BMJ 2001;323:773 ( 6 October )



Papers


Early enteral feeding versus "nil by mouth" after gastrointestinal surgery:
systematic review and meta-analysis of controlled trials

Stephen J Lewis, consultant a, Matthias Egger, senior lecturer in
epidemiology and public health medicine b, Paul A Sylvester, specialist
registrar c, Steven Thomas, senior lecturer d.
a Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, b MRC
Health Services Research Collaboration, Department of Social Medicine,
University of Bristol, Bristol BS8 2PR, c Department of Surgery, Bristol
Royal Infirmary, Bristol BS2 8HW, d Department of Maxillofacial Surgery,
University of Bristol, Bristol BS1 2LY
Correspondence to: S Lewis [log in to unmask] <mailto:[log in to unmask]>



  Abstract
Objective: To determine whether a period of starvation (nil by mouth) after
gastrointestinal surgery is beneficial in terms of specific outcomes.
Design: Systematic review and meta-analysis of randomised controlled trials
comparing any type of enteral feeding started within 24 hours after surgery
with nil by mouth management in elective gastrointestinal surgery. Three
electronic databases (PubMed, Embase, and the Cochrane controlled trials
register) were searched, reference lists checked, and letters requesting
details of unpublished trials and data sent to pharmaceutical companies and
authors of previous trials.
Main outcome measures: Anastomotic dehiscence, infection of any type, wound
infection, pneumonia, intra-abdominal abscess, length of hospital stay, and
mortality.
Results: Eleven studies with 837 patients met the inclusion criteria. In six
studies patients in the intervention group were fed directly into the small
bowel and in five studies patients were fed orally. Early feeding reduced
the risk of any type of infection (relative risk 0.72, 95% confidence
interval 0.54 to 0.98, P=0.036) and the mean length of stay in hospital
(number of days reduced by 0.84, 0.36 to 1.33, P=0.001). Risk reductions
were also seen for anastomotic dehiscence (0.53, 0.26 to 1.08, P=0.080),
wound infection, pneumonia, intra-abdominal abscess, and mortality, but
these failed to reach significance (P>0.10). The risk of vomiting was
increased among patients fed early (1.27, 1.01 to 1.61, P=0.046).
Conclusions: There seems to be no clear advantage to keeping patients nil by
mouth after elective gastrointestinal resection. Early feeding may be of
benefit. An adequately powered trial is required to confirm or refute the
benefits seen in small trials.




What is already known on this topic
Enteral feeding within 24 hours after gastrointestinal surgery is tolerated
Theoretically, early enteral feeding improves tissue healing and reduces
septic complications after gastrointestinal surgery
What this study adds
There is no benefit in keeping patients "nil by mouth" after
gastrointestinal surgery
Septic complications and length of hospital stay were reduced in those
patients who received early enteral feeding
In patients who received early enteral feeding there were no significant
reductions in incidence of anastomotic dehiscence, wound infection,
pneumonia, intra-abdominal abscess, and mortality





