Key Questions

The guideline is framed around several key questions, outlined below. The key questions were developed by the authors and vetted through the ACG leadership. We developed specific questions to address the topics of clinical relevance in the Patient Intervention Comparison and Outcomes (PICO) format (seeSupplemental Materials). Emphasis has been placed on having practical recommendations that would be helpful for practicing providers in the US. A broad literature search was conducted to document, by means of detailed tables, information pertaining to the PICO questions, followed by a focused evaluation of the most relevant literature to develop recommendations (Table 1).

Literature Search

In February and March 2019, comprehensive literature searches were conducted by two health sciences librarians (JP and VMV) in PubMed (MEDLINE), EMBASE, and the Cochrane Library databases. Key concepts from the PICO questions were used to develop search terms and translated to appropriate controlled vocabulary for each database; detailed strategies for each section are provided inAppendix 1. Results for all searches were filtered for English language publications, and searches regarding therapeutics were further limited to human populations. Searches were updated in May 2021 using the same criteria to capture literature published during the screening and review process. A hand search of references was conducted, and relevant publications identified by content experts were incorporated for analysis.

Screening

Between February 2019 and July 2021, a team of five content experts (DA, TA, MC, BK, LN) screened a total of 1908 distinct references retrieved by the original and updated searches.

Each reference was screened independently by no fewer than two reviewers, with a third reviewer resolving any conflicts. The inclusion criteria were original research studies on the incidence, diagnosis, and treatment of gastroparesis in adult populations, predominantly based on observational studies and randomized, controlled trials. Open-label and observational studies of treatment modalities were included in the tables. Exclusion criteria were inclusion in the previous ACG guideline (although, where relevant, these were included in tables for completeness of the literature surveyed), theoretical studies using computational models, animal trials, pediatric populations, and publications without original data analysis.

While no restriction was placed on publication dates during the retrieval process, emphasis was placed during screening by content experts on studies published after the searches included in the previous guideline, and tables from the 2013 guideline were updated with more recent evidence from the literature. Similarly, searches were not limited by age range within the databases, but any retrieved studies on an exclusively pediatric population were manually excluded during screening. Review articles, correspondence, and other publications without original data were excluded from analysis, though relevant reviews were retained for hand search of their included references.

After screening, a total of 121 references were identified for inclusion and progressed for evidence appraisal in July 2021.

Assessment

The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process (Table 2) (21) was used to assess the quality of evidence for each question, by two formally trained GRADE methodologists (RHY & KG) to evaluate the quality of the evidence and strength of the recommendations. The quality of evidence is expressed as high (we are confident in the effect estimate to support a particular recommendation), moderate, low, or very low (we have very little confidence in the effect estimate to support a particular recommendation) based on the risk of bias of the studies, evidence of publication bias, heterogeneity among studies, directness of the evidence and precision of the estimate of effect. A strength of recommendation is given as either strong (noted as “recommendations,” and meaning that most patients should receive the recommended course of action) or conditional (noted as “suggestions,” and meaning that many patients should have this recommended course of action, but different choices may be appropriate for some patients) based on the quality of evidence, risks versus benefits, feasibility, and costs, taking into account perceived patient and population-based factors. Furthermore, a narrative evidence summary for each section provides important details for the data supporting the statements. The panel have additionally highlighted “key concepts” that were not included in the GRADE assessment. Key concepts are statements to which the GRADE process has not been applied and often include definitions and epidemiological statements rather than diagnostic or management recommendations.

Risk Factors

Diagnostic Testing

After exclusion of mechanical obstruction, diverse tests are available to objectively document the presence of delayed GE. The gold standard is scintigraphic gastric emptying (SGE); this section addresses the diverse methods available for diagnosis of gastroparesis.

Potential Confounding between Gastroparesis and Functional Dyspepsia

There is increasing attention (28) to the possibility that gastroparesis and functional dyspepsia (FD) may be on a spectrum of gastric dysfunction. Despite generally unaltered symptoms over time, 42% of patients initially diagnosed with gastroparesis and 37% of those diagnosed with FD were reclassified based on presence or absence of GE delay on repeat SGE (28). Degree of impairment of GE may vary over time in patients whose symptoms are generally unaltered over the same time. However, it is also conceivable that part of the overlap of the syndromes reflects the cut–off value of 10% retention at 4 hours that is applied to identify patients with delayed GE based on the ingestion of a 255 kilocalorie, 2% fat Eggbeaters® meal. Further studies are required to appraise the optimal meal composition and cut-off to define normality to address the reported significant overlap between gastroparesis and FD, which may be confounded by the low calorie and fat content of the meal and the use of >10% retention at 4 hours to define delayed gastric emptying. It has been emphasized that the distinction between the two diagnoses is relevant because of the better prognosis of FD in contrast to the persistence of gastroparesis (28).

