Caffeine intake enhances bowel recovery after colorectal surgery: a meta-analysis of randomized and non-randomized studies

Postoperative ileus (POI) after colorectal surgery is a major problem that affects both patient recovery and hospital costs highlighting the importance of preventive strategies. Therefore, we aimed to perform a systematic analysis of the effects of postoperative caffeine consumption on bowel recovery and surgical morbidity after colorectal surgery. A comprehensive literature search was conducted through September 2023 for randomized and non-randomized trials comparing the effect of caffeinated versus non-caffeinated drinks on POI by evaluating bowel movement resumption, time to first flatus and solid food intake, and length of hospital stay (LOS). Secondary outcome analysis included postoperative morbidity in both groups. After data extraction and inclusion in a meta-analysis, odds ratios (ORs) for dichotomous variables and standardized mean differences (SMDs) for continuous outcomes with 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed in cases of substantial heterogeneity. Six randomized and two non-randomized trials with a total of 610 patients were included in the meta-analysis. Caffeine intake significantly reduced time to first bowel movement [SMD −0.39, (95% CI −0.66 to −0.12), p = 0.005] and time to first solid food intake [SMD −0.41, (95% CI −0.79 to −0.04), p = 0.03] in elective laparoscopic colorectal surgery, while time to first flatus, LOS, and the secondary outcomes did not differ significantly. Postoperative caffeine consumption may be a reasonable strategy to prevent POI after elective colorectal surgery. However, larger randomized controlled trials (RCTs) with homogeneous study protocols, especially regarding the dosage form of caffeine and coffee, are needed. Supplementary Information The online version contains supplementary material available at 10.1007/s13304-024-01847-x.


Introduction
Postoperative ileus (POI), defined as a temporary disruption of intestinal motility is a common and concerning phenomenon especially following colorectal surgery with documented POI rates ranging from 10.2% to 19% [1,2].POI is not only associated with patient discomfort and increased susceptibility to ileus-related complications but may also be a reason of delayed hospital discharge, resulting in additional economic burden for healthcare providers [3].Many factors have been reported in the literature to be associated with prolonged cessation of bowel activity after colorectal surgery including smoking history, open approach, preoperative albumin levels, fluid management, and intra-abdominal complications [4][5][6][7].Implementation of fast-track protocols with concurrent attention to these adjustable perioperative variables have been successful strategies for overcoming POI [8].However, the quest for cost-effective and sufficient preventive measures to further reduce surgical morbidity and costs continues.Coffee and caffeinated drinks are among the most popular drinks being consumed worldwide.Coffee consists of a complex mixture of more than 1000 physiological and bioactive compounds, with anti-oxidative, anti-inflammatory and anti-cancer effects [9,10].In addition to natural constituents, the complex biochemical process of roasting and coffee preparation, such as the Maillard reaction, can alter the final composition and the degree of physiological interaction [11,12].Nevertheless, coffee consumption is associated with many health benefits in cardiovascular, metabolic, and neurodegenerative diseases and reduces the risk of all-cause mortality [13][14][15].Interestingly, the mechanism of action of coffee on the brain-gut axis with its propulsive effects is not fully understood [16].While the beneficial effect of coffee consumption on postoperative bowel recovery after gynecologic surgery and cesarean section has been consistently demonstrated in randomized controlled trials (RCTs) [17][18][19], there are still conflicting results regarding coffee and caffeine intake in colorectal surgery, especially with regard to bowel motility [20][21][22][23].Thus, the primary objective of this meta-analysis was to accurately evaluate the impact of caffeine and coffee consumption on postoperative outcomes after colorectal surgery, with a special focus on bowel recovery, as a potential cost-effective, easily accessible, and practical strategy for POI prevention.

Methods
The meta-analysis was conducted according to the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [24] and the Cochrane Handbook for Systematic Reviews of Interventions [25].

Search strategy
A systematic database search was conducted independently by two authors (S.V., and D.P.) in Pubmed (Medline), and the Cochrane Central trials register up to September 2023.There were no time or language restrictions.The following key search terms were used in combination with the Boolean operators AND or OR: "coffee", "caffeine", "drinks", "postoperative ileus", "colorectal surgery", and "intestinal transit".In addition, the reference list of the retrieved studies, systematic reviews or conference proceedings was screened to identify potentially relevant citations for the analysis.Each selected abstract and study was again independently assessed by two reviewers for eligibility and inclusion in the meta-analysis.Disagreements were resolved by discussion and consensus.If differences remained, a third author (S.O.D.) was consulted.

Selection criteria
All original studies comparing postoperative outcomes of caffeinated drink consumption (e.g.coffee, juice; defined as the intervention group) versus decaffeinated coffee, water, or tea (control) in open or minimally-invasive colorectal surgery for benign and malignant diseases were considered eligible.To be included in the meta-analysis, studies had to report on at least one of the following outcomes: gastrointestinal (GI) motility parameters (time to first bowel movement, time to first flatus, time to first oral diet intake), use of adjunctive laxatives, and surgical morbidity.Studies without colorectal resection (e.g.only rectopexy or only small bowel surgery) were excluded.In the case of duplicate or overlapping articles published by the same institution and authors, the most recent study was selected for inclusion.

