Innovative schemes of colonoscopy bowel preparation with oral lactulose: Optimizing traditional standards to improve colonoscopy quality

Abstract

The bowel preparation is a crucial step to achieve an optimal quality in colonoscopy. The major clinical impact of an adequate colonic cleansing is to allow a more detailed and thorough inspection reducing the rates of missing lesions during the procedure and consequently reducing the incidence of interval colorectal carcinomas. Currently there are different colonoscopic preparation schemes, being the polyethylene glycol (PEG) based regimen one of the most used and recommended by the main international clinical guidelines. Nevertheless, PEG preparation requires the ingestion of considerably large volumes to achieve an optimal colonic cleansing, leading to poor tolerability in may patients, particularly in an elderly population. Other aspects that make accessibility to most colonoscopy preparation regimens difficult is their high cost and low availability. New options of colonoscopic preparation schemes based on oral lactulose are emerging with promising results, showing excellent efficacy-safety profiles and high tolerability indexes. Lactulose regimens present other benefits such as low cost and wide availability. The aim of this review is to analyze the scientific evidence to date and the current status of colonoscopy bowel preparation utilizing lactulose-based regimens, in order to consolidate this agent as a feasible “new player” in the field of colonoscopic preparation.

Key Words: Colonoscopy; Lactulose; Polyethylene glycols; Adenoma; Colorectal neoplasms

Core Tip: Bowel preparation is critical for high-quality colonoscopy. Polyethylene glycol is considered the gold standard for bowel preparation, however the need for high volumes impairs patient’s tolerance. The oral lactulose-based scheme has emerged as a new alternative for colonoscopy preparation with a low cost, widely accessible to the general population and with optimal efficacy, safety and tolerability profiles.

INTRODUCTION

Colorectal cancer is currently considered by the World Health Organization (WGO) as one of the most frequent cancers of the gastrointestinal tract, presenting in 2020 a global prevalence of 10% of all cancer diagnoses worldwide, with an incidence of 9.6% of all new cancer cases in the world. In 2022, the WGO reported a colorectal cancer mortality of 9.3% of all cancer deaths worldwide[1]. Recent studies have demonstrated that the cumulative incidence of colorectal cancer is decreasing due to the implementation of screening programs and the increasing availability of image-enhanced endoscopy that has allowed improvements in the detection of flat lesions and early neoplasms. However, a crucial step for the efficiency of colorectal polyps and early neoplasms detection relies on the quality of bowel preparation for colonoscopy. Currently new colonoscopic preparation schemes are emerging and demonstrating a high efficacy-safety profiles with optimal tolerability indexes and wider availability[1-16].

An adequate colonoscopic preparation is of paramount importance not only for the diagnosis of premalignant and malignant colorectal lesions in early stages but also to enable safely interventional procedures such as polypectomy, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). Moreover, an optimal bowel preparation must present high tolerability, availability and low cost in order to generate in patients a better adherence to colonoscopy surveillance procedures when needed[16-35]. This manuscript aimed to review some recent advances in the field of bowel preparation for colonoscopy with a greater emphasis on the incorporation of lactulose-based regimens into clinical practice and the latest scientific evidences supporting these regimens.

CLINICAL IMPACT OF BOWEL PREPARATION IN THE DETECTION OF COLORECTAL POLYPS AND EARLY CANCER

Bowel preparation is a key element to provide a high quality colonoscopy. A clean colon helps the operator to minimize blind spots and to decrease the rate of missed lesions, particularly serrated adenomas in the proximal colon[7-11]. Several studies have highlighted the positive clinical impact of optimal bowel preparation in reducing the incidence of interval colorectal cancer[12-15]. In a prospective study by Froehlich et al[16] involving 5832 patients from 11 countries, the level of colonoscopic cleanliness was evaluated. The results showed that intermediate and high levels of bowel cleanliness allowed a complete evaluation of the entire colon, leading to a statistically significant reduction in the rate of missed colorectal polyps.

