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Use of a concentrated enteral nutrition solution to increase
calorie delivery to critically ill patients: a randomized, double-blind,
clinical trial1–3
Sandra L Peake, Andrew R Davies, Adam M Deane, Kylie Lange, John L Moran, Stephanie N O’Connor, Emma J Ridley,
Patricia J Williams, and Marianne J Chapman for the TARGET investigators and the Australian and New Zealand Intensive
Care Society Clinical Trials Group
ABSTRACT
Background: Critically ill patients typically receive w60% of estimated
calorie requirements.
Objectives: We aimed to determine whether the substitution of
a 1.5-kcal/mL enteral nutrition solution for a 1.0-kcal/mL solution
resulted in greater calorie delivery to critically ill patients and establish
the feasibility of conducting a multicenter, double-blind,
randomized trial to evaluate the effect of an increased calorie delivery
on clinical outcomes.
Design: A prospective, randomized, double-blind, parallel-group,
multicenter study was conducted in 5 Australian intensive care
units. One hundred twelve mechanically ventilated patients expected
to receive enteral nutrition for $2 d were randomly assigned
to receive 1.5 (n = 57) or 1.0 (n = 55) kcal/mL enteral nutrition
solution at a rate of 1 mL/kg ideal body weight per hour for 10 d.
Protein and fiber contents in the 2 solutions were equivalent.
Results: The 2 groups had similar baseline characteristics (1.5 compared
with 1.0 kcal/mL). The mean (6SD) age was 56.4 6 16.8
compared with 56.5 6 16.1 y, 74% compared with 75% were men,
and the Acute Physiology and Chronic Health Evaluation II score was
23 6 9.1 compared with 22 6 8.9. The groups received similar
volumes of enteral nutrition solution [1221 mL/d (95% CI: 1120,
1322 mL/d) compared with 1259 mL/d (95% CI: 1143, 1374 mL/d);
P = 0.628], which led to a 46% increase in daily calories in the
group given the 1.5-kcal/mL solution [1832 kcal/d (95% CI: 1681,
1984 kcal/d) compared with 1259 kcal/d (95% CI: 1143, 1374 kcal/d);
P , 0.001]. The 1.5-kcal/mL solution was not associated with larger
gastric residual volumes or diarrhea. In this feasibility study, there was
a trend to a reduced 90-d mortality in patients given 1.5 kcal/mL
[11 patients (20%) compared with 20 patients (37%); P = 0.057].
Conclusions: The substitution of a 1.0- with a 1.5-kcal/mL enteral
nutrition solution administered at the same rate resulted in a 46%
greater calorie delivery without adverse effects. The results support
the conduct of a large-scale trial to evaluate the effect of increased
calorie delivery on clinically important outcomes in the critically ill.
This trial was registered at Australian New Zealand Clinical Trials
(http://www.anzctr.org.au/) as ACTRN 12611000793910. Am J
Clin Nutr 2014;100:616–25.
INTRODUCTION
The optimal calorie delivery for critically ill patients is unclear.
It is widely believed that calorie delivery should approximate
energy expenditure; however, the direct measurement of energy
expenditure is rarely performed in routine clinical practice because
it is difficult and impractical. The calorie requirement is
usually estimated by using a variety of predictive equations,
which are believed to approximate energy expenditure, with
w25–30 kcal $ kg21 $ d21 generally recommended. There are 2
major difficulties in this approach. First, it has been universally
impossible to consistently deliver this amount of calories enterally
(1–4). Second, although such an approach is both logical
and plausible, the evidence to support the concept that matching
energy expenditure with calorie delivery improves clinical outcomes
has been limited to observational studies and small,
randomized, controlled trials (4, 5). Although it is logical that
energy delivery should match energy consumption (6), the
benefits of such matching remain to be confirmed by a robust,
high-quality clinical trial.
Enteral calorie delivery during critical illness has frequently
and consistently been shown to provide substantially less than the
full-recommended calorie requirement (3, 4, 7), mainly because
of gastrointestinal dysmotility, particularly delayed gastric
emptying (8), as well as fasting for procedures, surgery, and
radiology (9). In an attempt to increase calorie delivery, many
strategies have been tried with limited success, including promotility
drugs (10, 11), small intestinal catheters (12), aggressive
nutrition protocols (7), and supplemental intravenous nutrition
(13). Thus, there is a sizable and well-established dissociation
1 From the Queen Elizabeth Hospital (SLP, JLM, and PJW), the Royal
Adelaide Hospital (AMD, SNO, and MJC), the Discipline of Acute Care
Medicine, University of Adelaide, Adelaide, Australia; the Department of
Epidemiology and Preventive Medicine, Australian and New Zealand Intensive
Care Research Centre, Monash University, Victoria, Australia (ARD and
EJR); and the Centre for Research Excellence in Translating Nutritional
Science into Good Health, National Health and Medical Research Council,
University of Adelaide, Adelaide, Australia (KL).
2 Supported by the Royal Adelaide Hospital and the Australian and New
Zealand College of Anaesthetists. Provision and blinding of the study feed and
importation and delivery to the sites was provided by Fresenius Kabi (Germany).
