Pathogenesis, risk factors, and management of postoperative delayed gastric emptying after distal gastrectomy: a narrative review

Cheong Ah Oh

doi:10.15747/ACNM.25.0007

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Review Pathogenesis, risk factors, and management of postoperative delayed gastric emptying after distal gastrectomy: a narrative review: Cheong Ah Oh; Annals of Clinical Nutrition and Metabolism 2025;17(1):9-17.
DOI: https://doi.org/10.15747/ACNM.25.0007
Published online: April 1, 2025

Department of Surgery, Samsung Medical Center, Seoul, Korea

Corresponding author: Cheong Ah Oh, email: cheongah.oh@samsung.com

• Received: February 13, 2025 • Revised: March 14, 2025 • Accepted: March 26, 2025

© 2025 Korean Society of Surgical Metabolism and Nutrition · Korean Society for Parenteral and Enteral Nutrition · Asian Society of Surgical Metabolism and Nutrition · Japanese Society for Surgical Metabolism and Nutrition

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract
Introduction
Pathogenesis, etiology, and risk factors of postoperative DGE following distal gastrectomy
Diagnosis
Management
Conclusion
Notes
References

Abstract

Purpose
This narrative review elucidates the complex pathogenesis, key risk factors, and effective management strategies for postoperative delayed gastric emptying (DGE) following distal gastrectomy with D2 lymphadenectomy, a definitive procedure for middle and lower gastric cancer. It also explores opportunities for improved prevention and innovative treatment options.
Current concept
DGE significantly disrupts gastric motility and presents with symptoms such as early satiety, postprandial fullness, nausea, vomiting, and gastric atony. Although rarely fatal, DGE hampers oral intake, prolongs hospital stays, and diminishes quality of life. Current evidence indicates that DGE is a multifactorial disorder resulting from an interplay of vagal nerve disruption, damage to smooth muscle and interstitial cells of Cajal, imbalances in gastrointestinal hormones, and postoperative gut microbiome dysbiosis. Patient-specific factors, including advanced age, poor nutritional status, diabetes, and preoperative pyloric obstruction, along with surgical factors (most notably Billroth II reconstruction), further increase the risk of DGE. Management involves dietary modifications, prokinetic agents (such as metoclopramide and selective 5-HT₄ agonists like prucalopride), and gastric decompression.
Conclusion
DGE is a challenging complication following gastrectomy that demands a deeper understanding of its underlying mechanisms to improve patient outcomes. Emerging therapies, including microbiota modulation and advanced pharmacological agents, offer promising new treatment avenues.
Keywords: Gastrectomy; Gastrointestinal microbiome; Gastroparesis; Risk factors; Stomach neoplasms

Introduction

Background

Distal gastrectomy with D2 lymphadenectomy is a curative surgery for middle and lower gastric cancer [1]. However, this procedure can markedly disrupt the stomach’s normal anatomical and physiological functions, leading to regional abnormalities in motility and resulting in delayed gastric emptying (DGE) [2-4]. Also known as postoperative gastroparesis syndrome, DGE is characterized by early satiety, postprandial fullness, nausea, vomiting, and gastric atony, all occurring in the absence of mechanical gastric outlet obstruction [5-9]. Clinically, DGE is often observed during transitions to solid diets or when food consistency changes, highlighting the dynamic nature of postoperative gastric motility disturbances [7,10]. With an incidence rate ranging from approximately 5% to 25% [6,7], DGE is one of the major complications after gastrectomy. Although it is generally nonfatal and may be managed with nasogastric tube insertion or fasting, with or without prokinetic therapy [6], DGE can delay oral intake, extend hospital stays, and significantly diminish patients’ quality of life [2,6-8,11,12]. Furthermore, it may adversely affect oncological outcomes; for example, Zhang et al. [13] reported a mean recurrence-free survival time of 26.1 months for patients with DGE, compared to 33.4 months for those without.

The exact pathogenesis of postoperative DGE remains unclear [8]. Current evidence indicates that DGE is multifactorial, involving nerve damage, smooth muscle dysfunction, injury to interstitial cells of Cajal (ICC), hormonal imbalances, postoperative microbial dysbiosis, and other yet unidentified factors [8,14]. Moreover, the management of DGE following gastrectomy remains suboptimal and presents significant challenges [8].

