements in the function of multiple organ
systems using a lower calorie approach with
slow advancement.37,50,51 These approaches
involved rigorous medical monitoring, for example, two studies used NG feeding with prophylactic oral phosphate and potassium and
intravenous glucose.50,51 It is not known whether
such critically ill patients could tolerate higher
caloric loads and what level of medical management this might require. Two studies of higher
calorie refeeding found comparable weight gain
and manageable RH in severely malnourished
sub-samples within larger studies of primarily
moderately malnourished patients. 35,42 While
low expected weight is a risk factor for RH in
such populations,24 among critically ill adults
with AN (average BMI around 13), Gaudiani
et al. (2012) reported that admission BMI did
not predict RH and neither did starting caloric
prescription.37 On the other hand, elevated
transaminases predicted the development of
hypoglycemia.37 Future studies are needed to
identify biochemical, behavioral, and anthropometric factors (such as rapidity/magnitude of
weight loss) that must be considered when
determining best approaches to refeeding.
TPN is Not Recommended Unless No
Other Form of Refeeding is Possible
Given the extent of weight gain that can be
achieved by other methods, the small incremental
increase in weight gain reportedly attributable to
supplemental TPN53 does not outweigh the potential risks. TPN is associated with high rates of significant complications and requires intensive
medical monitoring, which adds to its expense. In
a large nation-wide database study from Japan
(which was beyond the scope of this review
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GARBER ET AL.
because it included diagnoses other than AN),
Michihata et al. (2014)69 compared TPN alone
(N 5 278) to NG feeding (N 5 634). They found significantly higher rates of sepsis, disseminated
intravascular coagulation, and death in the TPN
group.69 Also beyond the scope of this systematic
review are case reports of both successful weight
restoration,70 as well as deaths from TPN refeeding in AN.63 Given the serious medical risks, further research is not indicated for TPN refeeding.
The only indication for administering TPN in AN
is when there are no alternatives for achieving
weight restoration. This may be considered in
cases where gastrointestinal complications preclude enteral refeeding (e.g., following gastroenterological surgery, or in the setting of severe
recurrent vomiting when naso-jejunal feeding has
also proven unsuccessful) or in the context of
acute hepatitis or pancreatitis.
Meals and Liquid Formulas with
Nutrient Compositions within
Recommended Ranges Are
Appropriate for Refeeding
The macronutrient composition of the diets used
in the studies included here fell within range of the
standard recommendations for the general population (25–35% of calories from fat, 15–20% protein,
and 50–60% carbohydrate).71–73 In theory, lowering
the glucose load of the diet or formula could
attenuate risk for the refeeding syndrome.68 This
may be accomplished by changing the nutrient
content of the diet, such as lower carbohydrate or
lower glycemic load meals or liquids. This has also
been postulated as a benefit of NG feeding,33,34,68
since delivering a formula at a lower, continuous
rate may avoid the wide glucose and insulin excursions associated with bolus-feeds. Another strategy
employed to ameliorate the post-prandial hypoglycemia associated with risk for the refeeding syndrome is to continuously infuse intravenous
glucose during the initial phase of refeeding.35,50,51
The only study that focused on micronutrient content was Rigaud et al. (2010),56 which indicated
that a lower sodium diet reduces fluid shifts during
refeeding in severely malnourished patients.
Beyond this review, Schebendach et al. reported
that dietary variety and energy density may predict
recovery outcomes in AN.74,75 Further study is
needed to build on these lines of evidence and
determine if there is an optimal nutrient profile for
refeeding in AN.
306
Research is Needed on Approaches to
Refeeding Outside of the Hospital
Weight restoration can be successfully achieved in
non-hospital treatment settings. A recent study has
shown there is no evidence to support extended
hospitalization as a strategy for weight restoration
in adolescents who were discharged from hospital
to Family Based Therapy (FBT), the ambulatory
treatment that has the strongest evidence for effect
in adolescents with AN. Madden et al. (2014) compared short-term medical stabilization to longerterm weight recovery in hospital, both followed by
FBT, and found no difference in 12-month weight
recovery despite about twenty additional days in
hospital.76 Other treatment settings include day
programs and residential programs.77–79 The only
clinical trial in these settings is a large scale German RCT by Herpertz-Dahlmann et al. (2014),80
which reported that, after a 3-week admission to
achieve medical stabilization, day treatment was
not inferior to prolonged hospitalization (14.5
weeks) at achieving weight restoration at 12
months in adolescents presenting for their first
admission for AN.80 An important feature of both
of these RCTs76,80 is that patients were required to
be physiologically stable prior to initiation of treatment. Therefore, these finding may suggest that
non-inpatient settings are cost-effective for longterm nutritional rehabilitation.76,80 Short-term
refeeding to restore medical stability is a critical
requirement for many patients.
There is insufficient evidence to attribute the relative success of various treatment settings to a particular refeeding approach at this time. Only one study
of refeeding in a non-hospital setting met criteria
for inclusion in this systematic review,66 and it was
biased by differing severity of illness between treatment groups. Most of the available studies did not
meet our requirement that the refeeding protocol be
described in sufficient detail that it could be reproduced in other settings. It is clear that FBT, an
approach where parents temporarily take control of
refeeding, produces superior remission rates
(weight and cognitive recovery at 12 months)
compared to adolescent-focused therapy in the outpatient setting.7 In both psychotherapeutic modalities, weight gain of 0.8–0.9 kg (1.7–1.9 lb) per week
during the first 3–4 weeks predicted remission at the
end of treatment. This importance of early weight
gain early for long-term recovery has been demonstrated by other studies in both the outpatient81–83
and inpatient settings.1–3 These findings underscore
the need to identifying approaches to refeeding that
can safely optimize weight gain.