3 Address correspondence to MJ Chapman, Intensive Care Unit, Royal
Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia. E-mail:
[email protected].
Received February 24, 2013. Accepted for publication May 29, 2014.
First published online June 25, 2014; doi: 10.3945/ajcn.114.086322.
616 Am J Clin Nutr 2014;100:616–25. Printed in USA. 2014 American Society for Nutrition
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between the recommended calorie requirement and calories actually
delivered. Concentrated formulae have been used frequently in
clinical practice (14),mainly to provide calories while limiting fluidvolume
administration; however, the safety and efficacy of the
administration of a concentrated formula at a higher delivery rate to
deliver 100% calorie goals has not been reported to our knowledge.
The primary aim of this study was to determine whether the
substitution of a 1.0-kcal/mL enteral nutrition solution with a 1.5-
kcal/mL solution delivered at the same rate resulted in the delivery of
more calories to critically ill patients over the first 10 d of their
enteral nutrition therapy. A secondary aim was to provide data to
inform the design of a large-scale, multicenter double-blind, randomized,
controlled trial to investigate whether additional enteral
calorie delivery to critically ill adults affects clinically important
outcomes by 1) establishing that the intervention could be blinded,
2) ensuring that the intervention could be safely delivered, 3) determining
event rates of various outcomes for the selected patient
population, 4) determining the recruitment rate, and 5) determining
the size of the treatment effect for the phase III primary outcome of
interest (90-d mortality).
SUBJECTS AND METHODS
Setting
This study was conducted in 5 Australian university-affiliated,
tertiary-referral, intensive care units (ICUs).
Patients
Patients aged $18 y who were undergoing invasive mechanical
ventilation and expected to receive enteral nutrition for $2 d were
randomly assigned to receive either a 1.5- or 1.0-kcal/mL enteral
nutrition solution. Patients were excluded if they had already received
.12 h enteral or parenteral nutrition during their ICU stay or
for whom the study goal rate was contraindicated (eg, requirement
for fluid restriction), or there was a requirement for a specific enteral
nutrition solution (as determined by the treating clinician).
Eligible patients were randomly assigned in a 1:1 ratio by using
a permuted block method with variable block sizes stratified by site.
Allocation concealment was maintained by using a centralized,
Web-based randomization schedule accessible 24 h a day.
Patients were recruited between 23 January and 4 May 2013,
and the study was carried out in accordance with the Helsinki
Declaration of 1975 as revised in 1983. All participating institutional
ethics committees approved the study and allowed
delayed consent to be sought from either the next of kin or the
patient. [Australian and New Zealand Clinical Trials Registry
(http://www.anzctr.org.au/); ACTRN 12611000793910].
Study design
This was a multicenter, randomized, controlled, parallel-group,
clinical feasibility trial. Patients, clinicians, and all study personnel
were blinded to caloric contents of study enteral nutrition solutions.
Intervention
The blinded enteral nutrition solutions were supplied by
Fresenius Kabi in identical 1-L bags, which differed only in terms
of the caloric concentration (Fresubin 2250 Complete 1.5 kcal/mL
compared with Fresubin 1000 Complete 1.0 kcal/mL; Fresenius
Kabi Deutschland GmbH) (Table 1). This difference in the caloric
concentration was shared between fat (0.058 compared
with 0.027 g/mL) and carbohydrate (0.18 compared with
0.125 g/mL). Protein and fiber contents in the study solutions
were similar at 0.056 compared with 0.055 g/mL and 0.015
compared with 0.02 g/mL for the 1.5- and 1.0-kcal/mL solutions,
respectively. The 2 study interventions were clinically
indistinguishable in color and packaging. The effectiveness of
the blinding was confirmed in a formal bedside study at participating
sites. In addition, to confirm the successful delivery of
allocated enteral nutrition solutions, an independent analysis of
the osmolality of the 1.5-kcal/mL (430 mOsm/kg H2O) and
1.00-kcal/mL (360 mOsm/kg H2O) solutions was obtained for
a random sample of 261 study bags by using freezing point
depression osmometry.
The study enteral nutrition was delivered at a goal rate of
1 mL $ kg ideal body weight (IBW)21 $ h21 in both groups.
IBW was calculated from measured height as follows (8):
IBWfor men ¼ ½heightðcmÞ 152:430:9 þ 50 ð1Þ
IBWwomen ¼ ½heightðcmÞ 152:430:9 þ 45:5 ð2Þ
Patients received study enteral nutrition for the duration of
their ICU stay up to a maximum of 10 d unless enteral nutrition
was ceased earlier. To reduce risk of potential overnutrition
(15–17), the maximum goal rate was 100 mL/h for all patients;
and at the discretion of treating clinicians, study enteral nutrition
could be ceased if the goal rate was achieved for 5 consecutive
days. Patients for whom consent to continue the study intervention
was withdrawn were analyzed according to the intention-to-treat
principle unless consent for data collection was refused.
Other than the goal rate, the duration and method of enteral
nutrition delivery were at the discretion of the treating clinician
according to the usual unit nutrition protocols, including the
commencement rate, increments, use of promotility drugs, and
small-intestinal feeding tubes. It was recommended that the goal rate
be achieved within 48 h of the commencement of enteral nutrition. If
supplemental parenteral nutrition was deemed necessary (eg, enteral
nutrition intolerance), it was assumed that patients were receiving
a 1.25-kcal/mL enteral nutrition solution to calculate the total calorie
delivery and determine the amount of parenteral nutrition to administer.