  Introduction
A period of starvation ("nil by mouth") is common practice after
gastrointestinal surgery during which an intestinal anastomosis has been
formed. The stomach is decompressed with a nasogastric tube and intravenous
fluids are given, with oral feeding being introduced as gastric dysmotility
resolves. 1 <http://bmj.com/cgi/content/full/323/7316/#B1>  The rationale of
nil by mouth is to prevent postoperative nausea and vomiting and to protect
the anastomosis, allowing it time to heal before being stressed by food. It
is, however, unclear whether deferral of enteral feeding is beneficial.
Contrary to widespread opinion, evidence from clinical studies and animal
experiments suggests that initiating feeding early is advantageous.
Postoperative dysmotility predominantly affects the stomach and colon, with
the small bowel recovering normal function 4-8 hours after laparotomy. 1
<http://bmj.com/cgi/content/full/323/7316/#B1>  Feeding within 24 hours
after laparotomy is tolerated and the feed absorbed. 2
<http://bmj.com/cgi/content/full/323/7316/#B2>  3
<http://bmj.com/cgi/content/full/323/7316/#B3>  Gastrointestinal surgery is
often undertaken in patients who are malnourished, 4-6
<http://bmj.com/cgi/content/full/323/7316/#B4>  which in severe cases is
known to increase morbidity. 7
<http://bmj.com/cgi/content/full/323/7316/#B7>  In animals, starvation
reduces the collagen content in anastomotic scar tissue 8
<http://bmj.com/cgi/content/full/323/7316/#B8>  9
<http://bmj.com/cgi/content/full/323/7316/#B9>  and diminishes the quality
of healing, 9 <http://bmj.com/cgi/content/full/323/7316/#B9>  10
<http://bmj.com/cgi/content/full/323/7316/#B10>  whereas feeding reverses
mucosal atrophy induced by starvation 11
<http://bmj.com/cgi/content/full/323/7316/#B11>  and increases anastomotic
collagen deposition and strength. 12
<http://bmj.com/cgi/content/full/323/7316/#B12>  Experimental data in both
animals and humans suggest that enteral nutrition is associated with an
improvement in wound healing. 13
<http://bmj.com/cgi/content/full/323/7316/#B13>  Finally, early enteral
feeding may reduce septic morbidity after abdominal trauma 14
<http://bmj.com/cgi/content/full/323/7316/#B14>  and pancreatitis. 15
<http://bmj.com/cgi/content/full/323/7316/#B15>
Several clinical trials directly comparing strategies of early feeding with
nil by mouth after elective gastrointestinal surgery have been performed.
These studies, however, have not been systematically reviewed. We performed
a systematic review and meta-analysis of randomised trials to assess the
evidence on benefit and harm of early enteral feeding.




  Methods
Eligibility criteria and literature search---Clinical trials were eligible
if patients had undergone elective gastrointestinal surgery and were
randomly allocated to receive either enteral feeding (within 24 hours after
surgery) or the traditional management of nil by mouth and intravenous
fluids with introduction of enteral fluids and diet as tolerated. We
supplemented computerised searches of PubMed, Embase, and the Cochrane
controlled trials register with checks of relevant reference lists. We wrote
to trialists requesting additional data on outcomes not reported in
publications and on trial methods. We also approached pharmaceutical
companies that produce enteral feeds and asked whether they held data from
unpublished trials.
Data extraction and outcomes---From each study we collected data on the site
of surgery, whether an intestinal anastomosis was formed, whether the
pathology was benign or malignant, the type of feed used, and the method of
administration of the feed. The site of surgery was classified as
pancreatic, hepatobiliary, upper gastrointestinal (proximal to the jejunum),
or lower gastrointestinal (distal to the duodenum). Outcomes potentially
related to feeding included anastomotic dehiscence, infection of any type,
wound infection, pneumonia, intra-abdominal abscess, vomiting, mortality,
and length of hospital stay. The unplanned reinsertion of a nasogastric tube
was recorded. The data were extracted independently by two of the authors
(SJL and PAS), checked for consistency by another author (ST), and sent to
the trialists for review.
Assessment of methodological quality---Two of us (ST and ME) independently
assessed the two dimensions of methodological quality that empirically have
been shown to be associated with biased estimates of treatment effects:
adequacy of concealment of allocation to treatment groups and double
blinding. 16 <http://bmj.com/cgi/content/full/323/7316/#B16>  17
<http://bmj.com/cgi/content/full/323/7316/#B17>  Differences in assessment
were resolved by consensus.
Analysis---We combined results from individual studies on the relative risk
scale using fixed effects meta-analysis. 18
<http://bmj.com/cgi/content/full/323/7316/#B18>  Data on length of hospital
stay were pooled with non-standardised mean differences. We used a chi 2
test to test for homogeneity of relative risks. We used funnel plots to
determine the presence of publication bias and related biases and performed
a statistical test of funnel plot asymmetry. 19
<http://bmj.com/cgi/content/full/323/7316/#B19>  In a sensitivity analysis
we excluded data from patients who did not have an intestinal anastomosis
from analyses of anastomotic dehiscences. These patients had
abdominoperineal resections or stoma creations. In a planned subgroup
analysis we examined whether the risk of anastomotic dehiscence differed
according to whether the anastomosis was proximal or distal to the site of
feeding. Results are presented as relative risks (95% confidence intervals).
All analyses were performed with Stata version 6.0 (StataCorp, College
Station, Texas).




