Small bowel feeding and risk of pneumonia in adult critically ill patients: a systematic review and meta-analysis of randomized trials
Alhazzani et al. Critical Care
Small bowel feeding and risk of pneumonia in adult critically ill patients: a systematic review and meta-analysis of randomized trials
Waleed Alhazzani 0 3 4
Abdulaziz Almasoud 2 3
Roman Jaeschke 0 1 3
Benjamin W Y Lo 3 6
Anees Sindi 3 5
Sultan Altayyar 3 4
Alison E Fox-Robichaud 0 3
0 Department of Medicine, McMaster University Medical Centre , 1200 Main Street West, Hamilton, Ontario, L8N 3Z5 , Canada
1 Department of Clinical Epidemiology and Biostatistics, McMaster University Medical Centre , 1200 Main Street West, Hamilton, Ontario, L8N 3Z5 , Canada
2 Gastroenterology Department, Prince Sultan Military Medical City , Riyadh , Saudi Arabia
3 Authors' details
4 Critical care department, Prince Sultan Medical City , Riyadh , Saudi Arabia
5 Department of Anesthesia & Critical Care, King Abdulaziz University , P.O. Box 80205, Jeddah , Saudi Arabia
6 Divisions of Neurosurgery & Critical Care Medicine, St. Michael's Hospital, University of Toronto , 30 Bond Street, Toronto, Ontario, M5B 1W8 , Canada
Introduction: This systematic review and meta-analysis aimed to evaluate the effect of small bowel feeding compared with gastric feeding on the frequency of pneumonia and other patient-important outcomes in critically ill patients. Methods: We searched EMBASE, MEDLINE, clinicaltrials.gov and personal files from 1980 to Dec 2012, and conferences and proceedings from 1993 to Dec 2012 for randomized trials of adult critically ill patients in the intensive care unit (ICU) comparing small bowel feeding to gastric feeding, and evaluating risk of pneumonia, mortality, length of ICU stay, achievement of caloric requirements, duration of mechanical ventilation, vomiting, and aspiration. Independently, in duplicate, we abstracted trial characteristics, outcomes and risk of bias. Results: We included 19 trials with 1394 patients. Small bowel feeding compared to gastric feeding was associated with reduced risk of pneumonia (risk ratio [RR] 0.70; 95% CI, 0.55, 0.90; P = 0.004; I2 = 0%) and ventilator-associated pneumonia (RR 0.68; 95% CI 0.53, 0.89; P = 0.005; I2 = 0%), with no difference in mortality (RR 1.08; 95% CI 0.90, 1.29; P = 0.43; I2 = 0%), length of ICU stay (WMD -0.57; 95%CI -1.79, 0.66; P = 0.37; I2 = 0%), duration of mechanical ventilation (WMD -1.01; 95%CI -3.37, 1.35; P = 0.40; I2 = 17%), gastrointestinal bleeding (RR 0.89; 95% CI 0.56, 1.42; P = 0.64; I2 = 0%), aspiration (RR 0.92; 95% CI 0.52, 1.65; P = 0.79; I2 = 0%), and vomiting (RR 0.91; 95% CI 0.53, 1.54; P = 0.72; I2 = 57%). The overall quality of evidence was low for pneumonia outcome. Conclusions: Small bowel feeding, in comparison with gastric feeding, reduces the risk of pneumonia in critically ill patients without affecting mortality, length of ICU stay or duration of mechanical ventilation. These observations are limited by variation in pneumonia definition, imprecision, risk of bias and small sample size of individual trials.