Stool sampleswere obtained from all patients with diarrhea
during the intervention period and screened for infectious causes and
Clostridium difficile toxin. Diarrhea was defined as $4 loose-bowel
actions within a 24-h period or the use of a fecal management
system for diarrhea control.
Blood glucose management was standardized, with the aim of
a blood glucose concentration #10 mmol/L. Blood glucose concentrations
#2.2 mmol/L were defined as a serious adverse event.
Data collection
Baseline data included patient demographics (age, sex, and
ideal and actual weights); ICU admission diagnosis, category
(elective or emergency surgical, medical), and Acute Physiology
and Chronic Health Evaluation II score; chronic comorbidities
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(including diabetes); and a dietitian assessment of nutritional
requirements. Data were collected daily for up to 14 d after
randomization included: study enteral nutrition, nonstudy nutrition
administration [parenteral nutrition, incidental calories
(eg, 50% dextrose and propofol), intolerance to enteral nutrition
(gastric residual volumes, diarrhea, and promotility agents),
highest and lowest blood glucose concentrations, and insulin
administration].
Outcomes
The primary outcome was the daily calorie delivery (kcal/d)
from study enteral nutrition. Secondary outcomes were as follows:
1) the daily total calorie delivery from enteral nutrition,
parenteral nutrition, and incidental calories; 2) daily enteral and
total calorie delivery calculated per unit of IBW (kcal $ kg21 $
d21); 3) ICU and hospital length of stay; 4) ventilator-free days
(defined as the number of days between successful weaning
from mechanical ventilation and day 28 after study enrollment
in patients who survived to 28 d); and 5) ICU, hospital, and
28- and 90-d mortality.
Statistical analysis
The sample size of 112 patients for the feasibility trial was
based on data from previous studies by our group and other
nutrition studies conducted in Australia and New Zealand (7).
With the assumption of a mean (6SD) daily calorie delivery with
enteral nutrition of 1300 6 400 kcal/d in the 1.0-kcal/mL (usual
treatment) group, the expectation of at least a 20% increase in
calorie delivery with the higher-concentration 1.5-kcal/mL solution,
and with the use of a 2-group t test at 5% significance and
80% power, the estimated minimum required sample size was
38 patients/ group (ie, 76 patients in total). To allow for morereliable
estimates of the recruitment rate and baseline mortality
and compensate for some recruited patients receiving less than
the anticipated 2 d of enteral nutrition, 112 patients (56 patients/
group) were enrolled.
All analyses were conducted according to the intention-to-treat
principle. No stopping rules or interim analyses were planned.
For missing data, the number of available observations was
reported, and missing values were not imputed. Continuous
variables are reported as means (6SDs) or median (IQRs).
Proportions are reported as percentages with 95% CIs. Differences
between groups were analyzed, as appropriate, by using
Student’s t test, Wilcoxon’s rank tests or Mann-Whitney U tests
for continuous variables and Pearson’s chi-square or Fisher’s
exact test for categorical variables. The overall calorie delivery
was calculated as total intake divided by the number of days fed
and expressed as intake per 24 h Daily intakes were analyzed in
linear mixed-effects models with fixed effects for group, day,
and the group by day interaction with a heterogeneous first-order
autoregressive covariance structure for repeated measurements.
Ventilator-free days to day 28 were calculated as previously
described (18). Patients who died before day 28 were assigned
zero ventilator-free days. Absolute risk differences with 95% CIs
for 90-d all-cause mortality are reported. The survival time from
random assignment to day 90 was compared using a Kaplan-
Meier analysis and the log-rank test. The length of stay was
analyzed by using log rank tests with death considered a
TABLE 1
Composition of the enteral nutrition solutions1
1.0 kcal/mL 1.5 kcal/mL
Nutritional composition (/100 mL)
Energy (kcal) 100 150
Protein (g) 5.5 5.6
Carbohydrate (g) 12.5 18
Sugars (g) 1.1 1.2
Lactose (g) #0.04 #0.03
Fat (g) 2.7 5.8
SFAs (g) 0.23 0.5
MUFAs (g) 1.73 3.7
PUFAs (g) 0.74 1.6
EPA and DHA (g) 0.05 0.03
Fiber (g) 2 1.5
Water (mL) 83 76
Osmolarity (mOsm/L) 300 325
Osmolality (mOsm/kg H2O) 360 430