Objectives

This review examines current research on the pathogenesis and risk factors associated with DGE following distal gastrectomy. It also aims to provide insights into targeted prevention strategies and highlight promising therapeutic options that may improve the management of post-gastrectomy DGE in the future.

Pathogenesis, etiology, and risk factors of postoperative DGE following distal gastrectomy

The physiology of gastric emptying is a highly coordinated process that involves the central, autonomic, and enteric nervous systems, as well as smooth muscle cells, ICC, and gastrointestinal hormones [8,15]. Contractions of the gastrointestinal smooth muscle, stimulated by intrinsic cholinergic neurons, are essential for triturating solid food and facilitating gastric emptying [16]. Additionally, endocrine regulation via gastrointestinal hormones—commonly known as brain-gut peptides (e.g., gastrin, motilin, ghrelin, cholecystokinin, vasoactive intestinal peptide, and glucagon-like peptide-1)—plays a pivotal role in controlling gastrointestinal motility [8,17].

Pathogenesis of postoperative DGE

The underlying mechanisms of postoperative DGE remain incompletely understood, but current evidence points to a multifactorial etiology. Disruption of vagal innervation, direct injury to smooth muscle fibers, and disturbances in the ICC network are all implicated in the development of DGE [8,18-20]. The vagus nerve is critical for coordinating gastric motility by regulating smooth muscle contractions and ICC activity; however, surgical procedures such as gastrectomy can impair this neural pathway [8,18]. Such disruptions compromise the effective propulsion of gastric contents, thereby contributing to DGE [8].

Recent studies have increasingly emphasized the link between gut microbiota, its metabolites, and postoperative complications [8]. A meta-analysis by Tarazi et al., which reviewed 33 gastrointestinal surgeries, found that surgical interventions often lead to alterations in the gut microbiome [8,21]. Similarly, Guyton and Alverdy reported that gastrointestinal procedures can alter the composition and structure of the intestinal flora, frequently resulting in postoperative microbial dysbiosis [8,14]. Building on these findings, Mandarino et al. suggested that gut dysbiosis may play a key role in both the initiation and progression of gastroparesis [8,22]. Several studies have demonstrated that the intestinal microbiota partly regulates gastrointestinal motility by influencing the interactions between muscularis macrophages and enteric neurons [8,23]. Alterations in the gut microbiota can affect macrophage function, indicating that microbial changes directly impact immune modulation within the gastrointestinal tract [8,24]. Muscularis macrophages, which are essential for gut motility, are classified into pro-inflammatory M1 and anti-inflammatory M2 subtypes [8,23,25]. Notably, in rat models, abdominal surgery has been shown to activate M1 macrophages within the gastrointestinal plexus, leading to increased production of pro-inflammatory cytokines [8,26]. An inverse correlation has been observed between gastric emptying and the proportion of M1 macrophages in the gastrointestinal plexus [26]. Consequently, Wang et al. [8] proposed that, in addition to direct surgical factors like vagal injury and anatomical changes, DGE may also be partially influenced by postoperative microbiome alterations. These findings are summarized in Table 1.

Etiology of postoperative DGE

Gastroparesis most commonly arises from idiopathic causes, diabetes, and post-surgical conditions. Idiopathic gastroparesis accounts for 36% of cases, followed by diabetic gastroparesis at 29% [7,27]. Post-surgical conditions, particularly those following procedures such as partial gastrectomy and pylorus-preserving pancreatoduodenectomy, represent approximately 13% of cases [7,10]. This review focuses primarily on post-gastrectomy gastroparesis, specifically postoperative DGE. Surgical trauma—including traction injuries and disruptions to the blood supply—damages gastric smooth muscle and both gastric and retroperitoneal nerve plexuses, impairing the stomach’s ability to generate effective electrical rhythms and contraction waves, thereby contributing to DGE [2,4,18,28]. Additionally, surgical stress, which encompasses perioperative psychological responses (e.g., anxiety, fear, and insomnia), activates the sympathetic nervous system and inhibits the gastrointestinal nerve plexus, further exacerbating postoperative DGE [4,8,29,30]. These etiologies are summarized in Table 2.