Data extraction
All relevant data were entered independently by two authors (S.V., and D.P.) into an electronic data extraction sheet from articles meeting the inclusion criteria.Disagreements were discussed and resolved by consensus or reassessment by a third author (S.O.D.).The following data were extracted from each included study:

Outcome measures
The primary outcomes of this study were POI-related variables including time to first documented bowel movement, time to first flatus, time to first solid diet intake and LOS.In addition, the use of laxatives, nasogastric tube re-insertion, overall and major morbidity, re-operation rate, anastomotic leak, and mortality were parameters of our secondary outcome analysis.

Quality and certainty assessment
The risk of bias of the six included randomized trials was assessed using the RoB 2 criteria [27].Briefly, this recommended tool categorizes randomized trials into low to high risk of bias based on signaling questions derived from five potential bias domains (randomization process, deviations from the intended intervention, missing outcome data, measurement of the outcome, and selection of the reported results).In parallel, the risk of bias of the two remaining non-randomized studies was evaluated using the ROBINS-I tool [28], which also classifies studies from low to critical risk of bias according to the assessment of seven different bias domains.The authors independently evaluated the risk of bias of each included study.Disagreements were discussed and resolved by consensus.The revised AMSTAR 2 instrument [29] was used to critically appraise this metaanalysis.The level of evidence for important primary and secondary outcomes was classified into four categories (high, moderate, low, and very low) according to GRADE (The Grading of Recommendations, Assessment, Development, and Evaluation) [30].

Statistical analyses
Statistical analysis was performed using RevMan software (version 5.3.Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) according to the recommendations of the Cochrane Collaboration guidelines.Pairwise meta-analyses were performed.Summary treatment effect estimates with 95% confidence intervals (CIs) were calculated for each outcome of interest.Odds ratios (ORs) and the Mantel-Haenszel method were used for dichotomous outcomes.Standardized mean differences (SMDs) were calculated to analyze continuous outcomes.The methods by Luo et al. [31] and Wan et al. [32], or the Box-Cox (BC) method of McGrath et al. [33] were applied to estimate the sample mean and standard deviation from studies providing a summary set of median, quartile range, and sample size.In case of missing values, the study authors were contacted directly to provide the data if possible.Continuous values were expressed in hours (time to first bowel movement, time to first flatus and solid diet intake), and in days (length of hospital stay).The degree of heterogeneity among the included studies was interpreted as follows after applying the Cochrane Q test (chi-square test; Chi2) and measuring inconsistency (I 2 ): 0-40% low heterogeneity and may not be important, 30%-60% moderate heterogeneity, 50-90% substantial heterogeneity, 75-100% high heterogeneity.Note that starting with moderate heterogeneity, the significance of the obtained I 2 value is dependent on the size and direction of the effects and the power of evidence for heterogeneity (e.g., p-value of the Chi2 test or the I 2 confidence interval) [25].If heterogeneity was low or moderate (I 2 < 50%), summary estimates were calculated using a fixed-effects method.Otherwise, if I 2 > 50%, the randomeffects model was used.In cases of substantial heterogeneity, the source of heterogeneity was further investigated using one-way sensitivity and subgroup analyses.Subgroup analyses were performed according to surgical approach (open versus minimally-invasive), site of resection (right versus left colectomy), and type of coffee administered (caffeinated versus decaffeinated coffee) to test the stability of the meta-analysis when appropriate.Publication bias tests and funnel plots were not performed due to the small number of studies included in the meta-analysis.A p-value of < 0.05 was considered significant.

Study and patient characteristics
Our initial systematic database search identified 765 records.

Study quality and risk of bias
According to the RoB 2 criteria for randomized trials, the overall risk of bias was considered to be low in three RCTs, while some concerns were evident in the remaining three studies (Fig. 2a).The ROBINS-I tool assessment of the non-randomized studies showed an overall moderate risk of bias (Fig. 2b).The main limitations were that blinding of patients and outcome assessors was evident in only three studies [20][21][22].In addition, the different proportions of right-and left-sided colectomies performed in the caffeine and control groups in four studies [21,23,35,36] could lead to significant selection bias.The methodological quality of the present meta-analysis was determined as `high` using the AMSTAR 2 quality assessment tool.

Secondary outcome analysis
The results of the secondary outcome meta-analyses indicated no statistically significant differences between the caffeine and control groups in terms of laxative use, nasogatric  tube re-insertion, need of re-operation, overall complications, major complications (CD ≥ 3b), anastomotic leak, and mortality rates with a low level of heterogeneity (I 2 between 0% and 30%) (Table 4).

