Does Caffeine Enhance Bowel Recovery After Colorectal Surgery?
Condition: Postoperative Ileus
MeSH terms: Ileus
Study type: Interventional
Phase: Phase 2

Summary: 
      Postoperative ileus is a frequently occurring surgical complication. It is defined as
      temporary inhibition of propulsive bowel activity and is manifested by abdominal distention,
      nausea, vomiting and diet intolerance. It may lead to a prolonged hospital stay,
      hospital-acquired infections or complications that may require additional treatments (e.g.
      analgesia, fluids, electrolyte replacement, nasogastric tube decompression), and as a result
      increase medical costs.

      Previous studies showed that postoperative coffee consumption shortens the time to first
      bowel movement after colorectal resections. However, none could explain the mechanism by
      which coffee stimulates intestinal motility and the determinant agent for this action is
      still up for discussion (either caffeine or another coffee component).

      Coffee has a negligible caloric content; It has a pH that varies from 5 to 6 (less acidity
      than other beverages that have no similar effect on bowel motility) and it is hypotonic.
      Therefore, it is highly unlikely that bowel motility is due to the physical properties of the
      coffee. Much more likely, that one (or more) of the numerous phytochemicals of the coffee
      bean are responsible for this effect, when the most obvious candidate seems to be caffeine.
      However, as mentioned above, very little evidence exists that caffeine was responsible for
      the observed effect on colonic function in previous studies.

      The purpose of this single-centered, prospective, single blinded, randomized clinical trial
      is to evaluate whether the use of caffeine in the post-operative period significantly reduces
      the duration of postoperative ileus, and therefore, improves recovery and shorten the
      hospital stay.

      The study hypothesis is that post-operative use of caffeine will reduce time to recovery of
      GI function (post-operative ileus) by at least 15 hours and thus reduce hospital length of
      stay by at least 15 hours in patients undergoing elective colorectal operations.

      50 patients due to undergo large bowel resection via laparotomy or laparoscopy will be
      enrolled and randomized (1:1) to those who will receive caffeine (100 mg 3 times per day) and
      those who will receive placebo (tap water) starting on the morning of postoperative day 1
      after surgery until flatus will occur for the first time or to a maximal period time of 7
      days, whichever comes earlier.
    

Detailed description: 
      Background Postoperative ileus is a frequently occurring surgical complication. It is defined
      as temporary inhibition of propulsive bowel activity and is manifested by abdominal
      distention, nausea and vomiting and diet intolerance. It may lead to a prolonged hospital
      stay, hospital-acquired infections or complications that may require additional treatments
      (analgesia, intravenous fluid administration, electrolyte replacement, nasogastric tube
      decompression etc.) and as a result increase medical costs.

      Surgeons are continually trying to find ways to shorten postoperative ileus. The means are
      diverse and include advancing diet as tolerated, avoiding the use of nasogastric tubes, early
      ambulation, occasional use of gastrograffin or alvimopan (a selective μ-receptor opioid
      antagonist) and the use of minimally invasive surgery (laparoscopic colectomy) rather than
      laparotomy. Asao et al showed that chewing gum after laparoscopic colectomy leads to an
      earlier return of bowel function and shorten the hospital stay, probably via the
      cephalic-vagal reflex which increase the production of gastrointestinal hormones associated
      with bowel motility. However, up until now, there has been no strategy or drug that has been
      consistently effective in accelerating bowel recovery from abdominal surgery.

      Coffee is a popular beverage with known influences on the central nervous system and the
      cardiovascular system. Although coffee can stimulate intestinal function in healthy
      volunteers, the mechanism by which coffee stimulates intestinal motility is still unknown.
      The cholinergic anti-inflammatory pathway (CAIP) has been proposed as a key mechanism by
      which the brain, through the vagus nerve, modulates the immune system in the spleen. Vagal
      stimulation by nicotine was shown to reduce intestinal inflammation and improve postoperative
      ileus. It is known that caffeine stimulates vagal activity. An average cup of caffeinated
      coffee contains 50-150 milligrams of caffeine, depending on the type, concentration and
      amount of coffee consumed.