TRADITIONAL SCHEMES FOR COLONOSCOPY PREPARATION

Polyethylene glycol (PEG) is one of the most widely used substances for bowel preparation in colonoscopy. The traditional scheme is to administer 4 L of PEG the day before the procedure. Recently, research groups have proposed several modifications to the traditional regimen to improve PEG’s tolerability without compromising its clinical efficacy. One important modification has been to divide the single-dose regimen of 4 L into split doses. In this scheme, the first dose (2 L of PEG) is used to clean the intraluminal contents, while the second dose (2 L of PEG) is focused on cleaning the colonic walls and optimizing the proximal colonic segments[17]. Another recent modification is to reduce the total volume of PEG to 2 L or even 1 L by adding adjuvants such as citrate, ascorbic acid or bisacodyl. Recent studies have shown that low-volume (≤ 2 L) or very low-volume (≤ 1 L) colonoscopic preparation schemes offer better results than high-volume (> 2 L) regimens in terms of tolerability, without affecting the efficacy[17-24]. Spadaccini et al[25] performed a meta-analysis of 17 randomized controlled clinical trials (7528 patients), in which they found no statistically significant differences in the effectiveness of low-volume and high-volume colonoscopic preparation schedules. However, they did demonstrate statistically significant results in favor of the low-volume schedules in terms of likelihood of preparation completion and tolerability rates. Maida et al[26]. prospectively examined 1289 patients divided into three groups (4 L-PEG, 2 L-PEG, and 1 L-PEG), demonstrating an optimal level of bowel cleansing in favor of very low-volume schemes with statistically significant results, even in the most proximal colonic segments. This scientific evidence supports low-volume colonoscopic preparation schemes as an excellent alternative, achieving high efficacy, safety and tolerability rates.

Currently there are several substances for colonoscopic preparation available for the general population, which present a wide spectrum of efficacy-safety-tolerability profiles[3-5]. The oral lactulose scheme is a new alternative that is showing optimal results with advantages that overcome many of the limitations of traditional colonoscopic preparation regimens. Table 1 shows a comparative analysis of the main colonoscopic preparation agents and the emerging oral lactulose-based regimen.

Table 1 Comparative analysis of the main agents for colonoscopic preparation.

	Mechanism of action	Adverse events	Advantages	Limitations	Administration scheme
Oral Lactulose	Non-absorbable disaccharide fermented by colonic bacteria producing an increase in osmotic pressure and stimulating peristalsis	Nausea; Vomiting; Flatulence	Very low volume regimen for colonoscopic preparation. Good tolerability. Low cost Does not produce significant electrolyte alterations. Safe in patients with comorbidities	Little scientific evidence for its use in colonoscopic preparation	Single dose on the same day of the procedure (6 hours before the colonoscopy); 200 mL of lactulose diluted in 600 mL of water + simethicone
Sodium picosulfate + magnesium citrate	Diphenylmethane type stimulant laxative that after being hydrolyzed by colonic bacteria in its active form directly stimulates the submucosal plexus of Meissner in the colon, causing increased colonic motility and decreased reabsorption of water and electrolytes	Nausea; Vomiting; Headache	Low volume regimen for colonoscopic preparation. Good tolerability	High cost; Contraindicated in severe kidney failure (due to magnesium content)	Split doses: One dose the night before and the other the morning of the procedure; Each dose followed by at least 500 mL of clear liquids
Magnesium citrate	Osmotic salt that produces an increase of the intraluminal osmotic pressure in the colon inducing a dragging of water into the bowel lumen and increased motility	Contraindicated in kidney failure	Good tolerability; Low cost	Little scientific evidence for its use in colonoscopic preparation	Split doses: One dose the night before (300 mL) and the other the morning of the procedure (300 mL); Each dose followed by at least 250 mL of clear liquids
Sodium phosphate (NaP)	Hyperosmotic laxative that attracts water into the bowel lumen stimulating peristalsis	Hyperphosphatemia Hypocalcemia; Hypokalemia; Cardiac arrhythmias Phosphate nephropathy	Low volume regimen for colonoscopic preparation. Good tolerability; Fast action	Contraindicated in kidney failure; Congestive heart failure; Liver cirrhosis	Split doses: One dose the night before (45 mL) and the other the morning of the procedure (45 mL); Each dose followed by at least 500 mL of clear liquids
Polyethylene glycol	Non-absorbable inert polymer producing water retention at the intraluminal colonic level and increased peristalsis	Nausea; Vomiting; Abdominal distention	Does not produce significant electrolyte alterations. Safe in patients with comorbidities	Requires high volume intake; Unpleasant taste	Split doses: One dose the night before (2 L) and the other the morning of the procedure (2 L); Low volume alternatives can be combined with other available agents

NEW COLONOSCOPY PREPARATION REGIMEN BASED ON ORAL LACTULOSE

In recent years, an innovative colonoscopic preparation scheme based on oral lactulose has emerged, which is showing excellent efficacy, safety and tolerability profiles in recently published studies[29-35].