Diagnosis of gastroparesis using scintigraphy

Diagnosis of gastroparesis using stable isotope breath test and comparison with scintigraphy

The stable isotope gastric emptying breath test (GEBT) using 13-carbon spirulina has been validated in simultaneous measurements performed with the gold standard scintigraphy and a solid test meal. This has been validated both in patients with upper gastrointestinal symptoms and healthy controls as well as in pharmacologically induced slowing or acceleration of GE (43,44). Though the kappa statistic is not provided, a validation study of 38 healthy volunteers and 129 patients with clinically suspected delayed GE showed that, at 80% specificity, the 45- and 180-minute samples combined were 93% sensitive to identify accelerated GE, and 150- and 180-minute combined were 89% sensitive for delayed GE (43). The test is also approved for use in children.

Additional value of gastric function tests that do not measure emptying, including electrogastrography (EGG)

There are the three types of cutaneous electrogastrography (EGG): 1. Single channel, 2. Low-resolution, and 3. high resolution. They all measure different aspects of gastric electrical activity. In addition, both mucosal and serosal electrical measurements of EGG are also performed. Single channel cutaneous EGG measures only frequency; low resolution EGG measures frequency and amplitude and some measures of propagation; high resolution EGG measures frequency, amplitude, and more precise measures of propagation such as initiation and conduction of gastric electrical signals. The prevalence of 3 cycle per minute (cpm) electrical control activity measured by single channel EEG was more prevalent in patients with gastric outlet obstruction compared to patients with idiopathic gastroparesis (IG) or healthy controls (45). High-amplitude and excessively regular 3 cpm EGG patterns were identified in gastric outlet obstruction, whereas high-amplitude and excessively regular 3 cpm EGG patterns differentiated idiopathic gastroparesis (IG) and healthy controls and were more likely in those with delayed GE (45,46) and in patients with cyclical vomiting and diabetic gastropathy (47) including uremic diabetics and children with diabetes (48,49). In another study, patients with depleted interstitial cells of Cajal (ICC) (50) had significantly more tachygastria and significantly greater total symptom scores compared to those patients whose gastric full-thickness biopsies showed less ICC depletion.

Using high-resolution electrical mapping (256 electrodes; 36 cm²) (51), it was shown that 9 patients with chronic unexplained nausea and vomiting had slow-wave dysrhythmias, with only 1 of 9 controls showing these dysrhythmias. Dysrhythmias included abnormalities of initiation (stable ectopic pacemakers, unstable focal activities) and conduction (retrograde propagation, wavefront collisions, conduction blocks, and re-entry) across slow, normal, or fast frequencies; dysrhythmias also showed velocity anisotropy (mean, 3.3 mm/s longitudinal vs 7.6 mm/s circumferential; P <.01). Such high resolution, spatial mapping is recommended, especially because of the evidence that abnormalities of slow-wave initiation aberrant conduction and low amplitude activity in gastroparesis often occur at normal frequency, which could be missed by tests that lack spatial resolution (52).

In summary, studies suggest a complimentary role of spatial mapping EGG for identification of the pathophysiologic mechanism of gastric function (53). However, at this time, it is unclear that the information is clinically meaningful. Ongoing research of high-resolution EGG should help clarify its clinical role, including its role in patients with FD.

Other Tests for Gastroparesis Based on Full-Thickness Biopsies

The evidence regarding changes at the level of the stomach as identified in histological and molecular studies performed on biopsies taken from patients with gastroparesis are detailed in theSupplement. Similar to the European Society of Neurogastroenterology and Motility (ESNM) Consensus Statement (19), we do not recommend the routine use of full-thickness biopsies. Full-thickness biopsies should be reserved for research purposes to help better understand the causes of gastroparesis, identify biomarkers, guide therapy, and predict outcomes.

