Association between illness severity and timing of initial enteral feeding in critically ill patients: a retrospective observational study
Association between illness severity and timing of initial enteral feeding in critically ill patients: a retrospective observational study
Hsiu-Hua Huang 0 2 3
Chien-Wei Hsu 1 3 6
Shiu-Ping Kang 3 5
Ming-Yi Liu 0 3 4
Sue-Joan Chang 0 3
0 Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University , No.1, University Rd., Tainan City 701 , Taiwan
1 Medicine Department, School of Medicine, National Yang-Ming University , No.155, Sec.2, Linong Street, Beitou Dist., Taipei City 11221 , Taiwan
2 Department of Food and Nutrition, Taipei Veterans General Hospital , No.201, Sec. 2, Shipai Rd., Beitou Dist., Taipei City 11217 , Taiwan
3 Authors' information HH-H , RD, MS , Chief of Foodservice Management Division, Department of Food and Nutrition, Taipei Veterans General Hospital (a 3000-bed teaching hospital). Board Director of Taiwan Society for Parenteral and Enteral Nutrition. Executive Supervisor of Kaohsiung Dietetic Association. HC-W, MD, Visiting Doctor of Intensive Care Unit, Department of Medicine, Kaohsiung Veterans General Hospital (a 1361-bed teaching hospital). Assistant Professor of Medicine, School of Medicine, National Yang-Ming University. KS-P, RN, MS , Registered Nurse of Nutrition Support Team, Kaohsiung Veterans General Hospital (a 1361-bed teaching hospital). L M-Y , RD, MS , Chief of Department of Nutrition, Sin-Lau Hospital (a 526-bed regional hospital). Board Director of Tainan Dietetic Association. C S-J, PhD , Distinguished Professor of Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University. Secretary General of Health Food Society of Taiwan
4 Department of Nutrition, Sin-Lau Hospital , No. 57, Sec. 1, Dongmen Rd., Tainan City 70142 , Taiwan
5 Department of Nursing, Kaohsiung Veterans General Hospital , No. 386, Ta-Chung First Rd., Zouying Dist., Kaohsiung City 81362 , Taiwan
6 Intensive Care Unit, Department of Medicine, Kaohsiung Veterans General Hospital , No. 386, Ta-Chung First Rd., Zouying Dist., Kaohsiung City 81362 , Taiwan
Background: Early enteral nutrition is recommended in cases of critical illness. It is unclear whether this recommendation is of most benefit to extremely ill patients. We aim to determine the association between illness severity and commencement of enteral feeding. Methods: One hundred and eight critically ill patients were grouped as less severe and more severe for this cross-sectional, retrospective observational study. The cut off value was based on Acute Physiology and Chronic Health Evaluation II score 20. Patients who received enteral feeding within 48 h of medical intensive care unit (ICU) admission were considered early feeding cases otherwise they were assessed as late feeding cases. Feeding complications (gastric retention/vomiting/diarrhea/gastrointestinal bleeding), length of ICU stay, length of hospital stay, ventilator-associated pneumonia, hospital mortality, nutritional intake, serum albumin, serum prealbumin, nitrogen balance (NB), and 24-h urinary urea nitrogen data were collected over 21 days. Results: There were no differences in measured outcomes between early and late feedings for less severely ill patients. Among more severely ill patients, however, the early feeding group showed improved serum albumin (p = 0.036) and prealbumin (p = 0.014) but worsened NB (p = 0.01), more feeding complications (p = 0.005), and prolonged ICU stays (p = 0.005) compared to their late feeding counterparts. Conclusions: There is a significant association between severity of illness and timing of enteral feeding initiation. In more severe illness, early feeding was associated with improved nutritional outcomes, while late feeding was associated with reduced feeding complications and length of ICU stay. However, the feeding complications of more severely ill early feeders can be handled without significantly affecting nutritional intake and there is no eventual difference in length of hospital stay or mortality between groups. Consequently, early feeding shows to be a more beneficial nutritional intervention option than late feeding in patients with more severe illness.