Minerals and trace elements (/100 mL)
Sodium [mg (mmol)] 153 (6.7) 100 (4.3)
Potassium [mg (mmol)] 213 (5.4) 207 (5.3)
Chloride [mg (mmol)] 153 (4.3) 153 (4.3)
Calcium [mg (mmol)] 85 (2.1) 67 (1.7)
Phosphorus [mg (mmol)] 66 (2.1) 53 (1.7)
Magnesium [mg (mmol)] 35 (1.4) 24 (1)
Iron (mg) 2 1.33
Zinc (mg) 1.5 1.2
Copper (mg) 0.2 0.13
Manganese (mg) 0.4 0.27
Iodide (mg) 2.0 13.3
Chromium (mg) 10 6.7
Molybdenum (mg) 15 10
Fluoride (mg) 0.2 0.13
Selenium (mg) 10 6.7
Vitamins and other nutrients (/100 mL)
Vitamin A (mg) 105 70
b-Carotene (mg) 0.2 0.13
Vitamin D (mg) 1.5 1
Vitamin E (mg) 2 3
Vitamin K (mg) 10 6.67
Thiamine (mg) 0.2 0.13
Riboflavin (mg) 0.26 0.17
Niacin (mg) 2.4 1.6
Vitamin B-6 (mg) 0.24 0.16
Vitamin B-12 (mg) 0.4 0.27
Pantothenic acid (mg) 0.7 0.47
Biotin (mg) 7.5 5
Folic acid 40 26.7
Vitamin C (mg) 10 6.67
Choline (mg) 55 36.7
Typical fatty acid profile (g/mL)
14 (myristic acid) — 0.009
16 (palmitic acid) 0.16 0.291
16:n27 (palmitoeic acid) 0.02 0.011
18 (stearic acid) 0.09 0.144
18:1n29 (oleic acid) 1.95 3.486
18:2n26 (linoleic acid) 0.56 1.101
18:3 (a-linolenic acid) 0.23 0.418
20:5n23 (EPA) 0.03 0.029
22:6n23 (DHA) 0.02 0.019
n26:n23 ratio 2:1 2.3:1
Typical amino acid profile (g/100 mL)
Essential
Lysine 0.46 0.44
(Continued)
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competing event that precluded discharge. Deaths were censored
at values after the last observed discharge for ICU and
hospital stays.
Statistical analyses were performed with IBM SPSS Statistics
software (version 20, 2011; IBM Inc). Statistical significance was
defined as P ,0.05.
RESULTS
Study patients
Of 415 patients assessed for eligibility, 112 patients were
enrolled (1.5 patients per site per week) and randomly assigned to
receive 1.5 kcal/mL (57 patients) or 1.0 kcal/mL (55 patients)
enteral nutrition solution (Figure 1). All patients were assessed
for the primary outcome. One patient in the 1.5-kcal/mL group
requested to be withdrawn from the study on day 4, and one
patient in the 1.0-kcal/mL group was lost to follow-up by day 90.
Baseline characteristics
The mean age was 56.4 6 16.4 y, and the majority (74%) of
patients were men (74%) with an Acute Physiology and Chronic
Health Evaluation II score of 23 6 9.0. Seventy-one percent of
patients had a medical condition, and 14% of patients had an
emergency surgical condition. No differences in baseline characteristics
were observed between the 2 groups (Table 2). The
time from ICU admission to random assignment was not different
(21 h for both). A dietitian assessment of calorie requirements
was performed on 88 patients (79%), most
commonly by using a fixed prescription of 20–25 kcal/kg in 43
patients (48%) or Schofield’s equation (with or without a stress
factor) in 40 patients (45%). Dietitian-estimated daily calorie
requirements for the 1.5- and 1.0-kcal/mL groups were 19096
312 and 1840 6 318 kcal/d, respectively (P = 0.306).
Calorie delivery
The number of days study enteral nutrition was delivered over
the 10-d intervention period was 7 d (4–9 d) and 4 d (3–9 d) for
the 1.5- and 1.0-kcal/mL groups, respectively (P = 0.245). On
day 10, 15 patients (27%) and 14 patients (25%) were still receiving
study enteral nutrition in the 1.5- and 1.0-kcal/mL
groups respectively. Between days 11 and 14, 33 patients continued
to receive enteral nutrition [17 patients (30%) in the 1.5-
kcal/mL group; 16 patients (29%) in the 1.0-kcal/mL group].
The daily volume of study enteral nutrition delivered in the 2
groups was similar [1.5 compared with 1.0 kcal/mL:1221 mL
(95% CI: 1120, 1322 mL) compared with 1259 mL (95% CI:
1143, 1374) mL, respectively; P = 0.628] (Table 3). Overall,
there were a total of 364 feeding days in the 1.5-kcal/mL group,
and a daily goal rate (on the basis of 1 mL $ kg IBW21 $ h21)
was achieved on 136 d (37%). In the 1.0-kcal/mL group, there
were a total of 311 feeding days, and daily goal rate was achieved
on 137 d (44%). The number of patients who achieved
a goal rate on $1 d was 45 (82% of patients) and 47 (85% of
patients) in the 1.5- and 1.0-kcal/mL groups, respectively. The
time to achieve the goal rate was the same for both groups at 2
d (1–3 d). Reasons for not achieving the goal rate on any day
were similar between the 2 groups and included a planned endotracheal
extubation or procedure outside the ICU (63% of
patients), vomiting or regurgitation (22% of patients), large
gastric residual volumes (26% of patients) and enteral tube removal
or blockage (16% of patients).