enteral nutrition; critical illness; small bowel feeding; meta-analysis
Enteral nutrition delivery is the preferred optimal method
of nutritional supplement in patients in the ICU [
careful consideration of an individual patient’s illness
severity, level of physiologic stress, and baseline nutritional
status, early enteral feeding has been shown to attenuate
disease severity, maintain gastrointestinal (GI) physiology,
and modulate the immune system [
]. A meta-analysis of
randomized controlled trials (RCTs) suggested that early
enteral nutrition reduces infections when compared with
parenteral nutrition, although the results were limited by
the presence of heterogeneity and methodologic quality
individual trials [
]. However, enteral nutrition can be
associated with risk of aspiration, gastric and feeding
intolerance, and issues surrounding tube placements [
Guidelines from the American Society of Parenteral and
Enteral Nutrition (ASPEN) recommend using enteral
nutrition when feasible [
]. Strategies to optimize the
benefits and minimize the risks of enteral nutrition include
early initiation, within 24 to 28 hours of admission if
feasible, elevation of the head of the bed, use of motility agents,
minimizing narcotic dosages, and reevaluation of gastric
residual amounts. Although the value of routine
measurement of gastric residual volume (GRV) in enterally fed
critically ill patients has been challenged by a recent RCT [
the ASPEN guidelines recommend small bowel over
gastric feeding in patients with persistent high GRV [
It is not known if small bowel feeding is associated
with a lower risk of pneumonia in critically ill patients.
Multiple systematic reviews reached conflicting results
]. Recently, an RCT by Davies et al. that included
180 patients suggested that there is no difference in the
risk of ventilator-associated pneumonia (VAP) between
patients receiving gastric versus jejunal feeds . At
the time of writing, this is the largest published RCT on
In the view of unclear literature as well as presence of
new information we conducted an updated systematic
review and meta-analysis to examine the efficacy of
using small bowel feeding as opposed to gastric feeding
in critically ill patients.
Materials and methods
We searched EMBASE, MEDLINE from January 1980 to
December 2012, independently and in duplicate. Search
strategy is summarized in Additional file 1. We searched
clinicaltrials.gov, our personal files, and reference lists of
eligible studies and review articles for additional trials.
Utilizing a specialized search engine provided by McMaster
University library we searched conferences and
proceedings from January 1993 to December 2012 [
Eligibility criteria included all of the following: 1) design
parallel groups RCTs (cross-over or quasi-randomized
trials were not eligible); 2) population - critically ill adult
patients in the ICU who received enteral nutrition
supplementation through a tube or feeding device; trials
including acute pancreatitis were eligible if the patients were
admitted to the ICU or if they exclusively included
patients with severe acute pancreatitis (severe pancreatitis
should include at least one organ dysfunction or a
validated tool used to define this population); 3) intervention
- post-pyloric feeding (duodenal or jejunal feeding)
compared with gastric feeding strategy (trials using
percutaneous gastrostomy or jejunostomy tubes were not
eligible); and 4) outcomes - primary outcome was
pneumonia (including ventilator-associated, nosocomial, or
aspiration pneumonia). Secondary outcomes included:
mortality; ICU length of stay; duration of mechanical
ventilation (DMV); GI bleeding; aspiration defined as
suctioning of feeds through airways or endotracheal tube or
documented aspiration through other techniques (e.g.
radioisotope scanning, video fluoroscopy, or dye test);
vomiting defined as ejection of feeds through the oral
cavity; and nutritional outcomes (including daily caloric
intake, proportion of patients achieving target caloric
requirements, and time to achieve goal rate). We did not
apply any language restrictions.
In duplicate and independently, two of three
reviewers selected articles by examining titles and
abstracts and then full text after identifying potentially
relevant articles. Agreement was assessed using kappa
Data extraction and quality assessment
In duplicate and independently, two reviewers abstracted
data on the design, population, intervention,
comparison, and clinical outcomes. We wrote to authors to
clarify or obtain missing data.
In duplicate and independently, two reviewers assessed
the risk of bias of individual trials using the Cochrane risk
of bias tool. For each outcome in each included trial, the
risk of bias was reported as ‘low risk’, ‘unclear risk’, or
‘high risk’ in the following domains: random sequence
generation; allocation concealment; blinding of
participants and personnel; blinding of outcome assessment;
incomplete outcome data; selective reporting; or other
]. For each of the outcomes, we independently
rated the overall quality of evidence and confidence in
effect estimates using the Grading of Recommendations
Assessment, Development and Evaluation (GRADE)
approach in which randomized trials begin as high-quality
evidence, but may be rated down by one or more of five
categories of limitations: risk of bias, inconsistency,
indirectness, imprecision, and publication bias [
Disagreement was resolved by discussion and consensus.