Severity of illness; Early enteral feeding; Late enteral feeding; Critical illness
Critical illness changes substrate metabolism, thereby
altering body compositions and worsening clinical
outcomes . Intensive care unit (ICU) patients are
susceptible to malnutrition, immune dysfunction, severe
infections, multiple organ dysfunction, and death [2,3].
Early enteral feeding improves clinical outcomes, reduces
gastric intolerance, and promotes early reestablishment of
gastroduodenal motility [4,5]. Patients experiencing early
enteral feeding (within 24 to 48 h following ICU
admission) demonstrate reduced gut permeability and cytokine
release, compared to late enteral feeding patients (after
72 h) . However, Ibrahim et al. observed that the
administration of early enteral nutrition to mechanically
ventilated medical patients is associated with more severe
infectious complications and prolonged ICU stays .
Minard et al. stated that patients with severe closed-head
injuries demonstrated no differences in length of stay or
infectious complications in early vs. delayed feeding .
Therefore, the consistency of the current medical evidence
from systematic reviews may be insufficient to convince
clinicians to aggressively provide early feeding in more
severely ill patients . Although many studies have
investigated the timing of enteral nutrition in critical illness, its
effects on clinical outcomes in patients with varied illness
severity have not been fully examined.
This study aims to determine the association between
illness severity and commencement of enteral feeding.
The primary outcome measures are clinical outcomes
while secondary measures are nutritional outcomes. The
study investigates the association between illness severity
and feeding complications, length of ICU stay, length of
hospital stay, ventilator-associated pneumonia (VAP),
hospital mortality rate, serum albumin, serum
prealbumin, nitrogen balance (NB), and nutritional intake over a
21-d study period in critically ill patients receiving
enteral feeding within or after 48 h of ICU admission.
Materials and Methods
Subjects and Study Design
This retrospective observational study was conducted
between January 2005 and December 2006 at Kaohsiung
Veterans General Hospital. Study protocol was
conducted in accordance with the ethical standards of the
World Medical Association Declaration of Helsinki and
approved by the hospitals Research Ethics Committee.
All patients consecutively admitted to the medical ICU
were enrolled unless enteral feeding was contraindicated.
Contraindications included: paralytic ileus, intestinal
obstruction, intractable vomiting, persistent watery
diarrhea, active gastrointestinal (GI) bleeding, short bowel
syndrome or severe acute pancreatitis. Patients
intravenously supplemented with fat emulsion, amino acids or
albumin during the study period were also excluded. After
admission, patients were administered nasogastric or
nasoduodenal feeding tubes (12Fr enteral feeding tube,
Flexiflo, Abbott, Chicago, IL) with full-strength isotonic
formula (Jevity, Abbott Laboratories, Ontario, Canada),
starting at 20 mL/h, and increasing by 20 mL/h every
4 h to satisfy energy and protein requirements
recommended by a clinical dietitian based on the Ireton-Jones
equation: EEE (v) = 1784 11(A) + 5(W) + 244(S) + 239
(T) + 804(B) 609(O); REI = EEE (1.0-1.5), where
EEE = estimated energy expenditure (kcal/day), v =
ventilator dependent, A = age (yr), W = body weight (kg), S =
sex (male = 1, female = 0), diagnosis of T = trauma, B =
burn, O = obesity (if present = 1, absent = 0), REI =
recommended energy intake, and Canadian clinical practice
guidelines for critically ill adult patients . Daily
recommended energy and protein requirements ranged
from 2530 kcal/kg and 1.21.5 g/kg ideal body weight.