Discussion
The results of the current meta-analysis with eight included studies revealed, in contrast to the previously published literature [38], that postoperative caffeine intake accelerates bowel recovery after colorectal surgery, especially in the subgroup of patients undergoing elective minimally-invasive colorectal surgery with a low degree of heterogeneity.While the time to first bowel activity was significantly shorter in the caffeine group, there was no difference in the time to first solid diet tolerance in either the caffeine or control groups, although the subgroup analysis of elective minimally-invasive procedures suggested a significant benefit of postoperative caffeine intake in terms of oral diet resumption.As a result, the length of hospital stay was significantly shorter in the caffeine group.However, this benefit appeared to be relevant only in the cohort of open and non-colorectal procedures.To ensure homogenous groups, we distinguished between caffeinated drinks including coffee and drinks without caffeine such as decaffeinated coffee.Of note, in two of the included studies caffeine was dispensed in other drinks than coffee [21,22], and two studies used decaffeinated coffee as control [20,23].Therefore, in our opinion, the arbitrary inclusion of caffeine and coffee in one group could introduce a risk of bias.The development of postoperative ileus (POI), although to some extent considered a transient physiological response [39], is triggered by a complex neuro-immunoinflammatory interaction [40,41].Preventive strategies are becoming increasingly important to avoid operationrelated morbidities associated with postoperative ileus, thereby reducing hospital stay and healthcare costs [42].Coffee consists of hundreds of bioactive compounds that undergo multiple modifications during the preparation process from the native bean to the final product, explaining the complexity of its action.Several components including caffeine, CGA (chlorogenic acid), melanoidins, and diterpenes, are associated with mucous secretion and gastrointestinal motor function [16].Coffee consumption has been described to stimulate intestinal motility in healthy individuals [43] and after colorectal surgery [44] and small bowel resection [45].The physiological effect of caffeine on intestinal activity is based on several mechanisms, including calcium-mediated vasodilation [46], vagus nerve stimulation [47], and gastrin release [48].At the same time, the anti-inflammatory effect of chlorogenic acid by inhibiting tumor necrosis factor-α and interleukin-6 production results in less edema formation and pain relief [49,50].In fact, Piric et al. [35] were able to demonstrate significantly lower postoperative CRP (C-reactive protein) levels in the coffee group compared to the control group.
Interestingly, our subgroup analysis showed that decaffeinated coffee had a stronger effect on bowel movements than caffeinated coffee, as the resumption of the first documented bowel movement was earlier in patients who consumed decaffeinated coffee, suggesting that components other than caffeine may play a critical role in GI-tract motility [51].Furthermore, it is hypothesized that the decaffeination process itself may result in the formation of more bioactive products [52].
Several limitations must be considered when interpreting the results; the included studies served a variety of coffee products (e.g.instant coffee, coffee/caffeine capsules) with different volumes ranging from 100-150 ml.This could not only lead to significant heterogeneity between studies, but also complicate the investigation of a dose-response relationship.Studies using tea as a control [35,36] neglect the potential prokinetic effect of tea and its compounds on gastrointestinal motility [53,54].Remarkably, in all study protocols, the first coffee or caffeine administration was started in the postoperative period (the same day after surgery until second day).Based on pharmacokinetic principles, caffeine achieves its full effect at least 23 h after initiation [55], thus mitigating the potential impact on intestinal motility in the setting of postoperative ileus and recovery [56].Another important methodological weakness was the lack of blinding of investigators and patients, as only three trials masked the investigators [20][21][22].Blinding of the participating patients in a coffee or caffeine study is difficult due to the nature of the protocol.However, in two studies the taste of caffeine was neutralized by dispensing [21,22].The type of approach and the extent or side of resection may also significantly influence outcomes.It has been shown that patients undergoing open surgery and right-sided colectomy have a higher incidence of postoperative ileus [57,58].This is consistent with our observation showing a GI motility benefit of caffeine in the subset of studies using minimally-invasive approaches [21,22,36,37].In our meta-analysis two studies included open resections [34,35], while in four studies the proportion of right-and left sided colectomy was not evenly distributed [21,23,35,36].Other important concerns include the relatively small and heterogeneous sample size (median 65.5 patients) with varying characteristics, lack of information on fast-track protocols [21,22,35,37], and the use of epidural analgesia as an important preventive POI factor [59] mentioned in only two studies [22,34].Finally, in all studies investigating postoperative GI motility after abdominal surgery, there is a variable definition of ileus, which may limit the results presented.None of the studies included in our analysis used the recommended and evidence-based composite outcome measure GI-2 (time to tolerance of oral diet and passage of stool) [60].

Conclusions
Postoperative caffeine consumption significantly reduces POI after colorectal surgery, especially when minimallyinvasive approaches are used.Therefore, this simple, safe, and easily implemented measure could be incorporated into enhanced recovery programs.However, the limited level of evidence due to various bias concerns must be rigorously addressed by larger studies with uniform protocols to provide generalizable recommendations.Thus, additional highquality prospective RCTs are needed to make a definitive statement.

Fig. 1
Fig. 1 PRISMA diagram of study identification and selection for review analysis Abbassi et al.[22] Caffeine 200 mg 0

Fig. 2 Fig. 3 a
Fig. 2 Risk of bias summary according to a RoB 2 b ROBINS-I

Table 1
Study characteristics and protocols

Table 4
Primary and secondary non-significant outcomes CD Clavien-Dindo, NG-tube nasogastric tube, NA not applicable, OR odds ratio, SMD standardized mean difference