  Results
Characteristics of trials, patients, and interventions
We identified 13 randomised controlled trials, all of which were published
in English. 13 <http://bmj.com/cgi/content/full/323/7316/#B13>  20-31
<http://bmj.com/cgi/content/full/323/7316/#B20>  We excluded two of these
trials because no information on relevant outcomes was given, and attempts
to obtain unpublished data from the authors were unsuccessful. 30
<http://bmj.com/cgi/content/full/323/7316/#B30>  31
<http://bmj.com/cgi/content/full/323/7316/#B31>  Additional unpublished data
were obtained for six of the studies. 21
<http://bmj.com/cgi/content/full/323/7316/#B21>  22
<http://bmj.com/cgi/content/full/323/7316/#B22>  24-26
<http://bmj.com/cgi/content/full/323/7316/#B24>  29
<http://bmj.com/cgi/content/full/323/7316/#B29>  The earliest study was
published in 1979 20 <http://bmj.com/cgi/content/full/323/7316/#B20> ;
however, most were published between 1995 and 1998.
Patients had a wide variety of gastrointestinal conditions. Table 1
<http://bmj.com/cgi/content/full/323/7316/#T1>  gives details of the 11
trials that we included. Six studies included only lower gastrointestinal
surgery. 13 <http://bmj.com/cgi/content/full/323/7316/#B13>  21
<http://bmj.com/cgi/content/full/323/7316/#B21>  22
<http://bmj.com/cgi/content/full/323/7316/#B22>  25
<http://bmj.com/cgi/content/full/323/7316/#B25>  27
<http://bmj.com/cgi/content/full/323/7316/#B27>  29
<http://bmj.com/cgi/content/full/323/7316/#B29>  Six studies did not state
the underlying pathology of the study participants, the five remaining
trials included both benign and malignant conditions. Thirty one patients
from five trials underwent abdominoperineal resections or stoma creation and
had no anastomosis. 20 <http://bmj.com/cgi/content/full/323/7316/#B20>  22
<http://bmj.com/cgi/content/full/323/7316/#B22>  24
<http://bmj.com/cgi/content/full/323/7316/#B24>  25
<http://bmj.com/cgi/content/full/323/7316/#B25>  27
<http://bmj.com/cgi/content/full/323/7316/#B27>  In six studies patients in
the intervention group were fed directly into the small bowel, and in five
studies patients were fed orally. In four studies feeding was started within
six hours after surgery. 13 <http://bmj.com/cgi/content/full/323/7316/#B13>
23 <http://bmj.com/cgi/content/full/323/7316/#B23>  24
<http://bmj.com/cgi/content/full/323/7316/#B24>  28
<http://bmj.com/cgi/content/full/323/7316/#B28>  In the nine remaining
studies it was started within 24 hours. One trial used a placebo feed
(water). 24 <http://bmj.com/cgi/content/full/323/7316/#B24>