The administration of the 1.5-kcal/mL enteral nutrition formula
resulted in a 46% greater daily calorie delivery [1832 kcal
(95% CI: 1681, 1984 kcal) compared with 1259 kcal (95% CI:
1143, 1374 kcal); P , 0.001) (Figure 2). The proportion of
estimated daily calorie requirements (on the basis of the dietitian’s
assessment) delivered by the study enteral nutrition was
102% and 72% for the 1.5- and 1.0-kcal/mL groups, respectively
(P , 0.001). The number of patients who achieved their estimated
daily caloric requirements on one or more study feeding
days was 40 patients (89%) and 7 patients (16%) in the 1.5- and
1.0-kcal/mL groups, respectively (Figure 3). Protein delivery
was the same for both groups (Table 3), with 75% of that estimated
by the dietitian in the 1.5-kcal/mL group and 79% of that
estimated in the 1.0-kcal/mL group.
Enteral nutrition calories delivered per kilogram of IBW were
substantially greater in the group given 1.5 kcal/mL than for
the group who received 1.0 kcal/mL (27.3 6 7.4 compared with
19.0 6 6.0 kcal $ kg21 $ d21, respectively; P , 0.001) (Table 3).
Total daily calorie delivery from study solution, parenteral nutrition
and other calorie sources combined was also higher for
the 1.5-kcal/mL group (P , 0.001).
TABLE 1 (Continued)
1.0 kcal/mL 1.5 kcal/mL
Threonine 0.26 0.26
Methionine 0.16 0.13
Phenalanine 0.29 0.32
Tryptophan 0.08 0.08
Valine 0.40 0.39
Leucine 0.55 0.56
Isoleucine 0.32 0.33
Conditionally essential — —
Tyrosine 0.3 0.28
Cysteine 0.03 0.05
Taurine — —
Histidine 0.16 0.17
Arginine 0.20 0.34
Nonessential
Glycine 0.10 0.21
Alanine 0.18 0.24
Proline 0.55 0.48
Serine 0.34 0.36
Glutamine 0.52 0.52
Glutamic acid — 0.73
Glutamine and glutamic acid 0.68 —
Aspartic acid and asparagine 0.41 0.58
Typical carbohydrate profile (g/100 mL)
Glucose 0.2 0.2
Fructose 0.08 0.03
Maltose 0.72 0.93
Sucrose 0.06 0.04
Lactose #0.04 #0.03
Polysaccharides and oligosaccharides 11.5 17.4
Starch — 0.2
1 Formulae: 1 kcal/mL (Fresubin 1000 Complete tube feed; Fresenius
Kabi Deutschland GmbH); 1.5 kcal/mL (Fresubin 2250 Complete tube feed;
Fresenius Kabi Deutschland GmbH).
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An independent analysis of the osmolality of a random sample of
study bags confirmed the delivery of the allocated solutions [1.5
kcal/mL (n = 147); median (IQR): 496 mOsm/kg H2O (488–507
mOsm/kg H2O) compared with 1.0 kcal/mL (n = 114); 383 mOsm/
kg H2O (377–388 mOsm/kg H2O); P , 0.001]. The 2 blinded
feeds were clinically indistinguishable (P = 1.0; Fisher’s exact test).
Clinical outcomes
At 90 d, 11 patients (20%) in the 1.5-kcal/mL group and 20
patients (37%) in the 1.0-kcal/mL group had died (P = 0.057;
Fisher’s exact test) (Table 4). The absolute risk reduction in
mortality for the 1.5-kcal group compared with the 1.0-kcal/mL
group was 17% (95% CI: 0.6, 33). The survival time from
random assignment to day 90 tended to be longer in patients
who received the 1.5-kcal/mL formula (P = 0.057) (Figure 4),
and there was no difference in the proximate cause of death (P =
0.882) (Table 3). ICU, hospital, and 28-d mortality were not
different between the 2 treatment groups. One patient in the 1.5-
kcal/mL group and 6 patients in the 1.0-kcal/mL group died
after hospital discharge. The number of mechanical ventilationfree
days to day 28, ICU, and hospital length of stay (for survivors
only) and destination at hospital discharge were also not
different (Table 3).
Complications of therapy
Enteral nutrition was never ceased because of treating clinician
concerns of overnutrition. Supplemental parenteral nutrition was
administered to 4 patients (1.5 kcal/mL, 2 patients; 1.0 kcal/mL, 2
patients). There was no difference between groups in terms of
gastrointestinal intolerance (large gastric residual volumes, use of
promotility or laxative agents, and diarrhea) (Table 3). Two of 40
patients with diarrhea had Clostridium difficile toxin detected.
The increased calorie delivery in the 1.5-kcal/mL group was
associated with a trend to a slightly higher peak blood glucose
concentration over the 10-d study period (1.5 kcal/mL; 12.4 6
3.9 mmol/L compared with 1.0 kcal/mL; 12.0 6 3.9 mmol/L;
P = 0.056); but the number of patients who required insulin on
$1 d was no greater in the 1.5-kcal/mL group [1.5 kcal/mL (54%)
compared with1.0 kcal/mL (42%); P = 0.183]. No episodes of
hypoglycemia (#2.2 mmol/L) were reported.
