Gastroparesis.

Abstract: Gastroparesis is a symptomatic disorder of the stomach characterized by slow or delayed gastric emptying. Diabetes and idiopathic factors account for over 60% of gastroparesis cases. Symptoms associated with delayed gastric emptying include nausea, vomiting, abdominal bloating and early satiety. Delayed gastric emptying due to gastroparesis is managed by dietary adjustments, prokinetic medications, avoidance of medications that retard gastric motor activity and optimizing glycemic control in diabetic patients. Electrical stimulation and gastric pacing are an evolving treatment option for patients who do not respond to standard medical therapy. This article provides a review of gastric motility, the etiologies of gastroparesis and therapeutic approaches to this disorder.

Key Words: gastroparesis, delayed gastric emptying, gastric motility

**********

Gastroparesis is a chronic symptomatic disorder of the stomach characterized by delayed gastric emptying in the absence of mechanical obstruction. (1)

Gastric Motor Function

The main motor functions of the stomach are the accommodation and storage of the ingested meal, the grinding down of solid particles and the emptying of meal constituents in a controlled and regulated fashion into the duodenum. A consistent feature of gastrointestinal smooth muscle is its myoelectric activity which is manifested by slow waves and a highly regular and recurring electrical pattern of depolarization and repolarization (Fig. 1). In the stomach, slow waves occur at a frequency of three cycles per minute. In contrast, the duodenum exhibits a higher slow wave frequency of 11 to 12 cycles per minute. Gastric slow waves are thought to originate at a site along the greater curvature in the proximal to middle corpus. Generation of slow wave activity in gastric smooth muscle cells is thought to originate from specialized intramuscular interstitial cells (interstitial cells of Cajal) which evoke electrical depolarization in a rhythmic manner. Muscular contraction occurs when an action or spike potential is generated, thus exceeding the mechanical threshold (Fig. 1). In a healthy young adult stomach, meal emptying occurs in about 90 to 120 minutes. Gastric emptying of liquids and solids is ultimately dependent on the interplay between the propulsive force generated by tonic contractions of the proximal stomach and the resistance presented by the antrum, pylorus, and duodenum. Liquids rapidly disperse throughout the stomach and begin to empty without a lag period. Emptying of liquids is influenced by the volume ingested and the osmolarity of the liquid. Carbonation further delays gastric emptying of liquids. Solids empty in two phases: an initial lag phase, followed by a linear emptying phase. The solid component is first retained in the proximal stomach; as liquids empty, the solid component moves to the antrum during the lag phase. The antrum produces high amplitude contractions that pulverize solids by physical and liquid shearing forces. Once solids have been reduced in size to particles of 1 to 2 mm in size (trituration), they are able to empty through the pylorus (Fig. 2).

Etiology of Gastroparesis

Gastroparesis can occur in many clinical settings. In one study, gastroparesis was observed to be idiopathic in 36% of subjects, was secondary to diabetes in 29%, and was a postsurgical consequence in 13% of patients. (2,4) Etiologic factors associated with gastroparesis are noted in Table 1 and Figure 3.

[FIGURE 1 OMITTED]

Idiopathic Gastroparesis

This condition represents the most common form of gastroparesis. Young and middle-aged women constitute the majority of patients with idiopathic gastroparesis. It is believed that gastric muscle contractility is reduced by progesterone. The histologic bases of idiopathic gastroparesis are poorly understood. In one case, myenteric hypoganglionosis and reduction in numbers of interstitial cells of Cajal were observed. (5)

Diabetic Gastroparesis

Patients with diabetes represent the second most common group with delayed gastric emptying. Autonomic neuropathy affecting vagal gastric innervation has been proposed to impair gastric motility. Duration (greater than 10 years) and severity (type 1) of diabetes and poor glycemic control are associated with impaired gastric emptying.

[FIGURE 2 OMITTED]

Hyperglycemia decreases antral contractility, stimulates isolated pyloric pressure waves, and causes gastric dysrhythmia (primarily tachygastria). (6) These factors which delay gastric emptying, in turn, contribute to destabilization of glycemic control.