Lactulose is a non-absorbable disaccharide composed of galactose and fructose, with minimal intestinal absorption (approximately 0.3%) in healthy individuals. Its mechanism of action in colonoscopy preparation is based on its osmotic effect. Since it is not absorbed in the small bowel, it reaches the colon intact, where it is fermented by the anaerobic colonic microbiota, producing gases (methane, hydrogen and carbon dioxide) and short-chain organic acids, such as lactic, acetic and formic acid. These acids generate an increase in intraluminal osmotic pressure, which causes an entrainment of water into the intestinal lumen, increasing the volume of colonic contents and stimulating peristalsis. In addition, this fermentation causes an acidification of the intraluminal colonic medium, reducing the pH from 7.0-7.5 to 5.0-6.0, which favors its laxative effect by inducing a mild irritation of the colonic mucosa. The onset of pharmacological action usually occurs between 6 and 12 hours after administration[2-4].

Method of application

Due to the relatively recent appearance of the oral lactulose-based colonoscopy preparation regimen, there is no specific international consensus on its method of use. However, based on recent published studies, the following method of application can be proposed, which has shown a wide adherence by patients due to its ease of use with high efficacy rates: Start a liquid diet without residues 24 hours before the procedure, then ingest 5 to 6 hours before the colonoscopy a single dose of 200 mL of oral lactulose (3.33 g/5 mL) plus 600 mL of water and 15 mL of simethicone. Then the patient should only ingest water and go to the digestive endoscopy room fasting.

One of the fundamental pillars to achieve an optimal colonoscopic cleaning with this scheme based on oral lactulose is an adequate and meticulous education of the patients by the specialized personnel (nurse and/or gastroenterologist), because the most frequent cause of an inadequate colonoscopic preparation with this method is the incorrect use of the instructions given. In patients refractory to the conventional scheme with oral lactulose described above, following the instructions given correctly, stimulant laxatives such as Bisacodyl can be added at a dose of 10 mg to 15 mg the afternoon before the procedure.

One of the main limitations of this oral lactulose-based colonoscopic preparation scheme is the scarce scientific evidence supporting its use as a bowel preparation agent for colonoscopy, however most of the studies that have been performed using this new regimen are showing high efficacy and safety rates in different groups of patients. Another limitation are some of the misconceptions associated with the use of oral lactulose for bowel cleansing is the risk of colonic explosion which would be increased in therapeutic endoscopic resection procedures in which an electrosurgical unit is used (hot snare polypectomy, EMR or ESD). However, to date, none of the large series that have analyzed the oral lactulose scheme have reported cases of colonic explosion with this substance. The few isolated case reports of colonic explosion, published several years ago and associated with the use of nonabsorbable carbohydrates in the colonoscopic preparation, involved mannitol and presented certain biases, such as poor bowel preparation or concomitant use of other laxatives[36,37]. These reports were based on the hypothesis of a high intracolonic production of potentially flammable gases (methane and hydrogen), generated by fermentation of this substance by anaerobic methanogenic bacteria. However, recent studies have challenged this hypothesis, demonstrating that in patients prepared with mannitol, intracolonic methane levels are low, which significantly reduces the risk of colonic explosion during endoscopic interventions with electrosurgical current application[38,39]. This reinforces the optimal efficacy, safety and tolerability profile of non-absorbable carbohydrates (such as lactulose, mannitol and sorbitol) in bowel preparation for colonoscopy. It is of note that our group including more than 20 interventional endoscopists, has been utilizing lactulose for bowel preparation in the past 10 to 15 years, including diagnostic and therapeutic procedures with EMR, ESD and Argon plasma coagulation usage and we have never experienced a single case of bowel explosion (observational unpublished data). Figure 1 shows a flow chart for decision making in the choice of oral lactulose scheme for colonoscopic preparation.

Figure 1 Flowchart for decision making in the choice of oral lactulose scheme for colonoscopy preparation. PEG: Polyethylene glycol.