Data synthesis and analysis
We combined data from all trials to estimate the pooled
risk ratio (RR) and associated 95% confidence intervals
(CI) for all binary outcomes. Weighted mean difference
(WMD) was used to summarize the effect measure for
continues outcomes. Pooled RRs were calculated using
random effects models, applying inverse variance
weighting, and the methods of DerSimonian and Laird [
Statistical heterogeneity was assessed by the I² statistic
]; we interpreted substantial heterogeneity as an I² of
more than 50%.
To address any observed heterogeneity associated with
the effect of small bowel feeding, and to test the
robustness of the data, we planned three a priori sensitivity
analyses: excluding studies that did not provide
definition of the outcome, using odds ratio (OR) to
summarize the results, and excluding studies that strictly
included patients with severe acute pancreatitis.
The number needed to treat (NNT) was estimated
based on a 15% assumed control risk (ACR) for
pneumonia or VAP; this was based on available literature [
Publication bias was assessed visually using funnel plot
and statistically using the Egger test .
Of 959 citations, 35 full-text articles were assessed for
eligibility and 16 were excluded (Figure 1). Overall, 19
fully published RCTs [
], were included in the
quantitative and qualitative analysis. We did not identify
any eligible abstracts. We translated one article that was
published in Chinese [
]. Agreement on article
inclusion after full-text assessment was excellent (kappa 1.0).
In Table 1 we describe characteristics of the included
trials. Trials included a wide range of critical illnesses
with patients in medical, surgical, and trauma ICUs.
Three trials included only patients with severe acute
]. In one of these trials, not all patients
were admitted to the ICU but due to inclusion of severe
pancreatitis patients with a mortality rate of 25% we
decided to include it [
]. Nine trials investigated the use
of jejunal feeding tubes [
] and six
the use of duodenal feeding tubes [
whereas the rest did not specify the location of the
feeding tube in the small intestine [
preventive strategies were not described consistently in
the included studies. Seven trials clearly reported
elevation of the head of the bed in both groups [
]; other VAP preventive measures were not
reported. The use of prokinetic agents were allowed in
most trials. Although one trial compared gastric feeding
in combination with erythromycin with small bowel
feeding alone [
], we included this trial because it only
reported mortality and nutritional outcome, which are
unlikely to be influenced by the use of erythromycin.
Risk of bias
Funnel plot (Figure 2) did not suggest the presence of
publication bias; this was confirmed statistically using
the Egger test (Egger: bias = 0.12; 95% CI = 1.05 to 1.30;
P = 0.82).
In Figure 3, we report methodologic quality
assessment using the Cochrane risk of bias tool for each trial.
Overall, five studies were judged to be at low risk of
bias, 13 at high risk of bias, and one had an unclear risk
of bias. We considered a lack of blinding to be of low
effect on mortality outcome; hence the risk of bias was
considered low for this outcome. However, lack of
blinding could introduce performance or ascertainment
bias when assessing other less objective outcomes (e.g.
pneumonia), so the risk of bias was considered to be
high in this setting.
A total of 12 RCTs [
including 994 patients reported pneumonia as an outcome.
The pooled estimate across trials suggested that the use
of small bowel feeding reduces the risk of pneumonia
(RR = 0.70; 95% CI = 0.55 to 0.90; P = 0.004; I2 = 0%).
The NNT is 17 for ACR 15% (Figure 4).
Eight RCTs [
] with 835 patients
reported pneumonia in ventilated patients as an outcome.
Small bowel feeding was associated with a lower risk of
VAP (RR = 0.68; 95% CI = 0.53 to 0.89; P = 0.005; I2 =
0%). The NNT is 21 for ACR of 15% (Figure 5).
Fifteen RCTs [
] with 1232 patients
reported mortality as an outcome. There was no
difference in mortality between both groups (RR = 1.08; 95%
CI = 0.90 to 1.29; P = 0.43; I2 = 0%; Figure 6).
ICU length of stay
Eight RCTs [
] that included 762
patients reported ICU length of stay as an outcome
(Figure 7). There was no difference in days of stay in the
ICU between both groups (WMD = -0.57; 95% CI = -1.79
to 0.66; P = 0.37; I2 = 0%; Figure 7).