Postsurgical Gastroparesis

Postsurgical gastroparesis is most often a consequence of peptic ulcer surgery with concurrent performance of vagotomy. The vagal nerves regulate fundic relaxations and antral contractions. Vagal denervation retards gastric emptying. Gastroparesis has been reported after heart and lung transplantation. (7) Explanations for postoperative gastroparesis in this setting include injury to the vagus nerve during surgery; opportunistic viral infection secondary to immunosuppressive medications, and motor-inhibitory effects of the immunosuppressive drugs.

[FIGURE 3 OMITTED]

Medication-induced Gastroparesis

Many medications, including anticholinergics, narcotics, tricyclic antidepressants, and calcium channel blockers, are known to delay gastric emptying. Table 2 presents a list of commonly used medications that can cause gastroparesis. Gastric emptying is also found to be delayed in patients receiving total parenteral nutrition (TPN). Gastroparesis associated with TPN has been postulated to result from induction of hyperglycemia by the intravenous (IV) nutrient infusion.

Clinical Presentation

Symptoms of gastroparesis are variable and include early satiety, nausea, vomiting, bloating, upper abdominal discomfort and weight loss. In a study of 146 patients with gastroparesis, nausea was present in 92%, vomiting in 84%, abdominal bloating in 75%, and early satiety in 60%. (2) The majority of patients with gastroparesis are women who tend to exhibit slower emptying rates than men, especially during the latter portion of the menstrual cycle (the luteal phase). It is believed that gastric muscle contractility is reduced by progesterone. (3)

Evaluation

Initial investigations include detailed history and physical examination that can lead to important clues and help in establishing the diagnosis and etiology of gastroparesis. Signs and symptoms of poorly controlled diabetes, hypothyroidism, and previous surgical history are few such examples. Routine blood tests including metabolic profile should be performed. If abdominal pain is a major symptom, serum amylase level and abdominal films will help rule out other potential causes like pancreatitis and intestinal obstruction. Further evaluation may include esophagogastroduodenoscopy (EGD) to evaluate for mucosal disease or gastric outlet obstruction. Furthermore, abdominal ultrasound may be helpful, particularly in patients with upper abdominal pain that may be of biliary and pancreatic origin.

Specific tests for delayed gastric emptying study include solid phase gastric emptying test. Table 3 summarizes the steps in the evaluation of gastroparesis.

Gastric Emptying Scintigraphy 

Gastric emptying scintigraphy of a solid-phase meal is considered the gold standard for the diagnosis of gastroparesis. Most centers use 99MTc sulfur colloid-labeled egg sandwich as a test meal. (8) In general, gastric emptying is reported as the percent retention of radio-labeled solid at defined intervals after meal ingestion (usually 2 and 4 h).

Patients should discontinue medications (Table 2) that may affect gastric emptying for an adequate period before this test. Hyperglycemia also delays gastric emptying in diabetic patients. It is appropriate to defer gastric emptying testing until relative euglycemia is achieved to obtain a reliable determination of emptying parameters in the absence of acute metabolic derangement (1) (Figure 4).

Breath Testing for Gastroparesis

Breath tests using the nonradioactive isotope 13C bound to a digestible substance have been validated for measuring gastric emptying. (9) After ingestion and stomach emptying, 13C-octanoate is absorbed in the small intestine and metabolized to 13CO2, which is then expelled from the lungs during respiration. Emphysema, celiac sprue, and pancreatic insufficiency can interfere with the results.

Electrogastrography (EGG)

EGG records gastric myoelectrical activity, known as the slow wave, using cutaneous electrodes affixed to the anterior abdomen overlying the stomach. (10) Gastric dysrhythmias (tachygastria, bradygastria) and decreased EGG amplitude responses to meal ingestion have been characterized in patients with idiopathic and diabetic gastroparesis. (11)

Clinically, EGG has been used to demonstrate gastric myoelectric abnormalities in patients with unexplained nausea and vomiting or functional dyspepsia. However, to date, there has been little investigation to validate the utility of EGG in the management of patients with suspected gastric dysmotility. (1)

[FIGURE 4 OMITTED]

Treatment

The general principles for treatment of symptomatic gastroparesis are to (1) correct fluid, electrolyte, and nutritional deficiencies; (2) identify and rectify the underlying cause of gastroparesis; and (3) reduce symptoms. Gastric decompression by nasogastric tube suction is important in the acute phase of gastroparesis. This condition may be encountered in individuals with poorly controlled diabetes and ketoacidosis.