Our research group conducted a prospective study comparing a very low volume colonoscopic preparation scheme based on oral lactulose (200 mL lactulose diluted in 600 mL water plus simethicone) with the traditional scheme based on PEG. A total of 111 patients were alocated in each arm. The results showed a higher level of colonic clearance in the group using lactulose, according to the Boston score (BBPS) (P < 0.001), as well as better colorectal adenoma detection rates (PEG group: 44.1%; lactulose group: 59.5%, P = 0.022) and high tolerability rates, with statistically significant results (overall satisfaction: PEG group: 27.9%; lactulose group: 62.2%, P < 0.001). This study constitutes one of the first solid scientific evidences on the clinical effectiveness of the oral lactulose schedule for colonoscopic preparation[31]. Table 2 presents a comparative analysis of our results with the main published studies in terms of clinical effectiveness of the colonoscopic preparation regimen using oral lactulose.

Table 2 Comparative table of world-wide outcomes in colonoscopic preparation using oral lactulose.

Ref.	Boston bowel preparation score	Colorectal adenoma detection rate	Inadequate bowel preparation	Side effects	Disagreeable flavor	Satisfactory overall experience
Aliaga Ramos et al[31]	8.36 ± 1.09	59.5% (66/111)	1.8% (2/111)	46.8% (52/111)	3.6% (4/111)	62.2% (69/111)
Wenqi et al[27]	7.19 ± 1.19	50.0% (100/200)	Not specified	6.5% (13/200)	Not specified	Not specified
Jagdeep et al[29]	6.25 ± 0.786	Not specified	Not specified	50% (10/20)	10% (2/20)	Not specified
Li et al[33]	7.95 ± 1.40	30.7% (27/88)	Not specified	39.7% (35/88)	0%	8.91 ± 1.34

Efficacy-safety profile

Other research groups have demonstrated the significant benefits of the combined use of oral lactulose and PEG in bowel preparation for colonoscopy, showing optimal efficacy rates, even in patients at high risk of inadequate preparation, and with low rates of adverse events. This combination offers an alternative to improve the standard regimen recommended by the main international guidelines. Recently, Zhang et al[32]. conducted a meta-analysis including 18 studies (2274 patients) with the aim of comparing the efficacy and safety profile between two colonoscopic preparation strategies: One based on the combination of PEG + lactulose and the other using PEG alone. The results showed that the group treated with the combination of PEG + lactulose had better efficacy rates, regardless of the presence of constipation, and lower rates of adverse events (abdominal pain, nausea and vomiting), with statistically significant differences compared to the group treated with PEG alone.

One of the drawbacks about the use of oral lactulose-based colonoscopic preparation schemes is the concern of side effects such as bloating sensation. However, the adequate dilution of lactulose in water, combined with the use of simethicone, generates a synergism that helps to mitigate the flatulent effect of lactulose and almost eliminates the formation of foam and bubles. Additional studies have shown that colonoscopic preparation schedules with oral lactulose have lower rates of side effects compared to the standard PEG-based schedule[33,34]. A recent meta-analysis by Aboursheid et al[35] that included 17 randomized controlled trials with 7528 patients compared the efficacy, safety and tolerability profile between lactulose and PEG for colonoscopic preparation. The results showed that there were no statistically significant differences in the degree of colonic cleansing between the two regimens. However, the lactulose-based regimen presented better tolerability and fewer side effects compared to the traditional PEG scheme.

Another advantage of using the oral lactulose-based regimen for colonic preparation is its high efficacy, regardless of the time of day when the colonoscopy is performed (morning or afternoon). This is because this innovative bowel preparation regimen conforms to the recommendations of the main international clinical guidelines, which indicate that the intake of the preparation should start 4 to 6 hours before the procedure and end at least 2 hours before the colonoscopy. In a non-inferiority clinical trial by Pasquale et al[17] involving 10 endoscopic centers and 320 patients, the level of colonic cleansing in colonoscopies performed in the morning (between 8 a.m. and 10 a.m.) was evaluated. The study compared two groups: One that received the standard PEG-based regimen with a single dose the night before the procedure (between 8: 30 p.m. and midnight) and another that used the same regimen with a split dose (the first dose the night before and the second dose 5 hours before the procedure). The results showed that in the single-dose group, the level of colonic clearance, as measured by the BBPS, reached 83.3% of patients with BBPS ≥ 6 and 35.9% with BBPS ≥ 8. On the other hand, in the split-dose group, the percentages were 97.5% with BBPS ≥ 6 and 61.1% with BBPS ≥ 8. These results highlight the importance of adequate intake of the colonic preparation on the same day of the procedure, especially when following the standard PEG-based regimen. However, one of the main limitations of the split-dose scheme is colonoscopies performed in the afternoon. Therefore, several research groups are proposing new preparation schedules that can be taken on the same day of the procedure. The oral lactulose-based preparation regimen is presented as an excellent alternative, which complies with international guidelines and maintains its high clinical efficacy in both morning and afternoon colonoscopies. Figure 2 shows illustrative images of optimal colonoscopic cleansing in different segments of the colon using the oral lactulose regimen.