      The gastrointestinal system can be stimulated by a substantial caloric intake, acidity,
      osmolality, or volume load. The caloric content of coffee is negligible (approximately 1
      kcal/ 100 mL). It has a pH which varies from 5 to 6 (less acidic than other beverages that
      have no similar effect on the bowel motility). Brewed and filtered coffee is hypotonic (as is
      water which serves as the control drink in previous studies). Therefore, it seems that the
      gastrointestinal effect of coffee is most probably not attributed to its physicochemical
      properties but to the biochemical activity of one or several of the many active compounds in
      coffee.

      In a study that was conducted in 1990, 29% of healthy volunteers claimed that coffee induced
      a desire to defecate. The effect of caffeinated coffee on recto-sigmoid motor activity was
      investigated with a manometry. The activity was accelerated four minutes after the intake of
      either regular or decaffeinated coffee. However, water had no comparable effect on the
      recto-sigmoid motility. Caffeine, when in the stomach, can act upon gastric myenteric and
      submucous nerves to induce gastric emptying. The influx of digestive metabolites into the
      small intestines may stimulate the gastrocolic reflex and be a possible mechanism behind
      caffeine causing the need to defecate shortly after consumption. The ultimate result of this
      reflex mediated by caffeine is an increased anal sphincter contraction power and less neural
      input required to induce contraction (decreased sensory threshold). Rao et al. performed an
      ambulatory manometry with inserting a catheter through the rectum up to the mid transverse
      colon. They investigated the effects of 240 mL regular coffee, 240 mL decaffeinated coffee,
      240 mL water and a 1000 kcal meal on colonic activity. Regular coffee, decaffeinated coffee
      and the calorie-rich meal induced more colonic contractions than water. Moreover, regular
      coffee induced colonic contractions at greater intensity compared to a caloric-rich meal, 60%
      stronger than water and 23% stronger than decaffeinated coffee. A randomized controlled trial
      performed in 2012 at the University of Heidelberg among patients after laparoscopic
      colectomy, studied the effect of coffee on the duration of postoperative ileus. The study
      showed that the time to first bowel movement was significantly shorter in the group (40
      patients) which received 3 caffeinated coffee cups per day compared to group (40 patients)
      receiving water only. No significant side effects were observed at the active treatment
      group. Dulskas.A et al. conducted a randomized controlled study in 2015 to evaluate whether
      consumption of 100 mL coffee is effective in reducing postoperative ileus. The study showed
      that coffee consumption after colectomy is safe and that decaffeinated coffee was associated
      with a shorter time to bowel movement and tolerance of solid food but not time to ﬁrst ﬂatus;
      caffeinated coffee did not impact the duration of postoperative ileus. In all the studies
      carried out so far, none could explain the mechanism by which coffee stimulates intestinal
      motility and the determinant agent for this action is still up for discussion: either
      caffeine or another component of the coffee, such as chlorogenic acids or melanoidins.

      Aim The purpose of this study is to evaluate whether the use of caffeine in the
      post-operative period significantly reduces the duration of postoperative ileus, and
      therefore, improves recovery and shorten the hospital stay. The study hypothesis is that
      post-operative use of caffeine will reduce time to recovery of GI function (i.e. reduce
      post-operative ileus) by at least 15 hours and thus reduce hospital length of stay by at
      least 15 hours in patients undergoing elective colorectal operations.

      Methods This will be a single-centered, prospective, randomized controlled, double blinded
      trial.

      50 patients due to undergo large bowel resection via laparotomy or laparoscopy will be
      enrolled. Patients will be randomized (1:1) to those who will receive caffeine (study group)
      and those who will receive placebo (control group). Randomization will occur via an online
      program (www.randomizer.org) which assigns participants to experimental conditions. Patients
      in the study group will be given 100 milligrams caffeine citrate orally diluted in 50
      milliliters of apple flavored water while patients in the control group will be given 50
      milliliters of apple flavored water only. Administration of caffeine or placebo will occur
      three times per day starting on the morning of postoperative day 1 after surgery until
      passage of flatus per rectum will occur for the first time or to a maximal period of time of
      7 days, whichever comes earlier.

      Sample size was calculated as 50 patients (25 pts in each group) which are required in order
      to have 1-sided α level of 0.05 and a power of 0.80 to detect a difference of 15 hours in the
      duration of postoperative ileus (standard deviation 21 hours), which is supported by prior
      studies. Any difference of 15 hours or more between the groups will be statistically
      significant.