Dietary Recommendations

1. Increasing the liquid nutrient component of the meal should be emphasized because liquid emptying is often preserved in patients with gastroparesis who have delayed solid emptying.

2. Fats and fiber intake should be minimized, as they tend to retard emptying.

3. Meal size should be restricted.

4. Alcohol should be avoided since it can decrease antral contractility and impair gastric emptying. (12)

5. Parenteral nutrition may be needed in some severe cases.

Prokinetic Agents

Prokinetic medications enhance gut contractility. In the stomach, prokinetic agents increase antral contractility, correct gastric dysrhythmias, and improve antroduodenal coordination.

Table 4 gives a list of such medications with their mechanism of action. Most commonly, these drugs are administered 30 minutes before meals to elicit maximal clinical effects. Bedtime doses often are added to facilitate nocturnal gastric emptying of indigestible solids. (1)

Metoclopramide

This dopamine receptor antagonist exerts both prokinetic and antiemetic actions. The usual starting dose of metoclopramide in adults is 10 mg 30 minutes before meals and at bedtime. For patients hospitalized for poorly controlled gastroparesis, metoclopramide may be administered IV. The side effects from metoclopramide result from antidopaminergic actions in the CNS. Acute dystonic reactions such as facial spasm, trismus and torticollis occur in 0.2 to 6% of patients and are often observed within 48 hours of initiating therapy. Drowsiness, fatigue, and lassitude are reported by 10% of patients. Prolonged treatment with metoclopramide can produce Parkinsonian-like symptoms, (13) and symptoms of depression have been observed, particularly in elderly patients. Tachyphylaxis may reduce drug effectiveness.

Erythromycin 

Erythromycin has been shown to stimulate gastric emptying in diabetic gastroparesis, idiopathic gastroparesis and postvagotomy gastroparesis. It is a macrolide antibiotic that increases gastric motility by acting on motilin receptors in the gut. Oral administration of erythromycin should be initiated at low doses (eg, 250 mg 3 times daily). IV erythromycin (100 mg every 8 h) is used for inpatients hospitalized for severe refractory gastroparesis. Side effects of erythromycin at higher doses include nausea, vomiting, and abdominal pain. Because these symptoms may mimic those of gastroparesis, erythromycin may have a narrow therapeutic window in some patients. Prolonged use is limited secondary to the development of tachyphylaxis.

Cisapride

Cisapride accelerates gastric emptying and decreases symptoms in patients with gastroparesis. It was withdrawn from the US market in 2000 secondary to its association with serious cardiac arrhythmias.

Domperidone

The effects of domperidone on the upper gut are similar to those of metoclopramide. Domperidone does not readily cross the blood-brain barrier; therefore, it is much less likely to cause extrapyramidal side effects than metoclopramide. Domperidone is not approved by the Food and Drug Administration (FDA) for clinical use in the United States.

Tegaserod

Tegaserod is a partial 5-HT4 receptor agonist approved for the treatment of constipation-predominant irritable bowel syndrome. Tegaserod has been shown to accelerate gastric emptying in some clinical trials (14); however its use for the treatment of gastroparesis is not an approved indication.

Management of Refractory Gastroparesis

There is no consensus regarding management of patients with gastroparesis who do not respond to antiemetic or prokinetic therapy or who develop severe medication-induced side effects. (1)

Gastric electric stimulation is an emerging treatment for refractory gastroparesis. This technique has been reported to accelerate gastric emptying and improve dyspeptic symptoms in a small uncontrolled series. (15) Because of potential benefits, the gastric electric neurostimulator was granted humanitarian approval from the FDA for the treatment of chronic, refractory nausea and vomiting secondary to idiopathic or diabetic gastroparesis. Figure 5 illustrates the gastric pacing assembly provided by Medtronic, Inc., Pacing wires are attached surgically by either laparotomy or laparoscopy to the lesser curvature of the antrum. The power unit which delivers the electrical stimulation is positioned in the subcutaneous tissue of the anterior abdominal wall. Further investigation is needed to confirm the effectiveness of gastric stimulation in patients with gastroparesis.

For patients with gastroparesis who are unable to maintain nutrition with oral intake, placement of a feeding jejunostomy may decrease symptoms, reduce hospitalizations, (16) and provide an enteral route for alimentation. Infectious complications and tube dysfunction are limiting factors.