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Table 1. Characteristics of eleven trials of early enteral feeding after
elective gastrointestinal surgery
Methodological quality of trials
Reporting on concealment of allocation of treatment and blinding was poor.
In three trials allocation was concealed with sealed envelopes, 23
<http://bmj.com/cgi/content/full/323/7316/#B23>  24
<http://bmj.com/cgi/content/full/323/7316/#B24>  26
<http://bmj.com/cgi/content/full/323/7316/#B26>  and one trial used an open
table with random numbers, 20
<http://bmj.com/cgi/content/full/323/7316/#B20>  but in the remaining
studies the exact method of randomisation was unclear. In the study by
Heslin et al the outcomes were assessed by "a physician not associated with
the surgical team." 26 <http://bmj.com/cgi/content/full/323/7316/#B26>  In
all other studies outcome assessment was probably open, although this was
explicitly stated in only one report. 28
<http://bmj.com/cgi/content/full/323/7316/#B28>
Outcomes
The effects of early feeding on anastomotic dehiscence, infections,
vomiting, and mortality are detailed in table 2
<http://bmj.com/cgi/content/full/323/7316/#T2>  and summarised in the
figure. Occurrence of anastomotic dehiscence was reported in eight of the 11
trials. Table 3 <http://bmj.com/cgi/content/full/323/7316/#T3>  gives
detailed information on the number of events---for example, the risk of
dehiscence ranged from 2% (2/95) to 7% (2/30) in early feeding groups and
from 1% (1/81) to 25% (4/16) in control groups. Seven trials showed that
early feeding led to a reduction in risk of anastomotic dehiscence (table 2
<http://bmj.com/cgi/content/full/323/7316/#T2> ) with a combined relative
risk of 0.53 (95% confidence interval 0.26 to 1.08, P=0.080) and no evidence
of heterogeneity between studies (chi 2=2.10, P=0.96). Results were similar
when 31 patients in whom no anastomosis had been formed were excluded from
the denominator of five trials (combined relative risk 0.54, 0.26 to 1.09).
20 <http://bmj.com/cgi/content/full/323/7316/#B20>  22
<http://bmj.com/cgi/content/full/323/7316/#B22>  24
<http://bmj.com/cgi/content/full/323/7316/#B24>  25
<http://bmj.com/cgi/content/full/323/7316/#B25>  27
<http://bmj.com/cgi/content/full/323/7316/#B27>  There was little evidence
that results differed between the two studies in which the anastomosis was
known to be proximal to the site of feeding 26
<http://bmj.com/cgi/content/full/323/7316/#B26>  28
<http://bmj.com/cgi/content/full/323/7316/#B28>  and the six trials in which
it was distal (P=0.42 for interaction).



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Table 2. Relative risk (95% CI) of anastomotic dehiscence, infection, and
death in eleven randomised trials of early enteral nutrition


 <http://bmj.com/cgi/content/full/323/7316/773/Fu2>
View larger version (18K):
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Risk of anastomotic dehiscence, infections, vomiting, and death after
elective gastrointestinal surgery: results from meta-analyses of randomised
trials comparing early enteral feeding with regimen of nil by mouth




View this table:
[in this window] <http://bmj.com/cgi/content/full/323/7316/773/T3>
[in a new window] <http://bmj.com/cgi/content-nw/full/323/7316/773/T3>