Small particle diet and nutrition interventions

Avoidant/restrictive food intake disorder symptoms are frequent in patients with gastroparesis (54), and the ESNM guidelines recommend that eating disorders must be considered in patients with gastroparesis (19).

After the pioneering randomized, controlled trial by Olausson et al. (55) demonstrated efficacy of small particle diet compared to normal diet for relief of symptoms, improving GE and enhancing glycemic control (56) in patients with diabetes, a systematic review (57) of all study types evaluated current evidence-based nutrition interventions involving a total of 15 studies and of 524 subjects, using a stepwise process, progressing from oral nutrition to jejunal nutrition and lastly to parenteral nutrition. Small particle, low-fat diets were significantly better tolerated than the converse, with jejunal nutrition prior to consuming oral food significantly improving oral intake and motility. In more progressive cases, percutaneous endoscopic gastrostomy with jejunal extension nutrition had lower reported symptoms than other enteral routes. Exclusive long-term parenteral nutrition is a feasible option for advanced cases, with a 68% survival rate at 15 years duration, though oral intake plus parenteral nutrition is associated with higher survival rates. The primary role of maintaining or reinstating oral intake was recommended to reduce morbidity and mortality risk.

Pharmacologic agent use in gastroparesis

The two medications with the largest number of individual clinical trials for gastroparesis are metoclopramide and domperidone.

Metoclopramide is the only U.S. FDA-approved medication for the treatment of gastroparesis. The FDA placed a Black-Box warning on metoclopramide because of the risk of side effects, including tardive dyskinesia. The efficacy of metoclopramide in the treatment of diabetic gastroparesis (DG) has been assessed in studies that are summarized inTable 3 (58–68) which include newer trials involving the intra-nasal formulation of metoclopramide. The most common adverse effects of metoclopramide nasal spray were dysgeusia (bad, metallic, or bitter taste), headache, and fatigue.

Regulatory authorities issued restrictions and recommendations regarding long-term use of metoclopramide at oral doses exceeding 10 mg 3–4 times daily because of the risk for development of tardive dyskinesia; the restrictions include use for <12 weeks and age <65 years. Studies in the last decade have addressed the risk of tardive dyskinesia in contrast to reversible involuntary movements on treatment with metoclopramide. First, the relative risk (69) of tardive dyskinesia in metoclopramide users in a VA medical center was not significantly greater than in non-user controls (RR: 1.67; 95% CI: 0.93 to 2.97). Second, it was estimated that the risk of tardive dyskinesia from metoclopramide use is likely to be <1% (70). The most comprehensive assessment (71) showed that the risk of tardive dyskinesia from metoclopramide is in the range of 0.1% per 1000 patient years, below a previously estimated 1%–10% risk suggested in treatment guidelines by regulatory authorities. High-risk groups are elderly females, diabetics, patients with liver or kidney failure, and patients with concomitant antipsychotic drug therapy which reduces the threshold for neurological complications.

The FDA package insert on metoclopramide specifies that restlessness, drowsiness, fatigue, and lassitude occurred in approximately 10% of patients who received 10 mg four times daily. No other quantitative data are provided in the FDA approved insert on the prevalence of other, reversible central nervous system disorders with metoclopramide. One study (72) that documented the epidemiology of extrapyramidal reactions to metoclopramide was studied by examining reports in the Adverse Reactions Register of the Committee on the Safety of Medicines in the United Kingdom in the period 1967–82. Out of an estimated 15.9 million prescriptions, there were 479 reports of extrapyramidal reactions (455 of dystonia-dyskinesia, 20 of parkinsonism, and 4 of tardive dyskinesia). A more recent study of metoclopramide adverse events in the FDA Adverse Event Reporting System (FAERS) for the period 2004–2010 yielded reports of 4,784 neurological reactions and 944 reports were for tardive dyskinesia; the total number of prescriptions was almost 40.5 million (73). These data suggest that 0.1% of prescriptions are associated with non-tardive dyskinesia neurological symptoms, which seem to be low estimates and may reflect the fact that medication cessation with reversal of the neurological symptoms may not be reported to regulatory agencies.

Domperidone is available for treatment of gastroparesis under a special program administered by the Food and Drug Administration.Table 4 provides a summary of clinical trials with domperidone (74–86). Domperidone has been tested in studies that involved patients with IG, DG, or post-surgical gastroparesis (PSG), and it has been associated with symptom improvement manifested as lower overall scores or reduction in frequency and intensity of symptoms of gastroparesis. Four studies have also documented acceleration of GE compared to control or baseline.