All patients were fed with heads elevated 30-45 during
feeding and for 1 h after feeding. Residual was checked
every 4 h and feeding was withheld for 1 h if residual
volume was over 250 ml. The nurses interrupted enteral
feeding in cases of: overt regurgitation or aspiration;
residual volume over 500 mL; residual volume between
250 and 500 mL with abdominal distention, nausea or
vomiting . Residual was rechecked before reinitiating
feeding. Once the residual volume was lower than
250 mL and patients showed no abdominal distention,
nausea or vomiting, tube feeding was restarted at a rate
of 20 mL/h and increased by 20 mL/h every 4 h until the
caloric target was achieved. Patients were monitored for
up to 21 days or observations were closed if they expired
or were transferred to an ordinary ward.
Definitions and outcome measures
The timing of initial enteral feeding was determined by the
ICU team following Society of Critical Care Medicine and
American Society for Parenteral and Enteral Nutrition
guidelines. Feeding commencement at less than 48 h after
ICU admission was considered early feeding while over
48 h was considered late feeding. Illness severity was
determined by Acute Physiology and Chronic Health Evaluation
(APACHE) II scores [12,13]. Previous studies have
indicated that the optimal cutoff estimate for APACHE II
scoring in predicting ICU mortality is 20; patients with
APACHE II scores 20 on ICU admission demonstrate a
significantly higher fatality risk than those with scores < 20
[14-16]. Based on this information, this study groups
eligible patients as less severe (APACHE II score < 20) or
more severe (APACHE II score 20) and then sub-groups
these categories into early or late feeding groups according
to when enteral feeding started. In clinical practice, NB
was calculated by: daily protein intake (g) 6.25 - (24-h
UUN (g) + 4 g obligatory loss) and can be used to estimate
the magnitude of stress response as reflected by the
catabolic rate . There were no massive extra renal nitrogen
losses (inflammatory bowel disease, GI fistulae, extensive
bed sores, burn exudates) in our patients. Because there is
no objective indicator of GI function in critically ill patients
[18,19], we assessed GI dysfunction based on the clinical
assessments of four tube feeding complications: gastric
retention, vomiting, diarrhea, and GI bleeding. Gastric
retention was defined as a residual volume >250 mL [6,18];
vomiting as feeding formula found in the pharynx or
mouth; diarrhea as 3 bowel movements or >200 mL
watery stool/day in patients who had not consumed
laxatives or hyperosmolar medications in the preceding 24 h;
and GI bleeding as presence of hematemesis, melena,
bloody stool, or coffee grounds-like material in the feeding
tubes. A feeding complication episode was based on the
first appearance of symptoms until the symptoms subsided.
Length of ICU stay equalled ICU admission until transfer
out of ICU. VAP was diagnosed by two pulmonologists
using a modified National Nosocomial Infections
Surveillance system . Hospital mortality was defined as death
while hospitalized. Caloric and protein intake were
calculated from the amount of administered formula as
specified in the medical records and nurse files. The
percentage of target caloric and protein intake achieved was
calculated as: mean % of target caloric (protein) intake =
[each days caloric (protein) intake recommended daily
caloric (protein) requirement] number of study days.
Basic patient characteristics (age, sex, height, weight),
ICU admission and transfer-out dates, diagnosis and
APACHE II score on ICU admission, survival or death at
hospital discharge, VAP, medications administered, start
and end dates of tube feeding, daily caloric and protein
intake, and clinical assessments of tube feeding
complications (gastric retention/vomiting/diarrhea/GI bleeding)
were recorded. Blood and 24 h urine samples were
collected on feeding days 1, 4, 7, 14, and 21 for laboratory
measurements of serum albumin, serum prealbumin,
and 24-h urinary urea nitrogen (UUN).
All statistical analyses were performed using SPSS
version 15.0 (SPSS Inc., Chicago, IL, USA) and Excel 2003
(Microsoft, Redmond, WA, USA). Distributions of
baseline characteristics, differences in clinical outcomes,
biochemical values and nutritional intake between groups
were compared using Students t-test for normally
distributed continuous variables or MannWhitney U-test
for non-normally distributed continuous variables.