Risk factors for post-gastrectomy DGE

The risk factors for DGE following distal gastrectomy are multifaceted and closely interrelated. Over the past decade, numerous studies have examined these factors, although their findings have been inconsistent [28]. Recent research broadly categorizes the risk factors for post-gastrectomy DGE into two groups: patient-related factors and surgery-specific attributes (Table 3).

Patient-related risk factors

Multiple studies have identified independent patient-related risk factors for DGE, including advanced age, poor nutritional status, preoperative pyloric obstruction, significant blood loss, postoperative intra-abdominal infections, and psychological factors [6,19,28,31,32]. Liu et al. [31] reported that advanced age, Helicobacter pylori infection, elevated anxiety levels, lower perioperative albumin concentrations, and preoperative pyloric obstruction significantly contribute to DGE.

Mukoyama et al. [6] further emphasized the roles of sex, diabetes, and distal gastric tumors in DGE. They noted that premenopausal women may be particularly vulnerable to impaired gastric motility due to higher levels of estrogen and progesterone, hormones known to influence gastrointestinal function.

Meng et al. [4] suggested that postoperative hypoproteinemia may result in edema of the gastrointestinal walls and anastomotic sites, causing localized dyskinesia and delaying the recovery of gastrointestinal motility, thereby increasing the risk of DGE. They also proposed that hyperglycemia plays a crucial role in gastric emptying dysfunction by inhibiting the secretion and release of motilin. This effect becomes particularly significant when blood glucose levels exceed 10 mmol/L, as hyperglycemic conditions disrupt normal electrogastric rhythms and reduce intragastric pressure [4].

Furthermore, Pang et al. [19] identified advanced age, a high body mass index, and low preoperative albumin levels in patients with pyloric obstruction as significant predictors of DGE. Preoperative pyloric obstruction has been consistently highlighted as a key risk factor by several researchers, including Pang et al. [19], Liu et al. [31], and Meng et al. [4]. Based on these findings, Pang et al. proposed two possible mechanisms: prolonged obstruction may lead to gastric wall edema and smooth muscle damage, thereby weakening peristalsis and impairing nerve conduction; and postoperative anastomotic edema with mucosal accumulation may further disrupt gastric motility.

Surgery-specific risk factors

Several studies have examined how different surgical techniques influence the incidence of post-gastrectomy DGE.

Meng et al. [4] and Liu et al. [31] demonstrated that Billroth II anastomosis is associated with a higher incidence of DGE compared to Billroth I. Mao et al. [33] reported that patients undergoing Billroth II reconstruction were more likely to develop DGE than those receiving other types of reconstruction, with Billroth I serving as the reference group (odds ratio=1). The odds ratio for Billroth II was 7.3 (P=0.001), while that for Roux-en-Y was 5.9 (P=0.15). They suggested that, regardless of surgical technique, Billroth II reconstruction alters the digestive tract in a manner that impairs its ability to efficiently process contractile chyme and reduces gastrointestinal smooth muscle contractility. In agreement with these observations, Yu et al. [28] reported that Billroth I reconstruction reduces the risk of DGE, whereas the use of a jejunal nutrition tube increases it.

Pang et al. [19] approached the issue from a different perspective by replacing the traditional Billroth II procedure with Roux-en-Y and uncut Roux-en-Y reconstructions in favor of enhancing the anti-reflux effect and focused on the configuration of the anastomosis. Although their study found no significant difference in the overall incidence of DGE between these techniques, they observed that DGE occurred more frequently with linear anastomoses than with circular ones. More specifically, linear stapler incisions made parallel to the greater curvature were more likely to induce DGE than vertical incisions, possibly due to potential damage to the gastric fundus pacing point, which is critical for coordinating motility.

Additionally, Pang et al. [19] proposed that a smaller residual stomach volume—typically resulting from high-level vessel disconnections along the greater curvature to ensure a secure anastomosis—might predispose patients to DGE. In contrast, Mukoyama et al. hypothesized that a larger remnant stomach could become more atonic and, therefore, more susceptible to DGE [6,34]. This discrepancy may stem from variations in surgical contexts and conditions. Mukoyama et al. [6] further emphasized the need for additional research, ideally incorporating imaging techniques such as computed tomography scans, to better define the relationship between remnant stomach volume and DGE.