Table 5 summarizes efficacy of other prokinetic agents (5-HT₄ and ghrelin receptor agonists) on symptoms or GE (64,87–100). As a group of medications, prokinetics have the most substantive clinical trials, and overall evidence suggests that they provide symptomatic benefit. For all the medications, the recommendation is conditional for use of treatment over no treatment to improve gastric emptying. The methodological assessment for the 5-HT4 agonists concluded that there was inconsistent data for symptom improvement.

Another class of agents is the motilin agonists which are used in the treatment of gastroparesis in adults and children. These medications include erythromycin, clarithromycin, and azithromycin. These medications are generally used in the short term (1–4 weeks) because of development of tachyphylaxis to motilides (101). Based on a systematic review and network meta-analysis of 33 studies and data on 22.6 million subjects, macrolide use was not associated with the risk of arrhythmia or cardiovascular mortality (102).

Antiemetics, central neuromodulators in gastroparesis

Table 6 summarizes efficacy of antiemetics and central neuromodulators in gastroparesis (103–109). These are therapies commonly used for symptom relief in gastroparesis. The central neuromodulator studied with the highest level of evidence was the tricyclic antidepressant, nortriptyline, in IG (105). In this randomized, placebo-controlled trial, nortriptyline was no better than placebo in relieving global symptoms of gastroparesis, but some improvement in abdominal pain was noted. In a study of amitriptyline, 50mg/day, there was no retardation of GE in patients with FD (110). Further RCTs are needed to determine the efficacy of other central neuromodulators. Although there are no formal randomized trials, experience with use of haloperidol in emergency room treatment of patients presenting with gastroparesis has led to reduced need for morphine treatment and admission to hospitals (111), rather than documenting effect on gastroparesis symptoms.

Other drug therapies for gastroparesis

A recent study has targeted previously described impaired nitric oxide metabolism and an abnormal tetrahydrobiopterin (BH-4) pathway in gastroparesis patients with diabetes mellitus. This phase II study needs confirmation in other larger controlled studies (112).

A number of other medications are being developed for treatment of gastroparesis. These include 5–HT4 receptor agonists (prucalopride, felcisetrag, and velusetrag) and dopamine D2/D3 receptor antagonists, and the therapeutic trials of these medications are included inTable 5.

Use of pharmacotherapy to reduce the future aggravation of gastroparesis

Based on a referral center experience, predictors of responsiveness to pharmacotherapy (113) were identified. A good response to pharmacological agents can be expected in the viral and dyspeptic subgroups of idiopathics, Parkinson’s disease, and the majority of diabetics; whereas a poorer outcome to prokinetics can be expected in post-vagotomy patients, those with connective tissue disease, a subgroup of diabetics (e.g., with evidence of vagal neuropathy), and the subset of IG dominated by abdominal pain and history of physical and sexual abuse (113). The comprehensive NIH Gastroparesis Consortium database of 748 patients (86) showed 181 (24%) on domperidone and 567 not receiving domperidone; 63% had IG. Compared to patients not receiving domperidone, those patients who were receiving domperidone (median time on domperidone following initiation of 32 weeks, 95% CI: 25–35 weeks) experienced moderate, but significantly more improvement in gastroparesis outcome measures of the Gastroparesis Cardinal Symptom Index (GCSI) total score, nausea and fullness subscales, upper abdominal pain score, gastroesophageal reflux disease (GERD) score, and the patient assessment of upper gastrointestinal disorders – quality of life (PAGI-QOL) score.

In a systematic review (114) of 14 studies that evaluated GE and upper GI symptoms, including IG or DG, and including only studies with optimal GE test methods being evaluated, there was a significant positive association between improvements in GE and upper GI symptoms in response to prokinetic agents.