      Caffeine or water will be supplied to the surgical floor per participating patient by the
      pharmacy in coordination with one of the co-investigators who will be un-blinded. At the
      floor the caffeine or water will be diluted with apple flavored water which will be supplied
      by the pharmacy, prior to each dose. The investigators (aside from the single un-blinded
      co-investigator) and primary team of doctors and nurses will be blinded to the patient's
      assignment.

      Postoperative care will be the same for all patients other than the administration of
      caffeine or placebo. Patients will be instructed to avoid consuming products that contain
      caffeine (e.g. coffee, tea, chocolate, cola etc.) until the first passage of flatus. No other
      restrictions on food or beverages consumption will be imposed other than usually are for
      patients undergoing the same kind of surgery. The patients will be hospitalized under
      surveillance and monitoring of the primary team during the study period. They will be
      instructed to keep in mind or to note the endpoints (time to first flatus, time to first
      bowel movement, time to tolerate solid diet) and to report them to the primary team and study
      investigators during the routine rounds.

      The criteria for hospital discharge include stable vital signs with no febrile morbidity for
      ≥24 hours, passage of stool, toleration of a regular diet and the absence of other
      complications.

      Safety Endpoints

        -  Any adverse events deemed possibly, probably or definitely related to treatment with
           caffeine: arrhythmia, muscle crumps/tremor, restlessness, irritability, headache,
           dizziness, tachycardia, allergic reactions (rare) or any other severe manifestation that
           can be attributed to caffeine side effects.

        -  Any major adverse event resulting from the surgery that might interfere with caffeine or
           might lead to meaningless endpoint data: organ failure, anastomotic leakage,
           intraabdominal abscess or invasive re-intervention (Clavien-Dindo classification of
           surgical complications > 3).

      Patients Patients who are scheduled for laparoscopy or open elective colon resection (right
      or left hemicolectomy, sigmoid resection, anterior resection, segmental colectomy), for an
      oncologic or inflammatory indication, that are willing to participate in the study will be
      informed verbally by a member of the study team of the aims, the risks, alternative
      therapies, their rights and the course of the trial. The investigator will emphasize that
      study participation is voluntary and the patient can withdraw at any time during the study.

      Patients will be included if they fulfill all inclusion criteria and none of the exclusion
      criteria listed below within the protocol and after written informed consent was obtained.
      Enrolment period to the study will be 18 months

      Statistical analysis Pearson r correlation coefficient will be used to examine the
      relationship between two Quantitative variables.

      T test will be used to compare Quantitative variable between two categories of Qualitative
      variable.

      ANOVA test will be used to compare Quantitative variable between three or more categories of
      Qualitative variable.

      Chi- square test will be used to examine the relationship between two Qualitative variables.

      The variables which will be found significantly related to the dependent variable in the
      monothetic analysis (one-factor-at-a-time method) will be inserted to a multivariate analysis
      of ANCOVA.

      Risks and risk management Most of the population consumes high doses of caffeine (an average
      coffee consumption of 9-11 kg per person per year) without even noticing. The side effects
      listed above were previously described after consuming dosages much higher than 3 X 100
      mg/day. The safety of caffeine consumption after elective colorectal surgery has been
      demonstrated through numerous clinical studies as detailed above.

      In this study, any patient suffering from a medical condition or requiring treatment with a
      drug which might interfere with caffeine will be excluded. Therefore, consumption of caffeine
      in a cumulative dose of 300 mg/day should not cause any side effects.

      Despite this, patients will be hospitalized under supervision and monitored by the primary
      team and study investigators. Documentation of vital signs, physical examination, medical
      consultants support and assessment of serious adverse events will be conducted. Any
      unexpected adverse event will be treated efficiently and quickly without extra cost for the
      patient.
    

Intervention name(s): Caffeine Citrate; Water
Intervention type(s): Drug; Other
Intervention description(s): 25 patients after elective colorectal surgery will be given 100 mg caffeine citrate orally diluted in 50 ml apple flavored water three times per day starting on the morning of postoperative day 1 after surgery until flatus will occur for the first time or to a maximal period time of 7 days, whichever comes earlier.; 25 patients after elective colorectal surgery will be given 50 ml apple flavored water three times per day starting on the morning of postoperative day 1 after surgery until flatus will occur for the first time or to a maximal period time of 7 days, whichever comes earlier.
Other intervention name(s): Cafcit
Intervention MeSH terms: Caffeine; Caffeine citrate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Postoperative Ileus; Caffeine Citrate