Multiple linear regression and logistic regression were used
to assess initial enteral feeding times effects on
measured outcomes after adjusting for potential confounders.
Two-tailed p-values < 0.05 were considered significant.
Values are presented as means standard deviation.
A total of 108 newly admitted ICU patients qualified for
the trial. Of these, 40 patients (43.5 %) received early
enteral feeding with 14 assigned to less severe and 26
assigned to more severe. The other 68 patients (56.5 %)
received late enteral feeding with 33 assigned to less
severe and 35 assigned to more severe. Demographic and
clinical characteristics of the patients are shown in
Table 1. The early feeding patients were significantly
older than those in the late feeding group, but these
differences did not exist between groups broken-down by
illness severity. Notably, early feeding patients had a
significantly higher incidence of antibiotic use.
The frequency of feeding complications was not
statistically different between early and late feeding groups.
However, more severely ill early feeding group patients
experienced significantly higher feeding complications
than their counterparts of the late feeding group
(Table 2). Diarrhea and GI bleeding were significantly
higher in early feeders among the more severely ill
(Table 3). After adjusting for gender, age and illness
severity, early enteral feeding had positive effects on
feeding complications (Table 4).
The incidence of VAP was significant higher in the early
feeding group; however, there was no significant
difference between both groups by illness category (Table 2)
nor was VAP related to enteral feeding commencement
Lengths of ICU stay and hospital stay
The early feeding group experienced longer ICU stays.
However, these differences only existed among more but
not less severely ill patients (Table 2). After adjusting for
gender, age and severity of illness, early enteral feeding
was associated with increased length of ICU stay among
the more severely ill patients (Table 4). There were no
differences in length of hospital stay (Table 2).
There were no differences between both groups in either
illness category (Table 2). Timing of enteral feeding
initiation was not associated with hospital mortality (Table 4).
However, after adjusting for gender, age and timing of
enteral feeding initiation, illness severity had an effect on
mortality rate. Patients with higher APACHE II scores
risked higher hospital mortality (adjusted OR = 0.897,
95 % CI = 0.835-0.964, p = 0.003).
There were no differences in caloric and protein intake
between both feeding groups for less or more severely ill
patients (Tables 2 and 4). We observed a mean of 80 %
above the caloric intake goal for both feeding groups
Serum albumin and prealbumin
The more severely ill early feeding patients showed
significantly higher serum albumin levels than those of the
late feeding group on feeding day 7; less severely ill
patients showed no differences (Table 2). The
commencement time of enteral feeding had no effect on
serum albumin levels after adjusting for gender, age and
illness severity (Table 4). Similarly, serum prealbumin
levels were significantly higher in the early feeding group
on feeding days 4 and 7 (Table 2) in the more severely ill
patients; less severely ill patients showed no differences
Gender (M/F), n
Table 1 Demographic and clinical characteristics of the patients categorized by timing of feeding initiation and break
down by illness severity
APACHE, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit; NG, nasogastric; ND, nasoduodenal; PPI, proton pump inhibitor.
Data are expressed as mean SD, number of patients, or percentage in parentheses. Students t-test for differences between early and late feeding groups,
MannWhitney U-test for differences between early and late feeding groups categorized by APACHE II <20 and APACHE II 20. Single asterisk (*) indicates
p < 0.05, double asterisks (**) indicate p < 0.01, and triple asterisks (***) indicate p < 0.001.
between groups. After adjusting for gender, age and
illness severity, early feeding was not associated with
increased serum prealbumin levels in more severely ill
patients (Table 4).