International Journal of Eating Disorders 49:3 293–310 2016
REFEEDING IN PATIENTS WITH ANOREXIA NERVOSA
Successful components of refeeding approaches
that may be implemented in other treatment settings have not been identified. While it is tempting
to assume that higher calorie intake explains at least
some of the success of FBT, the rate of weight gain
predictive of remission7 is comparable to that in
hospital patients on lower calorie refeeding.18,41 On
the other hand, rates ranging from 1.3 to 1.98
kg week21 35,40–43 and as high as 2.79 kg week21 76
have been reported in patients on higher calorie
meals and combined NG feeding with meals in hospital, respectively. Thus, higher calorie intake alone
does not account for the success of treatment
modalities such as FBT. Researchers have elucidated
some cognitive and behavioral factors that moderate the success of FBT, such as eating disorder psychopathology,84 however comprehensive diet and
activity data have not been examined. Weight restoration strategies in FBT, such as parents limiting
physical activity or serving higher energy density
foods,74,75 have not been assessed. Identification of
these components, in addition to actual caloric level
and intake, nutrient quality, and eating behaviors
could facilitate the dissemination of successful components of FBT by clinicians who currently lack
guidance85 and across patient populations and settings, including those that lack parental involvement (such as young adults living independently or
those in residential settings). Future studies of
refeeding in all treatment settings should strive to
collect both dietary and activity data.
The Impact of Approaches to
Refeeding on Long-Term Outcomes is
Unknown
Studies associating better weight gain during
refeeding with improved recovery1–3,81–83 support
the hope that higher calorie refeeding could lead to
better outcomes. Unfortunately, there is currently
no evidence to support this. The only study comparing long-term outcomes of defined refeeding
protocols was an RCT that compared a higher calorie combined enteral and meal feeding group to a
lower calorie meals-only group and found no difference in 1-year weight recovery.49 However, this
study did report earlier relapse in the meals-only
group receiving lower calories. Limitations of this
study include an open follow-up design (discussed
earlier) and ‘wait-list’ randomization scheme,
whereby one group of patients may have become
sicker during the 3-month period while awaiting
treatment. Nevertheless, the possibility that higher
calorie refeeding may reduce relapse warrants furInternational Journal of Eating Disorders 49:3 293–310 2016
ther investigation since high relapse rates86 contribute to the recognition of AN as one of the most
“common and costly” primary mental health diagnoses in pediatrics.87
There is even less evidence to indicate how
refeeding approach may impact long-term cognitive and behavioral recovery. Hatch et al. (2015)
reported no reduction of eating disorder thoughts
and behaviors in acutely malnourished adolescents
after 12 weeks of higher calorie combined NG feeding plus meals.33 In contrast, El Ghoch et al. (2014)
reported significant improvements in eating disorder and general psychopathology after 20 weeks of
higher calorie refeeding in severely and chronically
malnourished adults. These discrepant findings
may be explained in part by differing lengths of
follow-up (12 vs. 20 weeks) and variable types and
intensity of psychotherapeutic interventions.44
Nevertheless, both of these studies demonstrate
that refeeding in hospital impacts cognitive recovery. There is a pressing need to examine how
refeeding that takes place over a relatively shortperiod can support the long-term goals of recovery,
since weight recovery in the absence of concomitant behavioral recovery does not bode well for
complete or sustained recovery and renders
patients vulnerable to relapse.88
Conclusion
This systematic review of approaches to refeeding
reflects a growing body of evidence that supports
higher initial calorie feeding and faster approaches
to increasing calories in hospitalized patients with
AN. Collectively, these studies demonstrate that
higher calorie approaches than currently recommended are feasible for refeeding mildly and moderately malnourished patients with AN who are in
hospital, where close medical monitoring is possible.
In severely malnourished and more chronically ill
patients, lower calorie approaches with slow
advancement may still have a role. TPN is not indicated in these patients. The current evidence indicates that equally good weight gain can be achieved
with meal-based approaches and approaches that
combine meals and NG feeding to supplement oral
intake. More evidence is needed to determine
whether higher calorie refeeding is also feasible in
non-hospital treatment settings, where rigorous
medical monitoring may not be possible. This is particularly important because the safety of higher calorie refeeding has not been established. More studies
are needed to determine best practices for electrolyte monitoring and correction. Another gap in the
307
GARBER ET AL.
evidence is nutrient content: the optimal refeeding
diet and/or formula is not known. The available
studies only indicate that higher calories can be
delivered in standard macronutrient ranges that are
consistent with the current dietary recommendations and that lower sodium diets may attenuate
fluid shifts in severely malnourished patients. While
reduced carbohydrate feeding has been suggested as
a means to reduce the risk of RH, this hypothesis has
not been tested. These research gaps highlight the
need for prospective studies to directly compare different approaches to refeeding. Such studies should
examine both short- and long-term outcomes, since
the benefits of higher calorie refeeding in hospital,
including faster weight gain or shorter hospital stay,
could be easily outweighed by unintended consequences, such as higher rates of relapse.
The authors thank Victoria G. Riese, MLIS, AHIP, Clinical Informationist at the Welch Medical Library of Johns
Hopkins Medical Institutions for executing the search
strategy. The authors have no conflicts of interest to disclose related to this paper, financial or otherwise.
Earn CE credit for this article!
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