Kim et al. [2] identified laparoscopic distal gastrectomy as a significant risk factor for DGE, hypothesizing that the use of laparoscopic energy-based devices might cause thermal injury to the ICC, which are crucial for gastric motility. In contrast, Meng et al. [4] found no difference in the incidence of DGE between laparoscopic and open radical gastrectomy. Therefore, further research is warranted to clarify any disparities in DGE incidence between laparoscopic and open surgery, taking into account the wide range of relevant surgical factors. Moreover, since energy-based devices are now commonly used in open surgery, additional comparative studies are needed to determine whether similar risks exist in open procedures.

While these studies collectively shed light on the diverse factors influencing DGE, limitations such as variations in sample size, study design, and measurement methods across the literature must be acknowledged. These limitations underscore the need for further research to more precisely delineate the underlying mechanisms.

Diagnosis

Gastric scintigraphy is considered the gold standard for diagnosing DGE and remains the most widely used diagnostic technique [4,35]. However, in post-gastrectomy patients exhibiting symptoms of DGE, alternative imaging modalities—such as plain abdominal X-ray, an upper gastrointestinal series, or computed tomography scans—may also be employed [6]. It is important to note that the severity of symptoms and clinical presentation do not always correlate with the extent of DGE [4,36,37].

Management

The management of DGE requires a comprehensive approach that considers multiple factors to optimize patient care [27]. In the acute setting, correcting dehydration and electrolyte imbalances is essential and can be achieved via oral or intravenous routes depending on severity [35,38]. In more severe cases, gastric decompression with a nasogastric tube may be necessary to alleviate symptoms and prevent further complications [35].

Dietary modification

Dietary modification is a critical component in managing postoperative DGE [7,39]. Patients should be advised to consume several small meals while limiting fat and fiber content, as these components delay gastric emptying [7]. A meal frequency of 4 to 6 small meals per day is recommended, and high-caloric liquids can provide essential nutrition while minimizing symptoms in mild DGE [27]. Nutritional counseling by experts is vital, as DGE often leads to malnutrition due to inadequate oral intake and vomiting [27,40-42]. Patients with diabetes mellitus should maintain strict blood glucose control to reduce the risk of exacerbating gastroparesis symptoms [35,42]. Liquid nutrition is particularly beneficial because gastric emptying for liquids is generally preserved, especially when diets are low in fat and fiber [7,38]. Conversely, hypertonic foods should be avoided as they can worsen these conditions [7,38].

Prokinetic medications

Prokinetic agents play a crucial role in managing moderate to severe gastroparesis by promoting and coordinating gastrointestinal motility while alleviating symptoms [4,5,16,43]. These agents facilitate gastric emptying through specific receptor interactions, including serotonergic 5-HT₄ receptor agonists, dopamine D_2/3 receptor antagonists, and neurokinin-1 (NK1) recetpor antagonists [43]. However, their long-term use is often limited by adverse effects, drug resistance, financial burden, and psychological distress [4]. When selecting a prokinetic drug for postoperative DGE, several factors must be considered, including patient comorbidities (such as diabetes, neurological disorders, or cardiovascular disease), the severity of DGE, and altered pharmacokinetics in the gastrointestinal tract resulting from surgical anatomical and functional changes. Further research is needed to better understand these the effects of surgical changes on pharmacokinetics and to develop more effective treatment protocols. In cases of severe DGE, intravenous options may be more effective than oral medications. Additionally, the potential side effects and toxicity of the drug must be considered to ensure that treatment is safe and well-tolerated. Consequently, the pharmacological management of DGE remains suboptimal and continues to challenge healthcare providers [4]. A brief summary of these agents and their mechanisms of action is presented in Table 4.

Metoclopramide, the only medication approved for gastroparesis in the United States, is a D₂-receptor antagonist with partial 5-HT₄ receptor agonist activity that provides both prokinetic and antiemetic effects, available in oral and intravenous formulations [5,43,44]. Nevertheless, caution is warranted when administering metoclopramide to patients with postoperative DGE, as these patients are vulnerable to depression, and the drug may exacerbate this condition [7]. Moreover, because metoclopramide crosses the blood-brain barrier, it can cause central nervous system side effects—including anxiety, depression, tremors, and, in rare cases, severe extrapyramidal symptoms such as tardive dyskinesia. Consequently, the U.S. Food and Drug Administration has issued a black box warning limiting its use to a maximum of 12 weeks [5,43].