NB and 24-h UUN
The NB and 24-h UUN in both groups significantly
differed on feeding days 7, 14 or 21 among more but not less
severely ill patients (Table 2). Adjusting for gender, age
and illness severity, the timing of enteral feeding initiation
had effects on NB and 24-h UUN (Table 4). Patients with
higher APACHE II scores in the early feeding group
experienced more nitrogen loss and worsened NB.
clinical outcomes and nutritional outcomes. However,
for these patients, multiple linear regression and logistic
regression analyses verified the timing of enteral feeding
initiation had no effect on measured outcomes after
adjusting for confounding factors (Table 4). On the other
hand, in the case of APACHE II 20 patients, our study
had sufficient power to analyze length of ICU stay
(power = 0.9), NB on feeding day 14 (power = 0.85) and
24-h UUN on feeding days 14, 21 (power = 0.8, 0.99); but
insufficient power for analyzing the feeding
complications (power = 0.6), serum albumin on feeding day 7
(power = 0.6) and serum prealbumin on feeding days 4, 7
(power = 0.13, 0.72).
Post-hoc power analyses were performed using G*Power
3.1 software  to determine whether the sample size
could give acceptable results. Among less severely ill
patients, power was insufficient to analyze the
differences between early and late feeding groups in terms of
The early feeders among the more severely ill patients
experienced significantly more frequent feeding
complications than late feeders, but their caloric and protein
intake did not differ from the other groups. This was due
to their major feeding complications being diarrhea and/
or GI bleeding and not gastric retention or vomiting,
which would significantly affect nutritional intake.
Severely ill patients commonly develop GI problems such
as mucosal damage, motility disturbances, and
hypoalbuminemia-related mucosal edema due to severe
physiological stress [22,23]. Therefore, we inferred that the
higher incidence of diarrhea might have been due to early
aggressive feeding placing stress on damaged mucosa and/
or a higher usage of antibiotics in these patients. However,
diarrhea among the more severely ill early feeders was not
severe and it subsided after adjusting the feeding rate and/
or administration of anti-diarrhea medicines. Additionally,
the higher incidence of GI bleeding among these patients
is related to stress ulcers and not active bleeding. GI
Multiple linear regression
Table 4 Effects of the timing of enteral feeding initiation (early feeding) on different clinical and nutritional outcomes
APACHE, Acute Physiology and Chronic Health Evaluation; NB, nitrogen balance; UUN, urinary urea nitrogen; VAP, ventilator-associated pneumonia; ICU, intensive
Multiple linear or logistic regression for examining the effects of the timing of enteral feeding initiation (X) on measured outcomes (Y) after adjusting for gender,
age and illness severity. Coding for the timing of enteral feeding initiation (X): early feeding = 1, late feeding = 0.
bleeding subsided after controlling shock or use of
medications such as proton pump inhibitors or histamine type
2 receptor antagonists. Consequently, as we were able to
control diarrhea and GI bleeding, neither significantly
affected nutritional intake. These results, however, are
inconsistent with previous reports of early feeding improving
GI function [4,6]. Critically ill patients suffer from a
combination of physiological disturbances likely to influence GI
function [22,24]. Our results show an association between
illness severity and enteral feeding commencement. In more
severely ill patients, feeding within 24 to 48 h of ICU
admission may be too early as it can cause further stress to the
GI tract, and result in diarrhea and stress-induced ulcers.
We also observed that the higher the APACHE II score,
the longer the ICU stay for early feeders after adjusting for
confounding factors. These results are consistent with
Ibrahim et al., who observed greater incidence of diarrhea and
longer ICU stays among early feeders . We hypothesize
that the greater incidence of feeding complications is a
confounding factor increasing the length of ICU stay in the early
feeding group among more severely ill patients .
Our observations indicate that mortality is unaffected
by enteral feeding commencement time. The
metaanalysis study conducted by Marik and Zaloga also found
no relationship between early enteral nutrition and
decreased mortality . Expectably, our study
demonstrates that illness severity governs the mortality rate and
neither late enteral feeding nor early enteral feeding
reduces the mortality rate.
Clinically, serum albumin level most likely acts as a
prognostic rather than nutritional indicator .