Figure 2 Illustrative images showing the optimal level of colonic cleansing using oral lactulose-based. A: Descending colon; B: Ascending colon; C: Transverse colon; D: Transverse colon; E: Cecum; F: Sigmoid colon.

Clinical effectiveness in patients with comorbidities

Due to the fact that the oral lactulose-based colonoscopy preparation scheme is a regimen that is recently being consolidated in the field of bowel preparation, there is very little scientific evidence that analyzes its clinical effectiveness and safety specifically in certain population groups such as diabetes mellitus, chronic kidney failure, congestive heart failure, liver cirrhosis, and the elderly. However, based on its pharmacokinetics, its high safety profile in these comorbidities can be induced. Its mainly colonic metabolism and its low intestinal absorption makes it a safe colonoscopy preparation scheme in diabetic patients, since it does not generate systemic adverse events such as hyperglycemia peaks, ketoacidosis or hyperosmolar states.

Likewise, in patients with congestive heart failure or chronic kidney failure, this new regimen of bowel preparation in colonoscopy using oral lactulose could be considered safe because it is a very low volume scheme (< 1 L) avoiding water overload and electrolyte disorders in this group of patients. However, since lactulose has a low kidney excretion in patients with terminal chronic kidney failure with anuria or oliguria, an individualized scheme should be used with the support of the nephrologist, calculating and carefully monitoring the exact amount of substance to be ingested and the possible adverse events that may occur during the colonoscopic preparation. In patients with liver cirrhosis this emerging scheme of colonoscopic preparation based on oral lactulose is an attractive alternative because it not only avoids water overload and electrolyte disorders as it is a very low volume scheme but also by reducing serum ammonia levels it contributes to improve hepatic encephalopathy in this group of patients. The few studies using this innovative oral lactulose colonoscopic preparation regimen have included a high percentage of elderly and have shown optimal results in terms of efficacy - safety and tolerability mainly due to the need for low volume intake to achieve adequate colon cleansing as well as the ease of use and pleasant taste that most patients report.

One of the population groups at greatest risk for inadequate colonoscopic preparation are patients with obesity, even when the standard PEG-based regimen is optimized. This has prompted the investigation of new preparation schemes, such as the use of oral lactulose, to overcome these limitations. Wenqi et al[27] conducted a prospective study of 400 patients to evaluate the efficacy and safety profile of two different colonoscopic preparation schemes (lactulose group: 200 patients; PEG group: 200 patients) in patients with various body mass indices (low, normal and high). The results showed that in patients with a high body mass index, the level of colonic clearance was significantly higher in the lactulose group (7.15 ± 1.07) compared to the PEG group (6.72 ± 0.92), with a statistically significant difference (P = 0.010). In addition, a lower rate of adverse events was observed in the lactulose group compared to the PEG group among patients with higher body mass index [lactulose group: 2.5% (5/200); PEG group: 9.5% (19/200), P = 0.003]. It is important to emphasize that the studies carried out with this new colonoscopy preparation scheme based on oral lactulose have shown optimal efficacy rates in colonic cleansing even in patients with chronic constipation. These findings highlight the high effectiveness of the oral lactulose regimen for colonoscopic preparation, even in patients with risk factors that may hinder adequate bowel preparation.

CONCLUSION

In conclusion, based on all the scientific evidence presented, the colonoscopic preparation scheme based on oral lactulose has the potential to revolutionize the field of bowel preparation for colonoscopy. Its unique combination of low-volume, efficacy, safety and tolerability positions lactulose as an atractive alternative that not only optimizes the quality of colonoscopy, but completely redefines the way colonoscopy preparation is conceived. This innovative approach elevates the detection rate of colorectal lesions, significantly improves the patient experience, overcomes challenging clinical scenarios in patients refractory and/or intolerant to conventional schemes and establishes a new paradigm in the search of colonoscopy excellence. The oral lactulose-based colonoscopic preparation scheme is not just another option, but is the future of colonoscopic preparation and the definitive push towards top quality colonoscopy globally, improving the daily endoscopic practice of many endoscopists worldwide.