Domperidone, a dopamine receptor antagonist, offers similar efficacy to metoclopramide but is associated with fewer extrapyramidal side effects since it does not cross the blood-brain barrier [5,42,43]. However, it carries a potential risk of cardiac dysrhythmias and, in rare cases, sudden death. This risk is attributed to its inhibition of hERG (human ether-à-go-go-related gene) channel activity and the resultant QTc (corrected QT interval) prolongation [5,44,45].

Several new-generation 5-HT₄ receptor agonists—including prucalopride, velusetrag, naronapride, and felcisetrag—are highly selective and do not exhibit hERG-related effects [5,43]. Among these, prucalopride is approved in several countries, including the United States, for the treatment of chronic constipation due to its enterokinetic properties [5,43]. Recent research suggests that prucalopride also has gastrokinetic effects, improving symptoms in patients with idiopathic gastroparesis [5,43]. Additionally, prucalopride may enhance gastric neuromuscular function through its anti-inflammatory actions, such as facilitating vagal stimulation, modulating T helper cell responses, and reducing postoperative ileus [43,46]. In a study by Carbone et al. [47], 4 weeks of prucalopride treatment significantly improved symptoms, quality of life, and gastric emptying compared to placebo in patients with idiopathic gastroparesis [47].

Velusetrag, another selective 5-HT₄ receptor agonist, has demonstrated efficacy in relieving symptoms and accelerating gastric emptying in patients with diabetic and idiopathic gastroparesis [5,48].

Felcisetrag (TAK-954), when administered intravenously, has been shown to significantly accelerate gastric emptying as well as small bowel and colonic transit in patients with gastroparesis and DGE [49]. In a double-dummy, parallel-group, randomized trial, felcisetrag improved gastric retention in mechanically ventilated patients with enteral feeding intolerance (gastric residual volume ≥200 mL), outperforming metoclopramide [50].

Motilin and ghrelin, hormones secreted in the upper digestive tract, are crucial in stimulating gastric emptying [5]. Macrolide antibiotics, used as motilin receptor agonists, are especially focused on their effects in the stomach [43]. Erythromycin, the most extensively studied agent in this class, enhances gastric emptying and transiently improves gastroparesis symptoms by stimulating fundic and antral contractions while inhibiting pyloric activity [51,52]. However, its widespread clinical use is limited by side effects such as abdominal cramps, nausea, diarrhea, QTc prolongation, and tachyphylaxis [5,43,51]. In clinical practice, hospitalized patients typically receive erythromycin via intravenous infusion at a dose of 1.5–3 mg/kg over 45 minutes every 6–8 hours, whereas outpatients are managed with 125 mg twice daily in an oral liquid formulation, which improves drug absorption in cases of markedly DGE [43]. Caution is advised when erythromycin is used in combination with agents that interfere with CYP3A4 metabolism (e.g., diltiazem, verapamil, domperidone) due to an increased cardiac risk [53].

Relamorelin, a synthetic pentapeptide ghrelin receptor agonist, is 15–130 times more potent than natural ghrelin [43,54]. Administered subcutaneously at a dose of 100 µg, it has been shown to accelerate gastric emptying in patients with type 1 or type 2 diabetes mellitus experiencing DGE [43,55]. Unlike erythromycin, relamorelin increases distal antral contraction frequency without impairing gastric accommodation or altering postprandial satiation in healthy individuals [43,56]. However, because patients who have undergone distal subtotal gastrectomy lack an antrum, further research is needed to determine whether relamorelin is effective in this population based on its proposed mechanism of action.

Cholinesterase inhibitors also promote gastrointestinal motility and are particularly useful for managing various intestinal motor disorders such as postoperative ileus, constipation, and chronic intestinal pseudo-obstruction [5]. Acotiamide, a newer cholinesterase inhibitor, additionally inhibits presynaptic muscarinic autoreceptors, thereby enhancing gastric contractility and accommodation to alleviate dyspeptic symptoms associated with gastroparesis. However, it is less effective for treating epigastric pain and burning sensations [5,58].