Definition of pneumonia
New or persistent infiltrate on CXR for at least
5 days with any three of the following:
a) purulent sputum with >25 WBC and <10
squamous epithelial cells on Gram stain and
b) purulent sputum with >25 WBC and <10
squamous epithelial cells on Gram stain and
nosocomial or respiratory isolates on culture
c) temperature > 38.6 ºC
d) peripheral WBC >10,000 cells/mm3
New infiltrate on radiograph (assessed by a
blinded radiologist) of more than 48 hours’
duration and at least two of the following:
a) temperature >38.5 ºC or <35 ºC.
b) blood WBC >10,000/cm3 or <3000/cm3.
c) purulent sputum or isolation of pathogenic
bacteria from endotracheal aspirate. A
radiographic infiltrate and positive quantitative
culture from BAL is also considered diagnostic
Presence of a new infiltrate on a chest
radiograph (assessed by 2 pulmonologists) in
the presence of two of the following:
a) WBC >10,000/mm3;
b) temperature >38.5°C; and
c) a positive glucose test or blue discoloration
in the endotracheal secretions
Pneumonia was not an outcome in this study
Pneumonia was not an outcome in this study
Aspiration pneumonia was an outcome but no
definition was provided
Pneumonia was not an outcome in this study
Consensus conference definition.
CDC criteria for VAP, but no description of the
Pneumonia not an outcome
Clinically significant aspiration defined as new
radiographic chest infiltrate that was
empirically treated with antibiotics or the
direct suctioning of feeding solution from
CDC, Centers for Disease Control; CPIS, Clinical Pulmonary Infection Score; CXR, chest x-ray; EMG, electromyography;NG, nasogastric; NJ, nasojejunal; ND,
nasoduodenal; NR, not reported; VAP, ventilator-associated pneumonia; APACHE, acute physiology and chronic health evaluation; TBI, traumatic brain injury; WBC,
white blood cell.
OD, once daily; CT, computed tomography; OG, oro-gastric; BAL, bronchoalveolar lavage
Due to marked variations in reporting of nutritional
outcomes, meta-analysis was not performed. We summarize
the nutritional outcomes of the included trials in Table 2.
Overall seven RCTs [
] reported the
mean daily caloric intake; in four studies the mean caloric
intake was higher in patients receiving small bowel
feeding, whereas the other studies did not report significant
difference between groups. Four trials reported the mean
time required to achieve target-feeding rate. Due to
variation in defining this outcome (i.e. time measured after
randomization, after initial attempt, or after successful
Figure 3 Risk of bias assessment. Figure showing risk of bias
assessment for each trial using Cochrane risk of bias tool.
Greencolored symbol corresponds to low risk of bias, yellow corresponds
to unclear risk of bias, and red corresponds to high risk of bias.
Figure 6 Mortality. Forest plot comparing small bowel feeding with gastric feeding for mortality outcome; results are shown using
randomeffects model with relative risk and 95% confidence interval (CI).
insertion of feeding tube) quantitative analysis was not
feasible. However, most of these studies report a statistically
significant delay in achieving target-feeding rate in the
small bowel feeding group (Table 2).
Although statistical heterogeneity was not observed
except for vomiting outcome (I2 = 57%), we performed
the a priori subgroup analyses to test the robustness of
the data. There was no subgroup difference in risk of
pneumonia or VAP by location of feeding tube
(duodenal vs. jejunal), nor by risk of bias (low risk vs. high or
unclear risk of bias). The heterogeneity observed in
vomiting outcome was not explained by our a priori
Despite a lack of heterogeneity we performed a priori
sensitivity analyzes for primary outcome. First analysis
excluded studies that did not provide a definition of
pneumonia outcome [
], the results remained
significant (RR = 0.71; 95% CI = 0.55 to 0.90; P = 0.004; I2 =
0%). A second analysis used OR as a measure of
treatment effect, the results remained statistically significant
(OR = 0.61; 95% CI = 0.39 to 0.97; P = 0.006; I2 = 0%).
A third planned sensitivity analysis excluded studies that
included patients with severe pancreatitis; only one
study reported pneumonia [
] and after excluding this
study the results remained statistically significant (RR =
0.69; 95% CI = 0.50 to 0.96; P = 0.004; I2 = 0%).