Conclusion

Gastroparesis, from various causes, can result in distressing symptoms and nutritional compromise. Disordered gastric emptying associated with diabetes poses a two component dilemma of disrupting nutritional delivery to the intestine and thus compromising efforts at glycemic control which can further disturb gastric motor function. Dietary measures and prokinetic agents are helpful but knowledge of these drugs, their limitations and side effects is important. The role of gastric pacing via electrical stimulation in difficult to manage patients holds promise and awaits further study. Evidence-based investigation will be required to better define appropriate approaches to this challenging condition.

[FIGURE 5 OMITTED]

References

1. Parkman HP, Hasler WL, Fisher RS, et al. American Gastroenterological Association Technical Review on the Diagnosis and Treatment of Gastroparesis. Gastroenterology 2004;127:1592-1622.

2. Soykan I, Sivri B, Sarosiek I, et al. Demography, clinical characteristics, psychological profiles, treatment and long-term follow-up of patients with gastroparesis. Dig Dis Sci 1998;43:2398-2404.

3. Datz FL, Christian PE, Moore J. Gender-related differences in gastric emptying. J Nucl Med 1987;28:1204-1207.

4. Stanghellini V, Tosetti C, Paternico A, et al. Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 1996;110:1036-1042.

5. Zarate N, Mearin F, Wang XY, et al. Severe idiopathic gastroparesis due to neuronal and interstitial cells of Cajal degeneration: pathological findings and management. Gut 2003;52:966-970.

6. Sodhi SS, Guo J-P, Maurer AH, et al. Delayed gastric emptying after combined heart and lung transplantation. J Clin Gastroenterol 2002;34:34-39.

7. Jebbink RJ, Samsom M, Bruijs PP, et al. Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type I diabetes mellitus. Gastroenterology 19941;107:1390-1397.

8. Parkman HP, Harris AD, Krevsky B, et al. Gastroduodenal motility and dysmotility: update on techniques available for evaluation. Am J Gastroenterol 1995;90:869-892.

9. Ghoos YF, Maes BD, Geypens BJ, et al. Measurement of gastric emptying rate of solids by means of a carbon-labeled octanoic acid breath test. Gastroenterology 1993;104:1640-1647.

10. Chen JD, McCallum RW. Clinical applications of electrogastrography. Am J Gastroenterol 1993;88:1324-1336.

11. Chen JD, Lin Z, Pan J, et al. Abnormal gastric myoelectrical activity and delayed gastric emptying in patients with symptoms suggestive of gastroparesis. Dig Dis Sci 1996;41:1538-1545.

12. Bujanda L. The effects of alcohol consumption upon the gastrointestinal tract. Am J Gastroenterol 2000;95:3374-3382.

13. Ganzini L, Casey DE, Hoffman WF, et al. The prevalence of metoclopramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med 1993;153:1469-1475.

14. Degen L, Matzinger D, Merz M, et al. Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects. Aliment Pharmacol Ther 2001;15:1745-1751.

15. McCallum RW, Chen JD, Lin Z, et al. Gastric pacing improves emptying and symptoms in patients with gastroparesis. Gastroenterology 1998;114:456-461.

16. Fontana RJ, Barnett JL. Jejunostomy tube placement in refractory diabeticgastroparesis: a retrospective review. Am J Gastroenterol 1996;91:2174-2178.

Tauseef Ali, MD, Muhammad Hasan, MD, Mehdi Hamadani, MD, and Richard F. Harty, MD

From the Department of Internal Medicine, Section of Gastroenterology, University of Oklahoma Health Sciences Center and the VA Medical Center, Oklahoma City, OK.

Reprint requests to Dr. Tauseef Ali, Department of Medicine, Section of Gastroenterology, PO Box 26901, WP1360, Oklahoma City, OK 73190. Email: [e-mail]

Accepted August 29, 2006.

RELATED ARTICLE: Key Points

* Gastroparesis is defined as delayed gastric emptying. Initial investigations for gastroparesis include comprehensive history and physical examination that can lead to important clues.

* The general principles for treatment of symptomatic gastroparesis are to correct fluid, electrolyte, and nutritional deficiencies, identify and rectify the underlying cause of gastroparesis, and reduce symptoms.