DISCUSSION
In this multicenter, randomized, double-blind study, the administration
of a 1.5-kcal/mL enteral nutrition formula resulted in
a near 50% increase in calorie delivery compared with a 1.0-kcal/mL
formula in mechanically ventilated patients. To our knowledge,
FIGURE 1. Patient flow diagram. Numbers of patients enrolled in the study, randomly assigned to receive 1.5- or 1.0-kcal/mL enteral nutrition solution,
and included in the final analysis. *1n = 1 lost to follow-up and excluded from the secondary outcome analysis: 90-d mortality; *2n = 1 withdrawal of consent
on study day 4. (Included in the intention-to-treat analysis of the primary endpoint, but data were not available beyond study day 4 for secondary outcomes.)
EN, enteral nutrition; PN, parenteral nutrition.
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this is the first study in this patient population to describe the use
of a concentrated enteral nutrition formula to deliver more calories
to patients in a double-blind fashion. Furthermore, in this
feasibility study, we have confirmed the effectiveness of the
blinding process, identified a cohort of critically ill patients
whose outcome may be improved by increased calorie delivery
(ie, longer-stay, mechanically ventilated patients with a 90-
d mortality w28%), and established the potential recruitment
rate and treatment-effect size necessary for sample-size calculations
for a large-scale trial.
Previous studies designed to deliver more calories to critically
ill patients have used techniques including nutrition protocols (7,
19–21) and small-intestinal feeding catheters (12, 22, 23). Both
strategies have had small effects on calorie delivery. The administration
of promotility drugs or supplemental parenteral
nutrition has resulted in a greater calorie delivery, but it is unclear
if this method offers advantages in terms of clinically
meaningful outcomes (10, 13, 24, 25). It is also possible that
potential benefits from an increased calorie delivery may be
outweighed by adverse effects from the method used. In the
EDEN study, a difference in enteral calorie delivery was achieved,
but in the full-feeding group, only 1300 kcal/d were delivered,
which was a similar amount of calories as was given to
our 1.0-kcal/mL group (1259 kcal/d; 19.0 kcal $ kg21 $ d21) (26).
In contrast, we have shown that .1800 kcal/d (27 kcal $ kg
IBW21 $ d21) was delivered to a heterogeneous population of
critically ill patients by using a 1.5-kcal/mL enteral nutrition
solution. Although the EDEN study results suggested there was no
difference in clinical outcomes when the administration of 1300
compared with 400 kcal/d was compared for the first week of ICU
nutrition therapy, it remains a plausible hypothesis that the delivery
of 1800 kcal/d (which is closer to expected requirements)
could be associated with improved clinical outcomes.
The use of concentrated enteral nutrition solutions has become
more popular in recent years in ICU patients (14). Concentrated
solutions may be prescribed when a patient is intolerant to enteral
nutrition on the assumption that the delivery of lower volume,
greater caloric content solutions may be better tolerated to allow
increased calorie delivery (14). This premise has never been
proven. Conversely, it is possible that concentrated solutions may
be less-well tolerated because of the formula being emptied more
slowly from the stomach into the small intestine, leading to
increased gastric residual volumes (27). There have also been
concerns that concentrated enteral nutrition solutions may be
associated with increased osmotic diarrhea (28); although studies
have refuted this association (29). The effects of concentrated
solutions on clinical outcomes, including mortality, have also
been questioned in an observational study of critically ill trauma
TABLE 2
Baseline characteristics of the study patients1
Variable 1.5 kcal/mL (n = 57) 1.0 kcal/mL (n = 55) P2
Age (y) 56.4 6 16.83 56.5 6 16.1 0.964
M 42 6 74 41 6 75 0.917
APACHE II score 23 6 9.1 22 6 8.9 0.560
APACHE III diagnostic code [n (%)] 0.442
Cardiovascular 12 (21) 8 (15)
Respiratory 9 (16) 12 (22)
Gastrointestinal 4 (7) 3 (6)
Neurological 8 (14) 15 (27)
Sepsis 7 (12) 4 (7)
Trauma 11 (19) 6 (11)
Other 6 (11) 7 (13)
ICU admission category [n (%)] 0.095
Emergency operative 11 (19) 5 (9)
Emergency nonoperative 35 (61) 44 (80)
Elective operative 11 (19) 6 (11)
Past medical history diabetes mellitus [n (%)] 13 (23) 13 (24) 0.917
BMI (kg/m2) 27.8 6 7.9 26.2 6 6.4 0.241
Actual weight4 (kg) 83 6 23.2 77 6 16.4 0.118
IBW5 (kg) 67 6 9.2 67 6 9.1 0.675
Energy requirements6 (kcal/d) 1909 6 312 1840 6 318 0.306
Protein requirements6 (g/d) 91 6 16 87 6 12 0.178
Time from ICU admission to random assignment7 (h) 21 (13–36) 21 (13–41) 0.836
SI tube [n (%)] 4 (7) 1 (2) 0.364
1 APACHE, Acute Physiology and Chronic Health Evaluation; IBW, ideal body weight; ICU, intensive care unit; SI,
small intestinal.
2A chi-square test was used to determine differences in baseline categorical variables, and a Student’s t test was used
for all continuous variables except time from ICU admission to random assignment (Mann-Whitney U test).