Levosulpiride, a sulpiride derivative, enhances gastrointestinal motility through dual mechanisms: antagonism of D₂ dopamine receptors and agonism of serotonin 5-HT₄ receptors, which together facilitate cholinergic activity [5,59].

Neurokinin-1 receptor antagonists show promise as a potential therapeutic option by improving multiple symptoms of gastroparesis, although they are not yet approved for the treatment of nausea and vomiting associated with this condition [43,60,61]. Preliminary results from a phase 2 trial of tradipitant, an NK1 receptor antagonist, were encouraging; however, its approval for gastroparesis management depends on the outcomes of phase 3 trials and further analyses [60,61].

Conclusion

Postoperative DGE remains a significant challenge following distal gastrectomy, resulting in reduced quality of life, prolonged hospital stays, and an increased psychological burden. This narrative review has examined the multifactorial etiology of DGE, including disruptions in vagal innervation, impaired smooth muscle and ICC function, and gut microbial dysbiosis. A comprehensive understanding of these pathophysiological mechanisms is essential for developing effective prevention and management strategies. Proactively identifying key risk factors may help optimize postoperative outcomes and improve quality of life. Furthermore, emerging therapeutic approaches, such as gut microbiota modulation and advanced pharmacological interventions, offer promising avenues for future management. Given the substantial influence of surgical techniques and perioperative factors on DGE incidence, further research is warranted to elucidate the underlying mechanisms and refine surgical strategies to mitigate its occurrence. Overall, this review underscores the importance of a comprehensive and personalized approach to DGE to minimize its impact on recovery and increase the overall success of gastrectomy in patients with gastric cancer.

Authors’ contribution

All work was done by Cheong Ah Oh.

Conflict of interest

The author of this manuscript has no conflicts of interest to disclose.

Funding

None.

Data availability

Not applicable.

Acknowledgments

None.

Supplementary materials

None.

Table 1.

Pathogenesis of postoperative delayed gastric emptying

Pathogenesis	Description	Reference
Disruption of neural pathways	Vagal nerve impairment disrupts coordination of gastric motility, smooth muscle contractions, and interstitial cells of Cajal (ICCs) activity.	[8,18-20]
Smooth muscle and ICC damage	Direct mechanical or ischemic injury to gastric smooth muscle and ICCs disrupts the synchronization of motor activity, resulting in a loss of effective electrical rhythms and contraction waves necessary for gastric emptying.	[8,18]
Gut microbial dysbiosis	Abdominal surgery-induced dysbiosis has been shown to activate M1 macrophages in the gastrointestinal plexus, leading to increased expression of pro-inflammatory cytokines that contribute to delayed gastric emptying.	[8,23-26]

Table 2.

Etiology of postoperative delayed gastric emptying

Cause	Description	Reference
Surgical trauma	Traction injuries and disruptions to the blood supply damage gastric smooth muscle and both gastric and retroperitoneal nerve plexuses, impairing the stomach’s ability to generate effective electrical rhythms and contraction waves, thereby contributing to delayed gastric emptying.	[2,4,7,8,10,18,28-30]
Surgical stress	Perioperative stress reactions (e.g., anxiety, fear, insomnia) activate the sympathetic nervous system, which inhibits gastrointestinal motility.	[2,4,7,8,10,18,28-30]

Table 3.

Risk factors for post-gastrectomy delayed gastric emptying

	Risk factor	Reference
Patient-related factors	Advanced age	[4,6,19,28,31,32]
	Female sex
	Poor nutritional status: hypoproteinemia and low albumin levels
	Preoperative pyloric obstruction
	Diabetes mellitus
	Higher body mass index
	Significant intraoperative blood loss
	Intra-abdominal infections
Surgery-related factors	Anastomotic method: Billroth II reconstruction	[4,28,31,33]

Table 4.

