DISCUSSION
Many treatments have been the subject of randomised controlled trials to
decrease the rate of post-operative ileus. Nevertheless, our previous
descriptive analysis of the literature did not allow us to draw clear
conclusions as to the superiority of one treatment over
another5. This finding led us to perform this network
meta-analysis. We included in this meta-analysis only randomised
controlled trials that reported the criteria commonly used in the return
to normal transit. This network meta-analysis shows that prokinetics
significantly reduce the duration of first gas, duration of first bowel
movements and duration of post-operative hospitalisation. This treatment
is ranked (SUCRA and rankogram) among the three best ones apart from
food tolerance and the number of patients requiring a nasogastric tube.
For food tolerance, opioid antagonists are the treatment that
significantly improve the duration of food recovery.
The definition of return to normal transit is an important point to
discuss. Indeed, not all segments are affected to the same extent. Small
bowel motility is disturbed within 24 hours, gastric motility within 24
to 48 hours and colonic motility within 48 to 72 hours
post-surgery4,50. The difference in time for recovery
of motor function explains why the passage of the first stool and gas is
most often used to define return to normal function. The complexity of
the definition lies in the fact that the return of the migrating motor
complex is not synonymous with a return to normal function, i.e. the
perception of peristalsis on auscultation is not indicative of a return
to normal transit. A recent literature review of 215 articles identified
a total of 73 criteria defining return to normal transit9. Thus, in descending order of frequency, the
criteria are: passage of first gas (140 studies out of 217, 64.5%),
passage of first stool (69 studies out of 217, 31.8%) followed by first
bowel movements (65 studies out of 217, 30%)9. The
commonly accepted outcome for assessing the pharmacological effects of
treatment for POI is the presence of first gas 9. Some
studies have proposed composite scores but this is variable across
studies. The COMET-registered core outcome set aims to standardise the
reporting of outcomes in clinical studies of post-operative
ileus8. Among recent work, the American Society for
Enhanced Recovery After Surgery (ERAS) and Perioperative Joint Consensus
have considered a more functional definition of POI and a classification
system for post-operative gastrointestinal transit disorders51. Classification was proposed on a
pathophysiological and functional basis using the following criteria:
tolerance to oral ingestion, nausea, vomiting and physical signs of
ileus (intake, sensation of nausea, vomiting, physical examination and
duration of ”I-FEED” symptoms). A three-category classification system
was therefore established. This recent score has never been evaluated in
a prospective cohort of GI tract surgery patients. This score would
allow a reproducible evaluation of the return to normal transit and
therefore have comparable criteria for pharmacological
studies51.
Adding duration of hospitalisation (a reproducible criterion) to the
criteria commonly used and reported in the literature made two
pharmacological principles stand out: prokinetics and opiate antagonists
(as reported above). Prokinetics are made up of active principles used
in clinical practice to treat nausea and vomiting. Their action on
peristalsis supported an interesting approach in
POI52,53. Among this class of potential active
molecules, 5HT3 receptor antagonists (metoclopramide), selective 5HT4
receptor agonists (mosapride, prucalopride, cisapride) and ghrelin
receptor agonists (ulimorelin) were the most evaluated. The results of
our meta-analysis show that prokinetics are among the three best
treatments for commonly used criteria (time for first bowel movement and
for first stool) to characterise POI as well as the post-operative
length of stay. Nevertheless, these results do not show a real
superiority.
One way to optimise the post-operative recovery of bowel function after
surgery would be to antagonise peripheral opioid receptors without
negating their central analgesic action. The most commonly used drug for
analgesia and anaesthesia is morphine which is a central and peripheral
μ receptor agonist54. This central and peripheral
action contributes to the prolongation of post-operative ileus although
it is gastrointestinal receptors that have a predominant role in
inhibiting post-operative gut motility. Morphine and other opioid
analgesics inhibit the release of acetylcholine from the mesenteric
plexus, thereby increasing colonic muscle tone and reducing propulsive
activity in the gastrointestinal tract. There are several types of
opioid receptors, the three main ones being μ, δ, and κ receptors with
each class having several subtypes as well54. Opioid
receptors are stimulated exogenously by agonists such as morphine and
codeine. Both alvimopan and methylnaltrexone are the main peripheral
opioid antagonists used that do not cross the blood-brain
barrier55. Since the early 2000s, randomised
controlled trials have been conducted in North America on cohorts of
patients who have undergone bowel resection and
hysterectomy23,26,28. Compared to placebo, patients
treated with alvimopan had a significant reduction in time to transit
recovery as evidenced by clinical functional signs such as first gas,
first bowel movements or first stools. These encouraging results were
not confirmed in a large clinical trial involving 70 hospitals in 10
countries on the European continent (Austria, Belgium, France, United
Kingdom, Germany, Greece, Poland, Portugal, Spain and Sweden) and New
Zealand22.
Despite the lack of a strict definition for POI resulting in
discrepancies regarding the endpoints reported across studies, the
current analysis provides the first Bayesian network analysis focused on
pharmacological intervention of POI. This analysis is based on 6 robust
endpoints, with nasogastric tube placement being the weakest endpoint
because it is not included in all studies.
In conclusion, based on our meta-analysis, the two most consistent
pharmacological treatments in terms of effectiveness for reducing POI
after abdominal surgery are prokinetics and opioid antagonists. The
absence of clear superiority of one treatment over another highlights
the limits of the pharmacological principles available. It therefore
appears necessary to act on other pathways. Indeed, there is a need to
study and develop new pharmacological approaches that target the
intimate mechanisms of intestinal damage involved in inflammation and/or
neuroinflammation observed during post-operative ileus. New research
approaches are required to help understand this phenomenon and develop
new pharmacological treatments.