3 Mean 6 SD (all such values).
4 Actual weight was measured or estimated if not possible.
5 IBW was calculated by using the measured height and the following formulae: IBW for men = [height (cm) – 152.4)
3 0.9 + 50; IBW for women = [height (cm) – 152.4] 3 0.9 + 45.5.
6 Energy and protein requirements were estimated by the dietitians at the site at study entry.
7Values are medians; IQRs in parentheses.
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TABLE 3
Nutrition data1
Variable 1.5 kcal/mL (n = 57) 1.0 kcal/mL (n = 55) P2
Calories (overall/24-h study period)
Study EN (kcal) 1832 6 3813 1259 6 428 , 0.001
Study EN/kg (kcal/kg) 27.3 6 7.4 19.0 6 6.0 , 0.001
Study EN 2 GRV (kcal) 1699 6 682 1194 6 454 ,0.001
EN + PN + other (kcal) 2040 6 578 1504 6 573 , 0.001
(EN + PN + other) 2 GRV (kcal) 1617 6 740 1291 6 623 0.014
Protein (overall/24-h study period)
Study EN (g) 68 6 21 69 6 24 0.847
Study EN/kg (g/kg) 1.02 6 0.28 1.05 6 0.33 0.618
EN + PN + other (g) 70 6 20 74 6 30 0.395
Volume (overall/24-h study period)
Study EN (mL) 1221 6 381 1259 6 428 0.628
Gastric residual volume (mL)
Total volume/24 h 166 (48–324)4 80 (37–261) 0.260
Returned/24 h 126 (41–262) 70 (29–145) 0.050
Largest individual measurement 200 (50–360) 105 (40–278) 0.129
Regurgitation (over study period) [n (%)] 12 (21) 13 (24) 0.743
Promotility drugs (over study period) [n (%)] 28 (49) 25 (46) 0.697
Laxative drugs (over study period) [n (%)] 36 (63) 29 (53) 0.263
Fecal management system [n (%)] (over study period) 8 (14) 13 (24) 0.193
Diarrhea [n (%)] 20 (35) 20 (36) 0.888
Day first had diarrhea 5 (3–8) 4 (2–6) 0.369
Insulin dose, mean dose/d (IU) 55 (22–131) 43 (24–67) 0.308
Blood glucose concentration #2.2 mmol/L [n (%)] 0 (0) 0 (0) —
1 In variables, “other” refers to incidental calorie intake provided by propofol and dextrose infusions. EN, enteral nutrition; GRV, gastric residual volume;
PN, parenteral nutrition.
2 Differences between 1.5- and 1.0-kcal/mL enteral nutrition solutions were assessed by using a Student’s t test for all continuous variables except for
measures of gastric residual volume, the day the patient first had diarrhea, and insulin dose (Mann-Whitney U test), and a chi-square test was used for
categorical variables.
3 Mean 6 SD (all such values).
4 Median; IQR in parentheses (all such values).
FIGURE 2. Mean (6SD) daily calorie delivery over the 10-d study-intervention period. A: Calories provided by the study enteral solution (kcal). B:
Calories per kilogram of ideal body weight provided by the study enteral solution (kcal/kg). C: Calories provided by study enteral solution (kcal) minus the
gastric residual volume (kcal). D: Total calories provided by the study enteral solution (kcal) plus intravenous nutrition, propofol, and glucose infusions (kcal).
622 PEAKE ET AL
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and surgical patients (22). This current study has shown that the
use of a concentrated solution is both effective and safe in delivering
more calories. There was no difference in enteral intolerance
(gastric residual volumes, regurgitation, use of
promotility drugs, or diarrhea) or glucose control between the 2
enteral nutrition solutions. Although our study was not powered
to detect differences in adverse effects, the sample size was
sufficient to observe useful numbers of events for these important
potential complications. The results also provide information to
determine the sample size for an adequately powered, future,
large-scale study for these outcomes.
To our knowledge, this is the first enteral nutrition study to
successfully blind the study intervention in this patient population
(26, 30). The concealment of the intervention was important
to prevent inadvertent bias (31). In previous studies,
blinding of the intervention has not been undertaken, which raises
concerns about reported differences in outcomes, particularly
when outcomes were subject to an ascertainment bias (eg,
nosocomial infections and functional outcomes) (6, 24, 25). We
were able to overcome the substantial logistical problems of
designing a double-blind enteral nutrition study by using 2
commercially available enteral nutrition solutions that were
similar in color, indistinguishable at the bedside, and delivered at
the same flow rate and volume to both study groups.
This feasibility study had several limitations. The study was
not powered to detect a mortality difference. However, as noted
by the Australian and New Zealand Clinical Trials Group consensus
panel meeting on endpoints for phase II trials, a signal for
improved survival supports the conduct of a phase III trial with
90-d survival as the primary outcome of interest (32). Nevertheless,
note that there were less deaths at 90 d numerically in the
group who received more calories. If calorie delivery affects
outcomes, it is likely to be late, possibly after ICU discharge. Our
findings suggest that the effects of nutritional interventions on
post–ICU-discharge mortality should be rigorously sought.
Another limitation of our study is that we did not assess
functional outcomes. However, there was no difference between
the 2 groups in the destination after hospital discharge, which
could be considered a crude measure of the functional outcome.