Overview of prokinetic agents for consideration in delayed gastric emptying management

Agent	Mechanism of action	Key benefits	Special comments and side effects	Reference
Metoclopramide	D₂-receptor antagonist, partial 5-HT₄ agonist	- Prokinetic and antiemetic effects	- CNS side effects (e.g., anxiety, depression, tremors); rare severe extrapyramidal symptoms (e.g., tardive dyskinesia); FDA black box warning limits use to 12 wk	[5,7,43,44]
Metoclopramide	D₂-receptor antagonist, partial 5-HT₄ agonist	- Available for intravenous administration		[5,7,43,44]
Domperidone	Dopamine receptor antagonist	- Similar efficacy to metoclopramide; fewer CNS side effects	-Risk of cardiac dysrhythmias and sudden death due to hERG channel inhibition and QTc prolongation	[5,42-45,57]
Domperidone	Dopamine receptor antagonist		-Gynecomastia, galactorrhea, menstrual irregularities	[5,42-45,57]
Prucalopride	Highly selective 5-HT₄receptor agonist	- Improvement of symptoms and gastric emptying; anti-inflammatory effects enhance neuromuscular function	-Generally approved for chronic constipation	[5,43,46,47]
Prucalopride	Highly selective 5-HT₄receptor agonist		-Limited availability and long-term safety data	[5,43,46,47]
Velusetrag	Highly selective 5-HT₄ receptor agonist	- Alleviation of symptoms and acceleration of gastric emptying in diabetic and idiopathic gastroparesis	-Limited availability and long-term safety data	[5,48]
Felcisetrag	Highly selective 5-HT₄ receptor agonist	- Similar effects to those of other highly selective 5-HT4 receptor agonists	-Limited availability and long-term safety data	[49,50]
Felcisetrag	Highly selective 5-HT₄ receptor agonist	- Available for intravenous administration	-Limited availability and long-term safety data	[49,50]
Erythromycin	Motilin receptor agonist	- Facilitation of gastric emptying	-Adverse effects: abdominal cramps, nausea, diarrhea, QTc prolongation, tachyphylaxis reversible deafness	[5,43,51-53,57]
Erythromycin	Motilin receptor agonist	- Available for intravenous administration		[5,43,51-53,57]
Acotiamide	Cholinesterase inhibitor	- Enhancement of gastric contractility and accommodation and alleviation of dyspepsia	-Less effective for epigastric pain and burning	[5,57,58]
Acotiamide	M1 and M2 muscarinic receptors antagonist		-Headache, diarrhea	[5,57,58]
Levosulpiride	D₂ dopamine receptor antagonist 5-HT₄ receptor agonist	- Enhancement of gastrointestinal motility through dual prokinetic action via dopaminergic and serotonergic pathways	-Limited to short-duration use to avoid side effects	[5,57,59]
Levosulpiride	D₂ dopamine receptor antagonist 5-HT₄ receptor agonist		-Drug-induced parkinsonism, galactorrhea and menstrual abnormalities	[5,57,59]

CNS, central nervous system; FDA, U.S. Food and Drug Administration; hERG, human ether-à-go-go-related gene; QTc, corrected QT interval.

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Pathogenesis, risk factors, and management of postoperative delayed gastric emptying after distal gastrectomy: a narrative review

Ann Clin Nutr Metab. 2025;17(1):9-17. Published online April 1, 2025

DOI: https://doi.org/10.15747/ACNM.25.0007

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Pathogenesis, risk factors, and management of postoperative delayed gastric emptying after distal gastrectomy: a narrative review

Pathogenesis	Description	Reference
Disruption of neural pathways	Vagal nerve impairment disrupts coordination of gastric motility, smooth muscle contractions, and interstitial cells of Cajal (ICCs) activity.	[8,18-20]
Smooth muscle and ICC damage	Direct mechanical or ischemic injury to gastric smooth muscle and ICCs disrupts the synchronization of motor activity, resulting in a loss of effective electrical rhythms and contraction waves necessary for gastric emptying.	[8,18]
Gut microbial dysbiosis	Abdominal surgery-induced dysbiosis has been shown to activate M1 macrophages in the gastrointestinal plexus, leading to increased expression of pro-inflammatory cytokines that contribute to delayed gastric emptying.	[8,23-26]