Previous studies have indicated that inflammatory mediators
and cytokines released during injury are major
contributors in lowering serum albumin and prealbumin levels
[28,29]. Serum prealbumin is more sensitive to changes
in protein-energy status than serum albumin is, and its
concentration reflects recent dietary intake rather than
an overall nutritional status . In critical illness,
hypoalbuminemia and hypoprealbuminemia are very
common and inversely related to C-reactive protein .
Therefore, increases in these two serum protein levels
(in response to enteral feeding on days 4 and 7) only in
the case of more severely ill early feeders might relate to
early feeding inducing the release of trophic endogenous
agents and the inhibitory effects of inflammatory
mediators and cytokines released during severe illness [26,31].
Negative NB indicates inadequate protein intake or
excessive catabolism. We observed no differences in
protein intake between both feeding groups but significantly
higher 24-h UUN losses in more severely ill early feeders.
This implies that levels of stress are higher among these
patients. Briassoulis et al. demonstrated that severity of
illness independently contributes to negative NB status
during acute stress phases . As disease becomes
more severe, more stress hormones are secreted, leading
to greater GI disturbances and nitrogen loss .
Therefore, the lower 24-h UUN loss and better NB in the
more severely ill of late feeding group is more likely due
to improved metabolic stress.
This study has important strengths. Firstly, it is
observational and feeding commencement was decided solely
by the ICU team in accordance with actual treatment
protocol. This connotes the de facto aspects of intensive
care. Second, our 21-d study period is longer than those
of previous studies. There were also limitations in our
study. First, the study population was within a single
medical ICU, meaning generalizations must be treated
cautiously. Second, the sample size of the early feeding
group limits the studys power to analyze the measured
outcomes. However, the results of multiple linear
regression and logistic regression analyses strongly support our
findings eliminating the issue of power insufficiency.
Further, larger randomized sample-sizes, controlled trials
with mixed ICU patients, data analyzed on tertiles,
quartiles or quintiles of APACHE II scores and enteral
feeding commencement time are required to fully investigate
the optimal timing of initial enteral feeding in managing
patients with varied illness severity.
Genetic polymorphisms, underlying pathology, and
patient heterogeneity limit the extent to which nutritional
intervention can be standardized. Our study
demonstrates a relationship exists between illness severity and
enteral feeding commencement time influencing clinical
outcomes. For more severely ill patients, early feeding is
associated with improved nutritional outcomes whereas
late feeding is associated with reduced feeding
complications and shorter ICU stays. Notably, the feeding
complications of more severely ill early feeders can be handled
without significantly affecting nutritional intake.
Additionally, the study shows there is no eventual difference
in length of hospital stay or mortality although such
patients experience longer ICU stays. Consequently, early
feeding shows to be a more beneficial nutritional
intervention option than late feeding in patients with more
ICU: Intensive care unit; GI: Gastrointestinal; APACHE: Acute physiology and
chronic health evaluation; VAP: Ventilator-associated pneumonia;
UUN: Urinary urea nitrogen; NB: Nitrogen balance; BMI: Body mass index;
PPI: Proton pump inhibitor.
The authors declare that they have no conflict of interest.
This study was financially supported by Kaohsiung Veterans General Hospital
(Grant no. VGHKS 94082) and National Science Council (Grant no.
NSC1002622-B-006-004-CC3), Taiwan. We gratefully acknowledge the technical
assistance of the medical personnel in the ICU of the Kaohsiung Veterans
General Hospital, and sincerely appreciate the participation of all patients in
this research. We especially thank Dr. Tzu-Ming Chang for his valuable
Author contributions to the manuscript are as follows: H H-H performed
statistical analyses, interpreted the results and wrote the manuscript; C S-J
supervised the process, provided significant advice and revised the
manuscript; H C-W developed the protocol, designed the experiment and
provided advice; K S-P collected data and L M-Y provided consultation. All of
the authors have read and approved the final manuscript.
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