FIGURE 3. Mean (6SD) estimated goal calories delivered per day from
1.5- and 1.0-kcal/mL enteral nutrition solutions. Estimated daily caloric requirements
were based on the dietitian’s assessment at study entry [available
for 88 patients (79%)].
TABLE 4
Clinical outcome data1
Variable 1.5 kcal/mL (n = 57) 1.0 kcal/mL (n = 55) P
Number of ventilator-free days to day 28 21.1 (3.4–25.0)2 18.7 (0–25.6) 0.638
Duration of ICU stay (d)3 9.6 (5.9–22.6) 11.8 (6.9–22.8) 0.408
Duration of hospital stay (d) 34.5 (16.9–83.6) 30.6 (15.2–undefined)4 0.700
Destination at hospital discharge [n (%)]
Home 21 (48) 19 (50) 0.953
Rehabilitation facility 10 (23) 7 (18)
Another acute care hospital 9 (21) 9 (24)
Chronic care facility 4 (9) 3 (8)
Mortality [n (%)]
ICU mortality 6 (11) 9 (16) 0.419
Hospital mortality [n (%)] 10 (19) 14 (27) 0.357
28-d mortality [n (%)] 11 (20) 18 (33) 0.135
90-d mortality [n (%)] 11 (20) 20 (37) 0.057
Duration of survival (d) 77 6 4.55 68 6 5.6 0.057
Proximate cause of death [n (%)]
Cardiovascular 4 (36) 6 (30) 0.882
Respiratory 2 (18) 6 (30)
Neurologic 4 (36) 7 (35)
Other 1 (9) 1 (5)
1 Differences between 1.5- and 1.0-kcal/mL enteral nutrition solutions were assessed by using a Mann-Whitney U test
for continuous variables, a chi-square test for categorical variables, and a Fisher’s exact test for mortality. ICU, intensive
care unit.
2 Median; IQR in parentheses (all such values).
3 ICU, intensive care unit.
4 The IQR was undefined when .25% of patients died or were not discharged from the primary hospital.
5 Mean 6 SE (all such values).
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The National Heart, Lung and Blood Institute Acute Respiratory
Distress Syndrome Clinical Trials Network group looked at
functional outcomes in a subset of patients enrolled in the
EDEN study and showed that there was no benefit in the administration
of 1300 compared with 400 kcal/d on functional
outcomes at 12 mo, albeit only 174 patients were included in
this subgroup analysis (33). Future studies that investigated the
effect of nutrition in this population should also include
functional outcomes.
Finally, it is important to emphasize that the optimal dose of
protein administration in critical illness is unclear. In this study,
both groups of patients receivedw1 g $ kg21 $ d21. Establishing
the feasibility of delivering 2 enteral nutrition solutions with
different caloric contents but the same protein contents would
allow additional investigation on the isolated effects of calorie
delivery. However, it should be noted that the difference in
calorie delivery achieved in this study reflected a difference in
carbohydrate and lipid concentrations in the 2 formulae, and the
effect of the macronutrient composition on clinical outcome is
an area that needs additional attention. Future clinical studies
that examined the effect of enteral nutrition on clinical outcomes
will need to carefully consider the calorie and protein balance.
In conclusion, the substitution of a standard 1.0-kcal/mL enteral
nutrition solution with a concentrated 1.5-kcal/mL solution, administered
at the same rate, resulted in anw50% increase in calorie
delivery. The delivery of more calories was achieved in a blinded
fashion and was also associated with a trend to improved survival.
These data support the conduct of a large, multicenter, randomized,
double-blind trial to determine whether the delivery of more calories
by using a concentrated enteral nutrition solution can result in
improved survival and functional outcomes for critically ill patients.
We are grateful for the assistance provided by Donna Goldsmith for the
unblinded management of study formulae distribution. Participating site investigators
(in alphabetical order) were as follows—Austin Health: Rinaldo
Bellomo, Leah Peck, and Helen Young; Royal Adelaide Hospital: SNO,
Justine A Rivett, and Sonya L Kloeden; Royal Prince Alfred Hospital: Suzie
Ferrie, Heidi Buhr, and Megan Keir; The Canberra Hospital: Sumeet S Rai,
Helen Rodgers, and Louise Herlihy; and The Queen Elizabeth Hospital: SLP,
Joanne McIntyre, and Jennie Phillips-Hughes.
The authors’ responsibilities were as follows—MJC, ARD, AMD, SNO,
SLP, EJR, and PJW: were management committee members and designed the
research (project conception, development of overall research plan, and study
oversight); MJC, ARD, AMD, KL, JLM, SNO, SLP, and EJR: formed the
writing committee and were responsible for drafting the manuscript; RB,
MJC, SF, SSR, and SLP: were involved in the study design, and management;
other participating site investigators: conducted the research (hands-on conduct
of experiments and data collection); KL and JLM: were involved in the
study design, analyzed data, performed statistical analyses, and participated in
the preparation of the manuscript; SLP and MJC: co-chaired the management
and writing committees, had responsibility for the final content of the manuscript.
Fresenius Kabi had no influence over the study protocol or the analysis
or interpretation of the results. None of the authors had a conflict of interest.
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