Cause	Description	Reference
Surgical trauma	Traction injuries and disruptions to the blood supply damage gastric smooth muscle and both gastric and retroperitoneal nerve plexuses, impairing the stomach’s ability to generate effective electrical rhythms and contraction waves, thereby contributing to delayed gastric emptying.	[2,4,7,8,10,18,28-30]
Surgical stress	Perioperative stress reactions (e.g., anxiety, fear, insomnia) activate the sympathetic nervous system, which inhibits gastrointestinal motility.	[2,4,7,8,10,18,28-30]

	Risk factor	Reference
Patient-related factors	Advanced age	[4,6,19,28,31,32]
	Female sex
	Poor nutritional status: hypoproteinemia and low albumin levels
	Preoperative pyloric obstruction
	Diabetes mellitus
	Higher body mass index
	Significant intraoperative blood loss
	Intra-abdominal infections
Surgery-related factors	Anastomotic method: Billroth II reconstruction	[4,28,31,33]

Agent	Mechanism of action	Key benefits	Special comments and side effects	Reference
Metoclopramide	D₂-receptor antagonist, partial 5-HT₄ agonist	- Prokinetic and antiemetic effects	- CNS side effects (e.g., anxiety, depression, tremors); rare severe extrapyramidal symptoms (e.g., tardive dyskinesia); FDA black box warning limits use to 12 wk	[5,7,43,44]
Metoclopramide	D₂-receptor antagonist, partial 5-HT₄ agonist	- Available for intravenous administration		[5,7,43,44]
Domperidone	Dopamine receptor antagonist	- Similar efficacy to metoclopramide; fewer CNS side effects	-Risk of cardiac dysrhythmias and sudden death due to hERG channel inhibition and QTc prolongation	[5,42-45,57]
Domperidone	Dopamine receptor antagonist		-Gynecomastia, galactorrhea, menstrual irregularities	[5,42-45,57]
Prucalopride	Highly selective 5-HT₄receptor agonist	- Improvement of symptoms and gastric emptying; anti-inflammatory effects enhance neuromuscular function	-Generally approved for chronic constipation	[5,43,46,47]
Prucalopride	Highly selective 5-HT₄receptor agonist		-Limited availability and long-term safety data	[5,43,46,47]
Velusetrag	Highly selective 5-HT₄ receptor agonist	- Alleviation of symptoms and acceleration of gastric emptying in diabetic and idiopathic gastroparesis	-Limited availability and long-term safety data	[5,48]
Felcisetrag	Highly selective 5-HT₄ receptor agonist	- Similar effects to those of other highly selective 5-HT4 receptor agonists	-Limited availability and long-term safety data	[49,50]
Felcisetrag	Highly selective 5-HT₄ receptor agonist	- Available for intravenous administration	-Limited availability and long-term safety data	[49,50]
Erythromycin	Motilin receptor agonist	- Facilitation of gastric emptying	-Adverse effects: abdominal cramps, nausea, diarrhea, QTc prolongation, tachyphylaxis reversible deafness	[5,43,51-53,57]
Erythromycin	Motilin receptor agonist	- Available for intravenous administration		[5,43,51-53,57]
Acotiamide	Cholinesterase inhibitor	- Enhancement of gastric contractility and accommodation and alleviation of dyspepsia	-Less effective for epigastric pain and burning	[5,57,58]
Acotiamide	M1 and M2 muscarinic receptors antagonist		-Headache, diarrhea	[5,57,58]
Levosulpiride	D₂ dopamine receptor antagonist 5-HT₄ receptor agonist	- Enhancement of gastrointestinal motility through dual prokinetic action via dopaminergic and serotonergic pathways	-Limited to short-duration use to avoid side effects	[5,57,59]
Levosulpiride	D₂ dopamine receptor antagonist 5-HT₄ receptor agonist		-Drug-induced parkinsonism, galactorrhea and menstrual abnormalities	[5,57,59]

Table 1. Pathogenesis of postoperative delayed gastric emptying

Table 2. Etiology of postoperative delayed gastric emptying

Table 3. Risk factors for post-gastrectomy delayed gastric emptying

Table 4. Overview of prokinetic agents for consideration in delayed gastric emptying management

CNS, central nervous system; FDA, U.S. Food and Drug Administration; hERG, human ether-à-go-go-related gene; QTc, corrected QT interval.