Table 3. Number of patients with complications reported in eleven randomised
trials of early enteral nutrition
The risk of any type of infection was reported in all but two trials (table
2 <http://bmj.com/cgi/content/full/323/7316/#T2> ). 21
<http://bmj.com/cgi/content/full/323/7316/#B21>  28
<http://bmj.com/cgi/content/full/323/7316/#B28>  Absolute risks ranged from
3% (1/29) to 30% (29/97) in the early feeding groups and from 5% (4/81) to
47% (14/30) in the control groups (table 3
<http://bmj.com/cgi/content/full/323/7316/#T3> ). The combined relative risk
was 0.72 (0.54 to 0.98), indicating a significant (P=0.036) reduction in the
risk of infection, with little evidence of heterogeneity between trials (chi
2=10.7, P=0.22). Similar reductions were observed for wound infection and
pneumonia (figure). There was an increase in the risk of vomiting among
patients fed early (1.27, 1.01 to 1.61, P=0.045). Absolute risks ranged from
21% (17/80) to 50% (15/30) in the early feeding groups and from 14% (11/81)
to 57% (17/30) in the control groups (table 3
<http://bmj.com/cgi/content/full/323/7316/#T3> ). When nasogastric tubes
were not placed routinely at the time of surgery the rate of placement
because of nausea and vomiting was higher in patients fed early (1.21, 0.73
to 1.99, P=0.46).
Mortality was reported in all but two studies, 21
<http://bmj.com/cgi/content/full/323/7316/#B21>  28
<http://bmj.com/cgi/content/full/323/7316/#B28>  but deaths occurred in only
five (table 2 <http://bmj.com/cgi/content/full/323/7316/#T2> ). When
reported, death occurred in hospital except for in one study in which 30 day
mortality was reported. 24 <http://bmj.com/cgi/content/full/323/7316/#B24>
Mortality ranged from none to 7% (2/30) in the early feeding groups and 13%
(4/30) in the control groups (table 3
<http://bmj.com/cgi/content/full/323/7316/#T3> ). There were four deaths in
the early feeding groups compared with 10 deaths in control groups (relative
risk 0.48, 0.18 to 1.29, P=0.15).
Length of hospital stay was reported in all 11 studies. When combining data
for meta-analysis we estimated the mean length of stay from the median for
one trial. 20 <http://bmj.com/cgi/content/full/323/7316/#B20>  We estimated
standard deviations (SD) by dividing ranges by factor 4 for two trials. 20
<http://bmj.com/cgi/content/full/323/7316/#B20>  21
<http://bmj.com/cgi/content/full/323/7316/#B21>  The mean length of stay
ranged from 6.2 days to 14.0 days in early feeding groups and from 6.8 days
to 19.0 days in control groups. Combined results showed a significant
reduction by 0.84 day (0.36 to 1.33 days, P=0.001), with some evidence of
heterogeneity between studies (chi 2=16.2, P=0.094). Results were similar
when we excluded the two trials with incomplete data. 20
<http://bmj.com/cgi/content/full/323/7316/#B20>  21
<http://bmj.com/cgi/content/full/323/7316/#B21>
Two major complications of feeding were reported in patients fed via
jejunostomies: one broke and migrated into the abdomen 26
<http://bmj.com/cgi/content/full/323/7316/#B26>  and one left a prolonged
fistula after it was removed. 26
<http://bmj.com/cgi/content/full/323/7316/#B26>
Funnel plots
We examined funnel plots for all nine outcomes (the seven shown in table 2
<http://bmj.com/cgi/content/full/323/7316/#T2>  plus length of stay and
replacement of nasogastric tubes). There was no clear evidence of asymmetry
in any of these plots (P>0.10 by regression test 19
<http://bmj.com/cgi/content/full/323/7316/#B19> ), except for mortality
(P=0.068).