Overall summary of findings
We summarize the overall quality of evidence for each
outcome in Table 3. Using GRADE criteria the quality
of evidence was judged to be ‘high’ for mortality and
ICU length of stay outcomes; ‘low’ for pneumonia,
DMV, and GI bleeding outcomes; and ‘very low’ for
aspiration and vomiting outcomes. The main reasons for
lowering the quality of evidence for most outcomes were
risk of bias and imprecision (Table 3).
In this systematic review we found that in critically ill
patients small bowel feeding reduces pneumonia
(including VAP) when compared with gastric feeding,
without affecting mortality, ICU length of stay, duration
of mechanical ventilation, or risk of GI bleeding.
The mechanism by which small bowel feeding could
reduce pneumonia risk is not entirely clear. It has been
presumed that the increased gastric volume leads to
regurgitation and aspiration, yet multiple studies have
demonstrated no relation between the GRV and the risk
of aspiration [
]. Indeed, the risk of VAP is not
increased when the GRV is not monitored . These
facts question the association between gastric feeding
and the risk of pneumonia. In our meta-analysis we did
not find a significant difference in the risk of clinically
detected aspiration of feeds or vomiting. Only six of 19
eligible trials reported these outcomes, and using
GRADE criteria the quality of evidence for those
outcomes was judged to be very low. Moreover, there was
variation in the definition and methods used for
detecting aspiration; these limitations minimize any inferences
we can make based on these outcomes.
Over the past decade four systematic reviews were
published on this topic, and seemingly reached conflicting
results. Two suggested that small bowel feeding reduces
the risk of pneumonia [
] whereas the other two did
]. This discrepancy in conclusion could be related
to differences in search strategies, inclusion criteria, or
outcome definition. In the one study the outcome
aspiration of feeds and pneumonia were combined as a single
outcome, which attenuated the effect on pneumonia [
The most recent and comprehensive review by Jiyong et
] included 966 patients from 15 RCTs suggested that
small bowel feeding reduces the risk of pneumonia in
critically ill patients. However, this review combined the
results of pediatric and adult trials; it did not include
other clinically important outcomes (e.g. mortality, ICU
length of stay, or GI bleeding) and did not assess the
quality of evidence; and two larger RCTs were published
Nutritional assessment outcomes
SD, standard deviation; SEM, standard error of the mean; IQR, interquartile range; N/A, not available.
after this review [
]. Hence, we conducted this
updated systematic review hoping to resolve the ongoing
controversy in the literature. In Table 4 we summarize
the major characteristics and results of prior systematic
reviews in comparison with our review.
One major limitation in the literature is the variation in
reporting and assessing nutritional outcomes among
studies; hence, we only were able to qualitatively describe
the data. Small bowel feeding was either similar or
superior to gastric feeding in the amount of calories delivered
per day. However, few studies reported that small bowel
feeding resulted in significant delay of achieving targeted
feeding goals. This is due to longer time required for
insertion of small bowel feeding tubes.
Although the insertion of small bowel feeding tube
appears to be safe, in one study [
] a patient developed
cardiac arrest requiring cardiopulmonary resuscitation
occurring during endoscopic insertion of jejunal tube.
Fortunately, this is an extremely rare event and was not
reported in other trials. However, insertion of small
bowel feeding tubes may be technically challenging. We
report the proportion of failed tube insertion in both
Quality of the
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on
the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI, confidence interval; GI, gastrointestinal; RR, risk ratio.
GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.
1 downgraded for risk of bias, most studies did not blind outcome assessors
2 downgraded for imprecision, total number of events is less than 200
3 downgraded for imprecision 95% CI ranged from - 3.35 to 1.35
4 downgraded for imprecision by 2 points, only 40 events in total and 95% CI ranged between 0.52 to 1.65
5 downgraded for inconsistency I2 = 57%
6 downgraded for imprecision, only 105 events in total
groups. Eight trials clearly reported failure of feeding
tube insertion; overall, there were more failures with
small bowel tube insertion (7% vs. 0%), especially with
blind insertion technique. This highlights the
importance of training of health care professionals to increase
success rate and to avoid delays in starting nutritional
support. The presence of backup methods (e.g.
fluoroscopic or endoscopic insertion) is thus important,
although not always available. On a practical level, if the
feeding tube does not reach the small bowel the
alternative of feeding into the stomach is available.