* Prokinetic agents increase antral contractility, correct gastric dysrhythmias, improve antroduodenal coordination and are used to treat the symptoms of gastroparesis.

* Gastric electric stimulation accelerates gastric emptying and improves dyspeptic symptoms.

Table 1. Etiology of gastroparesis

1    Idiopathic
2    Diabetes mellitus
3    Postsurgical
4    Medication associated
5    Miscellaneous
i    Pregnancy
ii   Collagen vascular disease
iii  Parkinson's disease
iv   Thyroid dysfunction
v    Liver disease
vi   CNS tumors
vii  Chronic renal insufficiency

Table 2. Medications and agents associated with gastroparesis

 1  Opioid analgesics
 2  Anticholinergic agents
 3  Tricyclic antidepressants
 4  Calcium channel blockers
 5  Progesterone
 6  Aluminum hydroxide antacids
 8  Adrenergic receptor agonists
 9  Alcohol
10  Tobacco/nicotine

Table 3. Evaluation of gastroparesis

1  Detailed history and physical examination
2  Laboratory data: CBC, CMP, TSH, HgbA1c amylase, lipase
3  Abdominal films
4  Special tests: EGD, Abd US
5  Specific tests: GES, Breath test, EGG

EGD, esophagogastroduodenoscopy; Abd US, abdominal ultrasound; GES,
gastric emptying scintigraphy; EGG, electrogastography.

Table 4. Prokinetic agents

Agent           Mechanism of action  Dose

Metoclopramide  Dopamine receptor    Oral: 10 mg 30 minutes before each
                  antagonist           meal and at bedtime
Erythromycin    Motilin receptor     200 mg infused IV initially
                  agonist              followed by 250 mg orally 3
                                       times/day 30 minutes before
                                       meals
Cisapride       5-HT4 receptor       Oral: 5-10 mg 4 times/day at least

                  agonist              15 minutes before meals and at
                                       bedtime
Domperidone     Dopamine receptor    Oral: 10 mg 3-4 times/day, 15-30
                  antagonist           minutes before meals
Tegaserod       5-HT4 partial        Oral: 6 mg twice daily, before
                  agonist              meals (for IBS with constipation)
Bethanechol     Muscarinic receptor  Oral: 25 mg 4 times/day
                  agonist

Agent           Adverse reactions

Metoclopramide  Restlessness, drowsiness, extrapyramidal symptoms,
                  diarrhea, weakness
Erythromycin    Ventricular arrhythmia, QTc prolongatin, abdominal
                  pain, cramping, nausea, tachyphylaxis
Cisapride       Ventricular tachycardia, ventricular fibrillation,
                  torsade de pointes, and QT prolongation
Domperidone     Does not cross blood-brain barrier; fewer CNS effects
                  compared to metoclopramide
Tegaserod       Headache, abdominal pain
Bethanechol     Headache, hypotension, tachycardia, flushed skin,
                  urinary urgency

IBS, irritable bowel syndrome; CNS, central nervous system.

Table 5. Key clinical recommendations

                                                        Label  Reference

Initial investigations for gastroparesis include        C       1,4,7
  comprehensive history and physical examination that
  can lead to important clues
Gastric emptying scintigraphy of a solid-phase meal is  C       1,8
  considered the gold standard for the diagnosis of
  gastroparesis
Electrogastrography has been used to demonstrate        B       1,11
  gastric myoelectric abnormalities in patients with
  unexplained nausea and vomiting
The general principles for treatment of symptomatic     C       1,12
  gastroparesis are to correct fluid, electrolyte,
  and nutritional deficiencies; identify and rectify
  the underlying cause of gastroparesis; and reduce
  symptoms
Prokinetic agents increase antral contractility,        C       1
  correct gastric dysrhythmias, and improve
  antroduodenal coordination and are used to treat
  the symptoms of gastroparesis
Gastric electric stimulation accelerate gastric         B      15
  emptying and improve dyspeptic symptoms

Label A: Recommendation based on consistent and good-quality patient-
oriented evidence
Label B: Recommendation based on inconsistent or limited-quality
patient-oriented evidence
Label C: Recommendation based on consensus, usual practice, opinion,
disease-oriented evidence, or case series for studies of diagnosis,
treatment, prevention, or screening