  Discussion
This meta-analysis yielded three principal findings. Firstly, there does not
seem to be a clear advantage in keeping patients nil by mouth after elective
gastrointestinal resection. Secondly, in these patients early feeding may be
beneficial. Thirdly, we believe these results indicate the necessity for an
adequately powered clinical trial to assess early enteral feeding in
patients undergoing elective gastrointestinal surgery.
Complications after operation
Anastomotic dehiscence is a major complication of gastrointestinal surgery
with considerable morbidity and mortality. 32
<http://bmj.com/cgi/content/full/323/7316/#B32>  The combined estimate
failed to reach conventional levels of significance but indicates that early
feeding may reduce the risk of dehiscence. Reporting on factors that could
have modified the effect of early feeding, 32-34
<http://bmj.com/cgi/content/full/323/7316/#B32>  such as the experience of
the surgeon, whether the resections were from the large or small bowel, the
length of the operation time, postoperative pain control, the use of
antibiotics, and the success of the operation, was incomplete. Furthermore,
the definition of dehiscence varied between trials. However, the estimated
effect in eight out of nine studies that reported anastomotic dehiscence
indicated benefit and was similar among patients fed proximally or distally
to their anastomosis.
A significant relative reduction in the risk of infection of any type was
observed for patients receiving early enteral nutrition, with the greatest
reduction seen in the frequency of wound infections. In most of the trials
assessed infections were not clearly defined. In absolute terms results were
heterogeneous, with the number of patients who would need to be treated to
prevent one infection of any type ranging from three 24
<http://bmj.com/cgi/content/full/323/7316/#B24>  to 58. 26
<http://bmj.com/cgi/content/full/323/7316/#B26>
Length of hospital stay
The length of hospital stay after surgery was reduced in eight of the eleven
studies. Overall the reduction corresponds to about one day, which is
economically important. Reduction in complication rates may explain this
observation, as might a faster return of gastrointestinal function. Early
postoperative feeding after non-gastrointestinal surgery has also been shown
to reduce length of stay in hospital. 35
<http://bmj.com/cgi/content/full/323/7316/#B35>  36
<http://bmj.com/cgi/content/full/323/7316/#B36>  Although not significant,
the direction of effect suggested a reduced risk of postoperative death
among patients who received early enteral feeding in all five studies in
which mortality occurred. There were insufficient data to comment on the
causes of death. Reductions in mortality tended to be larger in smaller
studies, which may be due to chance, publication bias, or lower
methodological quality of smaller studies. 19
<http://bmj.com/cgi/content/full/323/7316/#B19>  Mortality was one out of
nine outcomes examined, and no evidence of small study bias was evident for
the other outcomes. The association found for mortality was probably a
chance finding.
Statistical quality
The 11 randomised trials identified were clinically heterogeneous and most
of them were small and of doubtful methodological quality. Combination
trials that differ in terms of underlying condition, operation, and
intervention may be inappropriate. However, we were interested in the
pragmatic comparison of early versus deferred feeding strategies after
gastrointestinal surgery and not in differences between feed types or
specific routes of feeding. It is noteworthy that the effect of early
nutrition seemed to be homogeneous across a set of trials that were clearly
heterogeneous in clinical terms. Our ability to detect heterogeneity between
trials, however, was limited by the small number of trials and by the often
inadequate reporting. For example, definition of the patients' pre-existing
nutritional state and severity of underlying disease was generally poor. The
method of randomisation and blinding of outcome assessment was also not
described in sufficient detail, which means that uncertainty regarding the
methodological quality of trials remains. In particular, the identical or
closely similar number of patients in comparison groups in these trials must
be of concern. 37 <http://bmj.com/cgi/content/full/323/7316/#B37>  This
could occur only if blocked randomisation with a small block size had been
used. Blocked or stratified randomisation, however, was mentioned in only
two trials. 24 <http://bmj.com/cgi/content/full/323/7316/#B24>  28
<http://bmj.com/cgi/content/full/323/7316/#B28>
Conclusion
There is little evidence from these trials that keeping patients nil by
mouth is beneficial after elective gastrointestinal resection. Although the
data are clearly insufficient to conclude that early feeding is of proved
benefit, we believe that there is a good case for an adequately powered
clinical trial to assess early enteral feeding in such patients. With
anastomotic dehiscence as the primary end point, such a trial would need to
enrol about 1000 patients in each arm and would therefore involve several
centres.



  Acknowledgments
We thank the authors who provided additional data: R Beier-Holgersen, B
Stewart, S Wexner, J E Fischer, M F Brennan, and H Ortiz. We also thank the
following manufacturers of enteral feeds for assisting in the collection of
data: Nutricia, Fresenius Kabi, Novartis Nutrition UK, Ross Products,
Clintec Nutrition, Nestlé (Clinical Nutrition), SHS International, Mead
Johnson Nutrition.
Contributors: The data were extracted independently by SJL and PAS and
checked for consistency by ST. ST and ME assessed the two dimensions of
methodological quality. SJL wrote to all the trialists and feed companies
requesting additional data and coordinated the writing of the paper. ME
advised on the literature search and performed quality assessments and
statistical analyses. All the authors contributed to the writing of the
final draft of the manuscript. SJL is guarantor for the paper.

  Footnotes
Funding: None.
Competing interests: None declared.



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(Accepted 30 May 2001)


Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.