Immunological therapies

There is insufficient evidence to support routine clinical use of autoimmune therapies in management of gastroparesis. A retrospective analysis of 11 female patients (115) with drug and device resistant gastroparesis with coexisting positive autoimmune profiles who were treated for 8–12 weeks with diverse immunomodulatory treatment showed that total symptom score improved in 6 of 11 patients, with maximum GI symptom improvement with IVIg (2 of the 3 patients treated). In a subsequent open-label study, 14 patients (3 DG, 1 PSG, and 10 IG) with serological and/or tissue evidence of immunological abnormality, IVIg therapy (400 mg/kg infusion weekly for 12 weeks) was associated with significant improvement in symptoms scores for nausea, vomiting, early satiety, and abdominal pain, and 9/14 patients were responders to this open-label treatment (116). This study built upon the retrospective medical record review suggesting a positive experience among 11 patients treated with IVIg or combined mycophenolate mofetil with methylprednisolone, or only mycophenolate mofetil therapy (115).

Non-pharmacological therapy for gastroparesis: gastric electrical stimulation (GES), acupuncture, and herbal medicines

GES is approved as a humanitarian use (HUD), as defined by the FDA for medically refractory DG or IG. The recommendation includes the use of GES in humanitarian use.

Table 7 shows efficacy of several bioelectric treatments including vagal nerve stimulation, spinal cord stimulation and GES (117–142). A recent randomized, crossover trial of ON vs. OFF GES in patients with medically refractory vomiting with or without delayed GE, GES decreased the vomiting frequency. Severity of nausea and appetite improved while ON compared to OFF. However, there were no differences in GI quality of life, nutritional parameters, or GE (121). Randomized crossover trials of GES for medically refractory DG or IG have shown mixed results which may reflect the variation in trial designs with differing timing of the ON vs. OFF randomization and crossover (120–124). Other modalities of electrostimulation (vagal and spinal cord) appear promising; however, larger randomized, sham-controlled trials are needed to determine the efficacy. However, documented clinical usefulness in both IG and DG (documented inTable 7) suggests there is a role for GES in accordance with its HUD approval.

Table 8 summarizes information on effects of electro-acupuncture, acupuncture, and herbal medicines in gastroparesis (143–154). The evidence available does not support their use in clinical practice.

Pyloric Interventions: Diagnostic and Therapeutic

Table 9 shows results of EndoFLIP for selection of patients for pyloromyotomy or pyloric botulinum toxin injection (155–161). Current evidence suggests that such measurements of pyloric diameter and distensibility index or compliance are associated with greater gastric retention, and that the measurements may predict response to therapy, particularly, significant enlargement of the post-G-POEM pyloric diameter (159). It is reasonable to consider such pyloric interventions in a clinical trial and to include assessments of pyloric physiology to appraise the impact of pyloric dysfunctions on outcomes. Thus, whereas intrapyloric injection of botulinum toxin is not recommended for patients with gastroparesis based on randomized, controlled trials (162), a recent large multicenter study from France documents the efficacy of botulinum toxin injection, particularly for the relief of vomiting, when patients are selected based on measurements of pyloric distensibility (161).

Efficacy of G-POEM for gastroparesis based on open-label studies

Table 10 shows efficacy of G-POEM for gastroparesis based on open-label studies (163–181). Overall, these open-label studies suggest there is benefit in terms of symptom improvement and improved GE, though most studies were of only 3–6 months’ duration. A 12-month study showed 56% patients improved at 1 year (173). Symptom control after endoscopic pyloromyotomy is comparable to surgical myotomy; however, endoscopic myotomy has been associated with fewer post–procedural complications and shorter length of hospital stay. A recent study has identified benefit in relief of symptoms as well as improved GE with G-POEM procedure followed for 6 months in a sham-controlled study (174). Other pylorus-directed procedures are also available such as surgical pyloroplasty, though there is more evidence on G-POEM. Heineke-Mikulicz pyloroplasty involves longitudinal incision across the pylorus, which is then closed transversely, and this results in division of both longitudinal and circular muscle layers. In 177 patients with gastroparesis, laparoscopic pyloroplasty achieved improved GE in 90% of patients and induced short-term improvement of nausea, vomiting, bloating, and abdominal pain. However, morbidity rate was 6.8%, with problems such as confirmed leaks or further surgical interventions including jejunostomy and subtotal gastrectomy (182).

Financial support:

MC receives NIH funding for studies on gastroparesis (R01-DK122280 and R01-DK125680). TA receives NIH funding for gastroparesis (7U01-DK074007-07 and R56DK126935)

BK receives NIH funding for gastroparesis (R21-DK116029, U01-DK112193); NIDDK Diabetic Complications Consortium (DK076169, DK115255).

LN receives support for research by a philanthropic gift from Colleen and Robert D. Hass.

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