There are several strengths of our meta-analysis
including comprehensive search strategy, multiple clinically
important outcomes, inclusion of non-English trials,
duplicate abstraction, a priori subgroup and sensitivity
analyses, obtaining missing data from authors, and
adherence to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines [
However, there are major limitations of the existing data
that lowers our confidence in the observed treatment
effects. First, the included trials were small in size that
could have biased the overall estimate of treatment effect
- a recent study by Zhang et al [
] looked at the effect of
small sample size on the estimates of mortality outcome
in meta-analyses published in the critical care field and
found that meta-analyses of studies with small sample
size are more likely to be associated with larger treatment
effect independent of methodologic quality of these
studies. They used a cut off of 200 patients per study to
define small size studies, which is larger than any study
included in this meta-analysis. Second, the VAP
prevention measures were not reported in most trials, and it is
difficult to ascertain if they were applied, especially that
most included trials were conducted prior to recent
a Odds ratio (95% CI)
b Aspiration and pneumonia analyzed as single outcome
CI, confidence interval; DMV, duration of mechanical ventilation; GI, gastrointestinal; LoS, length of stay; RCT, randomized controlled trial; RR, risk ratio.
advances in VAP prevention. This may limit the
generalizability of the results to current patients in whom
application of VAP preventive strategies is the standard of
care. Third, the definition of pneumonia and VAP were
not consistent across trials. Although the optimal
definition of VAP is controversial [
], the lack of standardized
definition and the difficulty of blinding render the results
susceptible to ascertainment bias. These limitations and
other are reflected in low-quality evidence for pneumonia
outcome (Table 3) and should be considered when
interpreting the results of this meta-analysis.
Although the use of small bowel feeding as opposed to
gastric feeding appears to reduce the risk of pneumonia
including VAP in critically ill patients, these
observations are limited by several factors and need to be
interpreted with caution. Small bowel feeding did not affect
other clinically important outcomes. Insertion of small
bowel feeding tube appears to be safe but technically
more challenging than gastric tubes insertion, and may
require radiologic or endoscopic assistance. In our
opinion before implementing this intervention in routine
practice more information is required.
Literature surrounding small bowel feeding in
critically ill patients is ambiguous, with few meta-analyses
reaching opposing conclusions; there were variation in
inclusion criteria, outcome detention, and methodology
that lead to the discrepancy of results.
A recent RCT suggested that small bowel feeding
does not reduce the risk of VAP in critically ill patients.
This systematic review and meta-analysis of RCTs
suggests that small bowel feeding is associated with
significant reduction in risk of pneumonia compared with
gastric feeding. The effect on other clinically important
outcomes was not statistically significant.
Additional file 1: Search strategy and excluded references. Contains
electronic database search strategy (search terms) and reference list of all
excluded full-text articles that were assessed for eligibility.
ICU LoS (8)
ACR: assumed control risk; ASPEN: American Society of Parenteral and
Enteral Nutrition; CI: confidence interval; DMV: duration of mechanical
ventilation; GI: gastrointestinal; GRADE: Grading of Recommendations
Assessment: Development and Evaluation; GRV: gastric residual volume; NNT:
number needed to treat; OR: odds ratio; PRISMA: Preferred Reporting Items
for Systematic Reviews and Meta-Analyses; RCT: randomized controlled trials;
RR: risk ratio; VAP: ventilator-associated pneumonia; WMD: weighted mean
The authors declare that they have no competing interests.
WA and RJ conceived the idea. WA, AA, BL, AS and AF designed the study
and drafted the protocol. WA and AA performed data abstraction. WA and
SA conducted the analysis. WA, RJ, and AF drafted the article. All of the
authors critically revised the manuscript and agreed on the submitted
We thank Professor Sue-Joan Chang for providing us with requested
information, and Dr. Yu-Hong Yuan for helping with data abstraction from
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